Galactose Elimination Research Articles

Galactose: A Versatile Vector Unveiling the Potentials in Drug Delivery, Diagnostics, and Theranostics.

D-galactose, a simple natural compound, has been investigated as a powerful scaffold for drug delivery, diagnostics, and theranostics due to its distinctive properties and interactions with specific cell receptors. In the field of drug delivery, galactose functions as a ligand to selectively target cells expressing galactose receptors, such as hepatocytes, macrophages, and specific cancer cells. The direct attachment of galactose to the main drug or to drug-loaded nanoparticles or liposomes enhances cellular uptake, thereby improving drug delivery to the intended target cells. Galactose has also been found to be useful in diagnostics. Specifically, diagnostic tests based on galactose, such as the galactose elimination capacity test, are utilized to evaluate liver function and assess liver disease as well as hepatic functional reserve. Additionally, galactose-based theranostic agents can be designed by combining drug delivery and diagnostic capabilities. This review is an update of our previous review concerning the broad spectrum of possibilities for exploiting D-galactose as a vector for prodrug design and the synthetic strategies that allow its realization, jointly in diagnostics and theranostics, to highlight the versatility of this interesting vector.

Clearance tests as a diagnosis method of hepatobiliary system pathologies in animals

In present-day conditions of industrial agriculture, the animal's body works at the limit of its capabilities, which leads to degenerative diseases of various organs and systems. The development of ergonomic ways of modern diagnosis of these pathologies at the early stages contributes to the maintenance of quantitative and qualitative indices of productivity of animals and to the extension of the time of their economic use. The liver with a great number of functions performed is subjected to the highest load. The aim of the article is to review the available clearance tests in order to diagnose the pathology of the hepatobiliary system of animals at the early stage, considering advantages and disadvantages of the tests. As the result of the search of themed issues in various bibliographic databases there have been selected 45 mostly cited scientific articles. The article reviews such clearance tests as indocyanine green clearance test, aminopyrine breath test, sorbitol elimination test, galactose elimination test, phenylalanine breath test, and hepatobiliary scintigraphy method. Functional tests allow not only diagnosing and differentiating hepatopathologies, but also visualizing their course and liver recovery. Unlike laboratory tests, clearance tests make it possible to evaluate the work of the liver in dynamics. The disadvantages of clearance tests are lack of information for their wide use and frequency of particular differences in elimination of specific substances. To reduce the proportion of existing shortcomings, it is possible to combine clearance tests with other laboratory methods for diagnosing hepatopathy in animals.

Experimental non-alcoholic fatty liver disease causes regional liver functional deficits as measured by the capacity for galactose metabolism while whole liver function is preserved

BackgroundIncreasing incidence of non-alcoholic fatty liver disease (NAFLD) calls for improved understanding of how the disease affects metabolic liver function.AimsTo investigate in vivo effects of different NAFLD stages on metabolic liver function, quantified as regional and total capacity for galactose metabolism in a NAFLD model.MethodsMale Sprague Dawley rats were fed a high-fat, high-cholesterol diet for 1 or 12 weeks, modelling early or late NAFLD, respectively. Each NAFLD group (n = 8 each) had a control group on standard chow (n = 8 each). Metabolic liver function was assessed by 2-[18F]fluoro‐2‐deoxy‐D-galactose positron emission tomography; regional galactose metabolism was assessed as standardised uptake value (SUV). Liver tissue was harvested for histology and fat quantification.ResultsEarly NAFLD had median 18% fat by liver volume. Late NAFLD had median 32% fat and varying features of non-alcoholic steatohepatitis (NASH). Median SUV reflecting regional galactose metabolism was reduced in early NAFLD (9.8) and more so in late NAFLD (7.4; p = 0.02), both significantly lower than in controls (12.5). In early NAFLD, lower SUV was quantitatively explained by fat infiltration. In late NAFLD, the SUV decrease was beyond that attributable to fat; probably related to structural NASH features. Total capacity for galactose elimination was intact in both groups, which in late NAFLD was attained by increased fat-free liver mass to 21 g, versus 15 g in early NAFLD and controls (both p ≤ 0.002).ConclusionRegional metabolic liver function was compromised in NAFLD by fat infiltration and structural changes. Still, whole liver metabolic function was preserved in late NAFLD by a marked increase in the fat-free liver mass.

