PET imaging of liver

Anatomy and metabolism

The weight of liver in adult men is about 1500-1800 g and in women 1300-1500 g, comprising 2.3-3% of the total body weight. Its size is 25-30 × 12-20 × 6-10 cm. Respiratory movement is about 3 cm, and lesions detection in clinical PET can be improved by respiratory gating (Khandani & Wahl, 2005; Crivellaro et al., 2018).

Liver consists of lobules, about 0.7 mm in diameter and 2 mm in length. Blood from hepatic artery and portal vein travels in separate vessels located between the lobules. In the middle of the lobules is the central vein. Inside the lobules, hepatocytes are organized as plates, two hepatocytes thick, and the plates are separated by vascular spaces (sinusoids), which are wider than normal capillaries. Endothelial cells and resident macrophages (Kupffer's cells) form a fenestrated and very thin layer between the hepatocyte plates and sinusoids, and in addition, microvilli of the hepatocytes form an additional thin layer (space of Disse) between the plate and endothelial cells. Relatively large amounts of lymph is formed in the liver, and pumped away by the lymphatic system; cirrhosis can increase lymph flow from liver several fold. Space of Disse contains also vitamin A storing cells (fat-storing cells of Ito). Blood from both hepatic artery and portal vein passes slowly through the labyrinth of sinusoids towards the central vein. Arterial and portal vein blood are not necessarily well mixed in the sinusoids, but their local concentrations may vary, leading to zonal differences in substrate concentrations and liver metabolism. Adjacent hepatocytes have a tight connection and gap junctions between them, but they also delimit a small intercellular space into which bile is excreted, an finally collected to branches of bile ducts that are located interlobularly. Liver produces 700-1200 mL of bile per day; bile is stored and concentrated in the gall bladder. Most of the bile is resorbed in the small intestine and recycled by the hepatocytes; enterohepatic circulation (EHC) refers to the circulation of various substances from the liver to the bile, entry into the small intestine, absorption by the enterocytes, and transport via the portal vein back to the liver. Hepatocytes also recycle the IgA formed in the mucosa of the gastrointestinal tract back to the intestine via the bile.

Hepatic perfusion is about 100-130 mL/(100 mL×min), about 20-33% of that via hepatic artery and the rest via portal vein. Blood leaves the liver through the hepatic vein into the inferior vena cava. Blood content in liver is about 25-40%; about 10-15% of the total blood content is in the liver. Sympathetic nerve stimulation and adrenergic and angiotensin agonists can expel 50-60% of this blood from liver in 90 s leading to noticeable shrinkage of the liver and reduced blood flow. Adenosine and regadenoson increase hepatic arterial perfusion (Gregg et al., 2021). Since all the blood from the abdominal visceral organs and gastrointestinal tract is drained via the portal vein, the hormones released by these organs, such as insulin or glucagon (vasodilation) from the pancreas can directly affect the metabolism of the liver.

Hepatoportal system consumes about 20% of the total oxygen used by the body. Oxygen consumption of liver is about 6 mL/(100 mL×min). Oxygen extraction fraction is about 0.4, but it can increase to even 0.95 when necessary; oxygen concentration of blood may differ between liver regions (usually lowest in centroacinar and highest in acino-peripheral region), and may show high inter-subject variation, because 1/4 - 1/2 of people have "abnormal" hepatic arterial anatomy, and in some veins from digesting system may abut directly into liver parenchyma, not via the portal vein. However, PET scans are usually performed after fast, when arterioportal oxygen difference is very small. Variable regional perfusion has been seen with PET (Taniguchi et al., 1993 and 1996). Venous oxygen saturation (SvO₂) in hepatic and portal veins can be quantified using QSM MRI (Finnerty et al., 2018).

Metabolic functions of the liver are wide and complex, including but not limited to carbohydrate, amino acid and protein, lipid and lipoprotein metabolism. Protein synthesis rate in the liver is about 120 g/day, of which 70-80% is released to blood stream, including albumin and transferrin. Gluconeogenesis in the liver may produce glucose over 240 g/day. Insulin is produced in the pancreas and released into portal vein, and therefore liver is exposed to higher insulin concentrations than other organs. Insulin rapidly reduces hepatic glucose production, both directly and indirectly. In contrast to skeletal muscle, insulin does not regulate glucose transport in the liver, but it induces net glycogen synthesis by translocation and expression of glucokinase, and inhibition of glycogenolysis. Glucagon increases gluconeogenesis, uptake of amino acids, and ureagenesis.