The galactose elimination capacity test to monitor liver disease course in patients with Wilson’s disease

Background The prognosis of Wilson’s disease (WD) has changed radically since the introduction of medical therapy with chelators and zinc. However, there is an unmet need for methods to evaluate the long-term treatment response and the liver disease progression in order to identify treatment failures. The galactose elimination capacity test (GEC) is a physiological measure of the total metabolic capacity of the liver, and a strong predictor of long- and short-term mortality in patients with liver cirrhosis. Our aim was to investigate if the GEC test is useful for evaluation of treatment response and prediction of treatment failures in WD patients. Methods We included all patients with WD in Denmark from 1992 through 2017 and retrieved data on GEC along with data on transplantation and death. Results In total, 37 patients had completed one or more GEC tests. Of these, 31 were alive (three transplanted) and six were dead (two transplanted). A total of 24 patients had completed more than one GEC test. All 18 alive, nontransplanted patients showed improvement in GEC values following onset of treatment, except one patient, who was clinically confirmed with treatment failure. All six patients who underwent liver transplantation or died had a prior decline in their GEC. The difference in GEC development between patients alive and not transplanted and patients dead or transplanted was significant (p < .001). Index GEC values could not predict transplantation or death (p = .26). Conclusion The GEC test is a promising tool for monitoring treatment response and identifying treatment failures in patients with WD.

Dipeptidyl peptidase-3 is associated with severity of liver disease and circulatory complications in patients with cirrhosis

Background Patients with cirrhosis suffer from a complex multiorgan disturbance and their prognosis is influenced by the development of portal hypertension and systemic circulatory dysfunction. Although non-invasive techniques such as transient elastography aid in early detection, there is an unmet need for reliable markers of these clinically significant complications. Methods We conducted an exploratory single-center study investigating dipeptidyl peptidase-3 (DPP3) concentrations in various vascular beds in a cohort of 48 patients with cirrhosis and 16 healthy controls. Liver vein catheterisation with sampling from femoral artery and femoral, renal and hepatic veins as well as measurement of hepatic pressure and liver function via indocyanine green and galactose elimination tests were performed. Results DPP3 concentrations were higher in cirrhotic patients compared to controls (12.6 vs. 7.4 ng/mL, p = 0.006) and increased according to the severity of cirrhosis. DPP3 associated with MELD-Na score, Child class, indocyanine green clearance, increased DPP3 with the increased hepatic venous pressure gradient (p = 0.015) as well as increased heart rate and reduced systemic vascular resistance. DPP3 concentrations predicted the presence of clinically significant portal hypertension in cirrhotic patients (AUROC 0.78, 95% CI 0.65–0.9). Conclusion DPP3 is a promising marker for portal hypertension and systemic hemodynamic changes in cirrhosis.

Time‐dependent improvement of liver inflammation, fibrosis and metabolic liver function after successful direct‐acting antiviral therapy of chronic hepatitis C

Sofosbuvir-based direct-acting antiviral (DAA) therapy generally cures chronic hepatitis C (CHC) infections, however, the effects on the underlying liver disease and the potential rate of recovery are unclear. We aimed to investigate the effects of DAA therapy on liver inflammation, fibrosis, metabolic function and cognitive function and the time course in CHC patients with advanced liver disease. Seventy-one CHC patients with advanced liver disease were studied before, during and one year after successful sofosbuvir-based DAA therapy. Liver inflammation was assessed by plasma sCD163 and sMR levels (ELISA), fibrosis by liver stiffness (transient elastography), function by galactose elimination capacity (GEC) and cognitive performance by continuous reaction time (CRT). During DAA therapy, we observed a rapid sCD163 decline from baseline to end of treatment (6.9 vs 3.8mg/L, P<.0001), whereas the change in sMR was more subtle (0.37 vs 0.30mg/L, P<.0001). Liver stiffness decreased by 20% at end of treatment (17.8 vs 14.3kPa, P<.0001), together suggesting rapid resolution of liver inflammation. One year after treatment, liver stiffness decreased by an additional 15% (P<.0001), suggestive of fibrosis regression. The GEC improved at follow-up (all: 1.74 vs 1.98mmol/min), mainly at 12weeks post-treatment, both in patients with cirrhosis (n=56) and those with advanced liver fibrosis (n=15) (P<.001). The CRT improved at one-year follow-up (1.86 vs 2.09, P=.04). In conclusion, successful DAA therapy of CHC proves beneficial in advanced liver disease, with an initial rapid resolution of liver inflammation and a subsequent gradual but steady improvement in liver fibrosis, metabolic liver function and reaction time.

Non-alcoholic steatohepatitis, but not simple steatosis, disturbs the functional homogeneity of the liver - a human galactose positron emission tomography study.

The disease severity of non-alcoholic fatty liver disease (NAFLD) and the distinction between simple steatosis and non-alcoholic steatohepatitis (NASH) are based on the pathohistological presence of steatosis, inflammation, ballooning and fibrosis. However, little is known about the relation between such structural changes and the function of the afflicted liver. To investigate in vivo effects of hepatic fat fraction, ballooning and fibrosis on regional and whole liver metabolic function assessed by galactose elimination in NASH and simple steatosis. Twenty-five biopsy-proven, nondiabetic patients with NAFLD (13 NASH with low-grade fibrosis, 12 simple steatosis with no fibrosis) underwent 2-[18 F]fluoro-2-deoxy-d-galactose positron emission tomography and magnetic resonance imaging-derived proton density fat fraction of the liver. Nine healthy persons were included as controls. In the NASH patients, the standardised hepatic uptake of 2-[18 F]fluoro-2-deoxy-d-galactose was reduced to 13.5 (95% confidence interval, 12.1-14.9) as compared with both simple steatosis and controls (16.4 (15.6-17.1), P<0.001). Thus, the NASH patients had reduced regional metabolic liver function. The liver fat fraction diluted the standardised uptake equally in NASH and simple steatosis but the fibrosis and ballooning of NASH were associated with a further decrease. Moreover, the NASH livers exhibited increased variation in their standardised uptake values (coefficient of variation 13.8% vs 11.6% in simple steatosis and 10.2% in controls, P=0.02), reflecting an increased functional heterogeneity. In NASH, the regional metabolic liver function was lower and more heterogeneous than in both simple steatosis and healthy controls. Thus, NASH disturbs the normal homogeneous metabolic function of the liver.

Non-alcoholic fatty liver disease causes dissociated changes in metabolic liver functions

Non-alcoholic fatty liver disease (NAFLD) is a major health concern affecting 25% of the world's population. It is generally held that a fatty liver does not influence liver function, but quantitative measurements of metabolic liver functions have not been systematically performed. We aimed to study selected hepatocellular metabolic functions in patients with different stages of NAFLD. Twenty-five non-diabetic, biopsy-proven NAFLD patients [12 with simple steatosis; 13 with non-alcoholic steatohepatitis (NASH)] and ten healthy controls were included in a cross-sectional study. Hepatocyte cytosolic function was assessed by the galactose elimination capacity (GEC), mitochondrial-cytosolic metabolic capacity by the functional hepatic nitrogen clearance (FHNC), microsomal function by the aminopyrine breath test, and excretory liver function by indocyanine green (ICG) elimination. GEC was 20% higher in NAFLD than in controls [3.15 mmol/min (2.9-3.41) vs. 2.62 (2.32-2.93); P = 0.02]. FHNC was 30% lower in NAFLD [23.3 L/h (18.7-28.9) vs. 33.1 (28.9-37.9); P = 0.04], more so in simple steatosis [19.1 L/h (13.9-26.2); P = 0.003] and non-significantly in NASH [27.9 L/h (20.6-37.8); P = 0.19]. Aminopyrine metabolism was 25% lower in simple steatosis [8.9% (7.0-10.7)] and 50% lower in NASH [6.0% (4.5-7.5)] than in controls [11.9% (9.3-12.8)] (P < 0.001). ICG elimination was intact. The hepatocellular metabolic functions were altered in a manner that was dissociated both by different effects on different liver functions and by different effects of different stages of NAFLD. Thus, NAFLD has widespread consequences for metabolic liver function, even in simple steatosis.