Hepatic fat content is heterogeneous, and can be up to 30%, which can affect the distribution volume of PET radioligands (Keramida et al., 2016). Increased fat content in the liver (non-alcoholic fatty liver disease, NAFLD) is common in individuals with metabolic syndrome, and liver fat content is associated with body fat content, BMI, and waist circumference (Laine et al., 2022). Inverse correlation between liver fat content and PET results have been observed at least with [¹⁵O]H₂O, [¹¹C]palmitate, and [¹⁸F]FDG (Borra et al., 2008; Rijzewijk et al., 2010). Reduced blood volume in hepatic cirrhosis has been observed with [¹⁵O]CO (Taniguchi et al., 1996). Normal intrahepatocellular lipid content is less than 5%, and NAFLD is defined as fat content >5-10% (Neuschwander-Tetri & Caldwell, 2003; Thomas et al., 2005). In obese subjects liver fat content is very variable, on average ∼6-10%, and reduces to normal ∼2-3% level after bariatric surgery (Immonen, et al. 2017; Hedderich et al., 2017).

Imaging

PET radiotracers that have been used for liver studies include [¹⁵O]CO, [¹⁵O]H₂O, [¹³N]NH₄⁺, [¹¹C]palmitate, [¹¹C]choline, [¹¹C]acetate, [¹⁸F]FDG, 3-O-[¹¹C]-methylglucose, and [¹⁸F]FTHA.

Blood-to-hepatocyte transfer is practically unlimited for most PET tracers (Keiding, 2012).

Quantitative studies of the liver are complicated by its dual input function, including input from the arteries and portal vein, and most of the blood supply to the liver comes via the portal vein. Hepatic artery is the main blood supply for liver tumours (Breedis & Young, 1954; Ackerman, 1972), and therefore portal vein input has been assumed negligible in liver tumour studies with [¹⁵O]H₂O, [¹⁵O]O₂, and [¹⁸F]FDG (Fukuda et al., 2004).

Iron overload leads to low MRI intensity values in the liver, which may cause faulty attenuation correction and image artefacts in PET/MRI (Büther et al., 2017).

Clinical PET

Liver-related mortality is mainly caused by liver cancer and cirrhosis; end-stage liver diseases are largely caused by alcohol consumption (alcoholic steatohepatitis, ASH), obesity-related NAFLD and non-alcoholic steatohepatitis (NASH), and viral hepatitis B and C. Alcohol and many other toxins (including chemotherapeutics) can cause acute liver inflammation. PET and SPECT imaging of hepatic inflammation is difficult, because most radioligands used for inflammation imaging, including [¹⁸F]FDG, ⁶⁷Ga, and labelled white blood cells, are taken up by healthy liver, too, and usually only focal liver infections can still be detected. In fibrotic liver, the hepatic sinusoids are transforming into capillary-like vessels, reducing the hepatocellular extraction of albumin and other plasma proteins. TSPO imaging of inflammation in liver has shown promise in animal models (Hattori et al., 2015; Huang et al., 2018).

Oncological PET studies of the liver are usually conducted with [¹⁸F]FDG (Khandani & Wahl, 2005), and analysed either qualitatively or semiquantitatively with SUV calculation. Target-to-blood ratio (TBR) is also often used, since blood activity is readily available in the PET image by placing ROI on abdominal aorta or vena cava. [¹⁸F]FDG is usually performed after an overnight fast, with static scanning starting about 1 h after the tracer administration. Liver is often used as reference region in oncological [¹⁸F]FDG PET.

[¹⁸F]FDG is not an optimal tracer for detecting hepatocellular carcinoma (HCC); therefore other tracers like [¹¹C]acetate, [¹¹C]choline, and [¹⁸F]FMISO have been proposed. HCC lesions are commonly very vascular, offering a target for PSMA radioligands (Kesler et al., 2019).