High hepatic macrophage activation and low liver function in stable Wilson patients - a Danish cross-sectional study

BackgroundHepatic macrophage (Kupffer cell) hyperplasia is often described in Wilson’s disease (WD). In many liver diseases, Kupffer cell activation is related to disease severity, liver function, and fibrosis but the importance in WD is unknown. Kupffer cell activation can be assessed by the P-concentration of soluble (s)CD163, metabolic liver function by the galactose elimination capacity (GEC), and fibrosis by Fibroscan. We investigated the associations between sCD163, selected inflammatory cytokines, GEC, and liver fibrosis in Danish WD patients.MethodsIn a cross-sectional design, we studied 29 stable and well-treated patients (male/female15/14) with a median age of 35 years (IQR 24–50). P-sCD163 and cytokines were measured by ELISA. The GEC was measured by intra-venous galactose loading.ResultsThe median P-sCD163 value at 2.96 mg/L (1.97–3.93) was high in the normal range (0.7–3.9) and seven patients (24%) had a value above the upper normal value. sCD163 correlated with TNF-α, IL-6 and IL-8 (rho> 0.50, p < 0.005). A higher sCD163 value was closely associated with a lower GEC (rho = − 0.51, p = 0.02). sCD163 was not related to the liver fibrosis indices.ConclusionsStable WD patients showed various degrees of Kupffer cell activation which was accompanied by loss of metabolic liver function. Neither activation nor liver function was related to liver fibrosis. The findings suggest that in WD inflammatory Kupffer cell activation may be involved in the loss of liver function over time. sCD163 may serve as a non-invasive biomarker of loss of liver function in WD, which the degree of fibrosis evidently may not.This study is registered at clinical trials with name: “sCD163 and sMR in Wilsons Disease - Associations With Disease Severity and Fibrosis”, NCT02702765. Date of registration: 26.02.16. Date of enrolment of the first participant to the trial: 17.03.16. ULR: https://clinicaltrials.gov/ct2/show/NCT02702765.

SAT-058 - The Galactose Elimination Capacity test may monitor treatment response and disease progression in patients with Wilson Disease

SAT-058 - The Galactose Elimination Capacity test may monitor treatment response and disease progression in patients with Wilson Disease

SLC5A1 Mutations in Saudi Arabian Patients With Congenital Glucose-Galactose Malabsorption.

Congenital glucose-galactose malabsorption (cGGM) is a rare autosomal recessive disorder, caused by mutations in the SLC5A1 gene, encoding the sodium/glucose cotransporter 1, which may result in severe life-threatening osmotic diarrhea due to the accumulation of unabsorbed sugars in the intestinal lumen. If treated early with elimination of glucose and galactose from the diet, patients usually recover and develop normally. We present clinical and molecular data from 16 unrelated cGGM diagnosed Saudi patients from consanguineous families with majority of them having previous positive family history of cGGM. Sanger sequencing for the full coding regions of SLC5A1 for all patients resulted in the identification of 4 allelic variants in a homozygous state. Two mutations are novel; c.265G>A (p.G89R) and c.1304 G>A (p.G435D), and 2 have been previously reported to cause cGGM, c.765 C>G (p.C255W) and c.1136 G>A (p.R379Q). This is the first report delineating the clinical and molecular basis of cGGM in patients from this region.

On the Automatic Decellularisation of Porcine Aortae: A Repeatability Study Using a Non-Enzymatic Approach

Objective: To investigate the repeatability of automatic decellularisation of porcine aortae using a non-enzymatic approach, addressing current limitations associated with other automatic decellularisation processes. Materials and Methods: Individual porcine aortae (n = 3) were resected and every third segment (n = 4) was allocated to one of three different groups: a control or a manually or automatically decellularised group. Manual and automatic decellularisation was performed using Triton X-100 (2% v/v) and sodium deoxycholate. Protein preservation and the elimination of a galactosyl-α(1,3)galactose (GAL) epitope were measured using immunohistochemistry and protein binding assays. The presence of residual DNA was determined with gel electrophoresis and spectrophotometry. Scaffold integrity was characterised with scanning electron microscopy and uni-axial tensile testing. Manual and automatic results were compared to one another, to control groups and to current gold standards. Results: The results were comparable to those of current gold standard decellularisation techniques. Successful repeatability was achieved, both manually and automatically, with little effect on mechanical characteristics. Complete acellularity was not confirmed in either decellularisation group. Protein preservation was consistent in both the manually and automatically decellularised groups and between each individual aorta. Elimination of GAL was not achieved. Conclusion: Repeatable automatic decellularisation of porcine aortae is feasible using a Triton X-100-sodium deoxycholate protocol. Protein preservation was satisfactory; however, gold standard thresholds for permissible residual DNA levels were not achieved. Future research will focus on addressing this issue by optimisation of the existing protocol for thick tissues.

Modelling severe Staphylococcus aureus sepsis in conscious pigs: are implications for animal welfare justified?