Liver function can be evaluated noninvasively using nuclear imaging techniques (de Graaf et al., 2010). Determination of functional liver mass is useful before and after liver surgery or radiotherapy, and in diagnosis of liver steatosis, fibrosis, and cirrhosis (Bennink et al., 2012). Imaging of hepatocellular mass has been based on measuring the density of asialoglycoprotein receptor (ASGP-R), which is responsible for degradation of galactose terminated glycoproteins through receptor-mediated endocytosis. ASGP-Rs are reduced in chronic liver diseases, as shown using dynamic SPECT with ^99mTc-labelled diethylenetriamine-pentaacetic acid (DTPA) galactosyl human serum albumin, [^99mTc]GSA (de Graaf et al., 2010). ASGP-Rs are expressed only in the liver, on the sinusoidal surface of hepatocytes. [⁶⁸Ga]NOTA-GSA is an analogous radioligand for PET imaging (Haubner et al., 2017). The uptake of [⁶⁸Ga]DTPA-GSA was shown to be reduced with more severe fibrosis in a rat model (Schnabl et al., 2016). Hepatic portal perfusion, assessed using [¹⁵O]H₂O PET, correlates with hepatic function measured with [^99mTc]GSA SPECT (Shiomi et al., 2000).

Galactose elimination capacity (GEC) test measures total metabolic liver function (Tygstrup, 1966; Ranek et al., 1976; Bergström et al, 1993), based on the ability of functional hepatocytes to metabolize galactose. Galactose enters hepatocytes freely from the blood, and is then phosphorylated to galactose-1-phosphate in a rate-limiting step catalyzed by galactokinase. 2-[¹⁸F]fluoro-2-deoxy-D-galactose ([¹⁸F]FDGal) (Fukuda et al., 1986; Grün et al., 1992; Frisch et al., 2011), is also phosphorylated by galactokinase, and subsequently trapped in the hepatocytes (Ishiwata et al., 1988). The net uptake rate of [¹⁸F]FDGal in the liver has been validated as a measure of metabolic liver function in pigs (Sørensen et al., 2008; Sørensen, 2011), healthy subjects (Sørensen et al., 2011), and patiens with cirrhosis (Sørensen et al., 2013). [¹⁸F]FDGal PET is well reproducible, and SUV can be used as an index of metabolic liver function (Bak-Freslund et al., 2017). Image-derived input function from abdominal aorta could also be used in the analysis of [¹⁸F]FDGal PET data (Horsager et al., 2015).

Liver fibrosis can be detected with radioligands that target integrin and fibroblast activation protein (FAP) (Pirasteh et al., 2022). [¹⁸F]FDG liver-to-blood ratio first increases with increasing fibrosis, reaching its maximum in subjects with advanced liver fibrosis, and then decreases, but patients with liver cirrhosis still have increased liver-to-blood ratio as compared to subjects with no fibrosis (Verloh et al., 2018). Mitochondrial dysfunction can be assessed by measuring the activity of MC-I. Drug-induced acute liver injury can be assessed by measuring the reduction of hepatic uptake of 2-deoxy-2-[¹⁸F]fluoroarabinose ([¹⁸F]DFA), radioligand that targets ribose salvage pathway (Salas et al., 2018a and 2018b). Deoxyribonucleotide salvage pathway probe [¹⁸F]FAC shows increased infiltration of CD4 and CD8 T cells in mouse model of autoimmune hepatitis (Salas et al., 2018b).

Blood volume

Blood content of the liver can be measured with [¹¹O]CO. In pigs and humans it was found to be about 30% (Kiss et al., 2009; Honka et al., 2018), or about 20% in healthy human subjects, ∼18% in chronic hepatitis, and ∼16% in hepatic cirrhosis (Taniguchi et al., 1996). In pigs, Munk et al (2003) obtained value ∼19% for the blood volume.

Perfusion

Because of the fast blood-to-hepatocyte transfer, the blood-to-tissue clearance rate (K₁) for most of the PET tracers is mainly determined by perfusion (Munk et al., 2001; Iozzo et al., 2007; Keiding, 2012). The initial few minutes of dynamic PET data has therefore been used to calculate a perfusion index with glucose analogues (Choi et al., 1994; Winterdahl et al., 2011; Iozzo et al., 2007).

[¹⁵O]H₂O PET has been used to measure hepatic perfusion with good reproducibility (Taniguchi et al., 2003). Mean arterial blood flow was about 40-50 mL/(min×100g) and portal blood flow about 30-120 mL/(min×100g) in healthy subjects, depending on the model (Taniguchi et al., 1996) and cirrhotic liver 30-40 and 40-70 mL/(min×100g), respectively (Taniguchi et al., 1993, 1996, and 1999). In another study of liver cirrhosis patients somewhat higher results were obtained: the total blood flow (median) was 138 mL/(min×100g), arterial flow 56 mL/(min×100g), and portal flow 80 mL/(min×100g) (Shiomi et al., 2000). Parenchymal perfusion is lower in type 2 diabetic patients with increased liver triglyceride content (Rijzewijk et al., 2010). Portal flow, when adjusted with total liver volume, has been used to assess splanchnic blood flow (Honka et al., 2018).