BackgroundA porcine model of haematogenous Staphylococcus aureus sepsis has previously been established in our research group. In these studies, pigs developed severe sepsis including liver dysfunction during a 48 h study period. As pigs were awake during the study, animal welfare was challenged by the severity of induced disease, which in some cases necessitated humane euthanasia. A pilot study was therefore performed in order to establish the sufficient inoculum concentration and application protocol needed to produce signs of liver dysfunction within limits of our pre-defined humane endpoints.MethodsFour pigs received 1 × 108 cfu/kg BW of S. aureus, and two controls were sham inoculated with saline. A fixed infusion rate of 3 mL/min was used, while the inoculum concentration, i.e., the dose volume, was changed between the pigs. The following dose volumes were used: 10 mL (n = 1), 20 mL (n = 2), and 30 mL (n = 1), corresponding to infusion durations of 3.33, 6.66, and 10 min at dose rates of 3 × 107, 1.5 × 107, and 1 × 107 cfu/min/kg BW, respectively. Blood samples were drawn for complete blood count, clinical chemistry, and inflammatory markers before and every 6 h after inoculation. Prior to euthanasia, a galactose elimination capacity test was performed to assess liver function. Pigs were euthanised 48 h post inoculation for necropsy and histopathological evaluation.ResultsWhile infusion times of 6.66 min, and higher, did not induce liver dysfunction (n = 3), the infusion time of 3.33 min (n = 1) caused alterations in parameters similar to what had been seen in our previous studies, i.e., increasing bilirubin and aspartate aminotransferase, as well as histopathological occurrence of intravascular fibrin split products in the liver. This pig was however euthanised after 30 h, according to humane endpoints.ConclusionsA usable balance between scientific purpose and animal welfare could not be achieved, and we therefore find it hard to justify further use of this conscious porcine sepsis model. In order to make a model of translational relevance for human sepsis, we suggest that future model versions should use long-term anaesthesia.

Chemically sulfated galactomannan from Dimorphandra gardneriana seed: Characterization and toxicity evaluation

Dimorphandra gardneriana galactomannan (DG) was sulfated in pyridine:formamide using chlorosulfonic acid as the sulfation agent. The degree of substitution was 0.32, determined from the sulfur percentage. Confirmation of sulfation was obtained by FTIR spectroscopy through the presence of an asymmetrical SO stretching vibration at 1259cm−1. NMR data showed that the sulfation occurred on primary hydroxyl groups. NMR and GPC data indicate degradation during reaction with elimination of galactose. At the maximum tested concentration of 1000μg/mL, unmodified DG polysaccharide did not show a statistically significant cytotoxicity in Vero cells by the MTT method. Therefore, the CC50>1000μg/mL obtained for the sulfated polysaccharides from D. gardneriana in Vero cells point to its lower cytotoxicity than the sulfated galactomannan from Mimosa scabrella.

HepaRG: An Emerging In vitro Tool

Safety of new drug candidates is routinely assessed by using in vitro hepatocyte models such as primary human hepatocytes (PHH) and establishedhuman liver cell lines. Although PHH remain the gold standard, their limited and unpredictable availability, inability to proliferate, rapid loss of drug metabolising enzymes and interindividual variability are major disadvantages. To overcome these problems, many human liver cell lines have been developed. These stable cell lines are easy to work with and are available in large quantities but they lack most of the liver-specific functions and present altered gene expression profiles. Despite these issues, some of these cell lines such as nontumorigenic immortalised cell line Fa2N4 and hepatoma cell line HepG2 are frequently used in preclinical testing. Recently, a new human liver cell line HepaRG, derived from a female hepatocarcinoma patient has been made available. Bipotent progenitor HepaRG cells differentiate into hepatocytes and biliary epithelial cells and exhibit capability of maintaining liver-specific functions. A genome-wide gene expression profile analysis showed greater similarities between PHH and HepaRG cells as compared to HepG2 cells [1]. Regulation of carbohydrate metabolism, production of albumin and lactate, elimination of sorbitol and galactose at comparable rates to PHH make HepaRG cells the best differentiated cell line available and an in vitro tool of choice [2].