[¹³N]NH₄⁺ can be used to quantify arterial perfusion in the liver (Chen et al., 1991); arterial perfusion in dogs was 40 mL/(min×100g) and in healthy humans 26 ± 7 mL/(min×100g). Also [⁸²Rb]Rb⁺ has been used to estimate arterial perfusion in the liver (Gregg et al., 2021).

Glucose uptake

The uptake of glucose analogue [¹⁸F]FDG has irreversible component in most tissues because [¹⁸F]FDG-6-phosphate can not be metabolized further (or metabolism is relatively slow) and is trapped inside the cells, making [¹⁸F]FDG an optimal tracer for studying glucose metabolism. One of the main tasks of liver is to maintain glucose homeostasis by also releasing glucose to the blood stream, and therefore liver cells contain glucose-6-phosphatase (van Schaftingen and Gerin, 2002), which readily dephosphorylates [¹⁸F]FDG-6-phosphate. Also [¹⁸F]FDG-6-phosphogluconate is formed in the liver, but incorporation of ¹⁸F into glycogen is slow (Bender et al., 2001). During insulin stimulation the dephosphorylation rate seems to low, so that Patlak plot, assuming irreversible uptake, is applicable (Iozzo et al, 2007). When arterial-portal vein differences are characterized, irreversible compartmental model (K₁-k₃) could be used in rat studies across various diet interventions (Rani et al., 2013) using combined input function. Alternatively the gut could be included as a compartment in the model (Vivaldi et al., 2013; Garbarino et al., 2015).

In most organs increasing plasma glucose concentration decreases [¹⁸F]FDG uptake because of competition in the transport and phosphorylation, which is corrected in calculation of glucose uptake by using plasma glucose concentration and lumped constant (LC). In the liver glucose and [¹⁸F]FDG are mainly transported by GLUT2, which is abundant and not dependent on insulin, and [¹⁸F]FDG uptake in liver is actually increased with increasing plasma glucose concentration (Choi et al., 1994; Kubota et al., 2011). LC still should to be used for liver [¹⁸F]FDG studies, although studies suggest that it can be assumed to be unitary (Iozzo et al., 2007).

Hepatic glucose uptake, as measured with [¹⁸F]FDG PET, is inversely associated with liver fat content (Borra et al., 2008; Rijzewijk et al., 2010). High fat content reduces the distribution volume of [¹⁸F]FDG in the tissue, leading to reduced K_i. Metabolic rate of glucose could be corrected for this effect by dividing K_i with the Patlak plot intercept value (Keramida et al., 2016). SUV can be corrected with CT density (HU) (Keramida et al., 2014a, 2014b).

Lipid metabolism

Fatty acid tracers [¹¹C]palmitate and [¹⁸F]FTHA can be used to study hepatic lipid metabolism (Iozzo et al., 2003, 2004a, and 2004b; Guiducci et al., 2006; Rijzewijk et al., 2010). SGLT2 inhibitor dapagliflozin increases hepatic [¹⁸F]FTHA uptake (Oldgren et al., 2021). Hepatic steatosis is associated with increased [1-¹¹C]acetate uptake, and [1-¹¹C]acetate can be used to detect fatty infiltration in liver high accuracy (Nejabat et al., 2018).

Excretion of bile acids

Primary bile acids are synthesized in the liver from cholesterol, conjugated to taurine or glycine, secreted in the bile, stored in the gallbladder, and when needed, gallbladder contraction pushes the bile acids into the small intestine. Rats do not have gallbladder, but mice do. Bile acids not only facilitate the digestion and absorption of lipids, but work also as enteroendocrine hormones via bile acid receptors, regulating intestinal epithelial function (Hegyi et al., 2018). Cholesterol 7-alpha-monooxygenase (CYP7A1) is a rate-limiting enzyme in bile acid synthesis. Secondary bile acids are formed from primary bile acids by gut bacteria. Over 90% of bile acids are absorbed in the intestine, mostly by active transport in the distal small intestine (ileum). About 2-4 g of bile acids are cycling through the enterohepatic circulation, so that up to 30 g are excreted and reabsorbed each day. In humans, Na⁺-taurocholate co-transporting polypeptide (NTCP, SLC10A1) and organic anion transporting polypeptides (OATPs) transport bile acids from portal blood into hepatocytes. Bile salt export pump (BSEP, ABCB11) transports bile acids from hepatocytes into the bile. Unintended inhibition of BSEP is one possible mechanism of drug-induced liver injury. Endogenous bile acid conjugates are deconjugated in the intestinal lumen and colon by bacterial choloylglycine hydrolase (CGH). Apical Na-dependent bile acid transporter (ASBT, SLC10A2) transports bile acids into enterocytes in the distal ileum. From enterocytes the bile acids are effluxed into portal blood by organic solute transporters (OSTs) and MRP3 (ABCC3). Most of sulphate conjugates stay as conjugates and are not reabsorbed.

[N-methyl-¹¹C]cholylsarcosine ([¹¹C]MGCA, [¹¹C]CSar) is an analogue of one of the endogenous bile acid conjugates, cholylglycine. In pig study, after intravenous administration, the tracer was be rapidly taken up by the liver, with subsequent excretion to bile; tracer was not metabolized, and it reappeared in the liver after 70 min (Frisch et al., 2012). This suggests that the tracer could be useful in research of normal and pathologic enterohepatic circulation (EHC), and has already showed promise as PET tracer for cholestatic conditions (Schacht et al., 2016). A related but F-18 labelled cholylglycine analogue, N-(4-[¹⁸F]fluorobenzyl)cholylglycine ([¹⁸F]FBCGly), may also be useful in studies of EHC (Frisch et al., 2018).

For ¹⁹F MRI, trifluorinated bile acid CA-sar-TFMA has been developed (Vivian et al., 2014), to be administered orally for quantifying intestinal bile acid uptake.

Secretion of bile salts

Prieto et al. (1999) have studied the secretion of biliary bicarbonate by PET using intravenously administered [¹¹C]NaHCO₃.

Drug clearance

Liver is an important organ for the metabolism and elimination of drugs, including PET radioligands. The activity of the SLC and ABC transporters at the sinusoidal (basolateral) and canalicular membranes of hepatocytes determine the uptake of drugs into hepatocytes and the excretion of the drugs or their metabolites into bile or back to blood.

Guhlmann et al (1995) studied hepatobiliary function and leukotriene elimination in rats and monkeys using N-[¹¹C]acetyl-leukotriene E₄.

[¹¹C]telmisartan, (15R)-¹¹C-TIC-Me, [¹¹C]dehydropravastatin, and [¹¹C]rosuvastatin have been used in animal studies to measure the hepatic activity OATPs and MRP2 (ABCC2) (Takashima et al., 2010, 2011, and 2012; Shingaki et al., 2013; He et al., 2014). Takashima et al (2010, 2011, and 2012) and Shingaki et al (2013) estimated clearance rate from blood to liver or kidneys using "integration plot method", similar to Patlak plot except that total tissue radioactivity is used instead of concentration; linear fit was obtained from data collected during the first minute after injection; canalicular efflux clearance was estimated from the slope of plot of total tissue radioactivity vs AUC of the TAC of liver, between about 2 and 7 min after injection (Shingaki et al., 2013). He et al (2014) fitted a five-compartment model simultaneously to the TACs from the liver, kidney, and intestine, using blood TAC as input function.

In vitro study by Bauer et al. (2017) suggests that [¹¹C]erlotinib can be used to measure hepatic OATP2B1 activity, and the group also applied compartmental model to analyse the liver PET data from human subjects.

The activity of Bcrp in the liver can be measured in mice using [¹¹C]SC-62807 (Takashima et al., 2013).

Metformin is an orally administered drug, used as an insulin sensitizer in the treatment of type II diabetes. [¹¹C]Metformin may be a suitable PET ligand for quantifying the activities of the organic cation transporter 1 (OCT1) and the multidrug and toxin extrusion transporter 1 (MATE1) in the liver (Hume et al., 2013).

[⁶⁴Cu]histidine can be used to measure biliary excretion of copper (Bahde et al., 2012), which is impaired in Wilson's disease.

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Tags: Liver, Dual-input, Bile acids

Updated at: 2023-02-10
Created at: 2015-02-05
Written by: Vesa Oikonen