Physiological and Biochemical Basis of Clinical Liver Function Tests

To review the literature on the most clinically relevant and novel liver function tests used for the assessment of hepatic function before liver surgery. Postoperative liver failure is the major cause of mortality and morbidity after partial liver resection and develops as a result of insufficient remnant liver function. Therefore, accurate preoperative assessment of the future remnant liver function is mandatory in the selection of candidates for safe partial liver resection. A MEDLINE search was performed using the key words "liver function tests," "functional studies in the liver," "compromised liver," "physiological basis," and "mechanistic background," with and without Boolean operators. Passive liver function tests, including biochemical parameters and clinical grading systems, are not accurate enough in predicting outcome after liver surgery. Dynamic quantitative liver function tests, such as the indocyanine green test and galactose elimination capacity, are more accurate as they measure the elimination process of a substance that is cleared and/or metabolized almost exclusively by the liver. However, these tests only measure global liver function. Nuclear imaging techniques ((99m)Tc-galactosyl serum albumin scintigraphy and (99m)Tc-mebrofenin hepatobiliary scintigraphy) can measure both total and future remnant liver function and potentially identify patients at risk for postresectional liver failure. Because of the complexity of liver function, one single test does not represent overall liver function. In addition to computed tomography volumetry, quantitative liver function tests should be used to determine whether a safe resection can be performed. Presently, (99m)Tc-mebrofenin hepatobiliary scintigraphy seems to be the most valuable quantitative liver function test, as it can measure multiple aspects of liver function in, specifically, the future remnant liver.

Diarrhée néonatale par malabsorption du glucose et du galactose : à propos de 7 observations

Congenital glucose-galactose malabsorption (CGGM) is a rare autosomal recessive disorder, which presents as a protracted diarrhea in early neonatal life. We describe the clinical history, diagnostic evaluation, and management of 7 children with CGGM in western France. There were 4 girls and 3 boys from 5 families, born between 1984 and 2010. The principal complaint was a neonatal onset of watery and acidic severe diarrhea complicated by hypertonic dehydration. The diarrhea stopped with fasting. In 2 cases, the family history supported the diagnosis. In the other cases, elimination of glucose and galactose (lactose) from the diet resulted in the complete resolution of diarrhea symptoms. In 2 cases, the H2 breath tests were positive. In 2 cases, the HGPO or oral glucose tolerance test (OGTT) demonstrated an abnormal curve with glucose and a normal curve with fructose. DNA sequencing was not used. When glucose and galactose were eliminated from the diet, the infants had normal growth and development. In conclusion, CGGM is a rare etiology of neonatal diarrhea; however, the diagnosis is easy to make and the prognosis is excellent.

Quantitative liver function tests improve the prediction of clinical outcomes in chronic hepatitis C: Results from the hepatitis C antiviral long-term treatment against cirrhosis trial

Risk for future clinical outcomes is proportional to the severity of liver disease in patients with chronic hepatitis C virus (HCV). We measured disease severity by quantitative liver function tests (QLFTs) to determine cutoffs for QLFTs that identified patients who were at low and high risk for a clinical outcome. Two hundred and twenty-seven participants in the Hepatitis C Antiviral Long-term Treatment Against Cirrhosis (HALT-C) Trial underwent baseline QLFTs and were followed for a median of 5.5 years for clinical outcomes. QLFTs were repeated in 196 patients at month 24 and in 165 patients at month 48. Caffeine elimination rate (k(elim)), antipyrine (AP) clearance (Cl), MEGX concentration, methionine breath test (MBT), galactose elimination capacity (GEC), dual cholate (CA) clearances and shunt, perfused hepatic mass (PHM), and liver and spleen volumes (by single-photon emission computed tomography) were measured. Baseline QLFTs were significantly worse (P = 0.0017 to P < 0.0001) and spleen volumes were larger (P < 0.0001) in the 54 patients who subsequently experienced clinical outcomes. QLFT cutoffs that characterized patients as "low" and "high risk" for clinical outcome yielded hazard ratios ranging from 2.21 (95% confidence interval [CI]: 1.29-3.78) for GEC to 6.52 (95% CI: 3.63-11.71) for CA clearance after oral administration (Cl(oral)). QLFTs independently predicted outcome in models with Ishak fibrosis score, platelet count, and standard laboratory tests. In serial studies, patients with high-risk results for CA Cl(oral) or PHM had a nearly 15-fold increase in risk for clinical outcome. Less than 5% of patients with "low risk" QLFTs experienced a clinical outcome. QLFTs independently predict risk for future clinical outcomes. By improving risk assessment, QLFTs could enhance the noninvasive monitoring, counseling, and management of patients with chronic HCV.

Hepatic Galactose Metabolism Quantified in Humans Using 2-18F-Fluoro-2-Deoxy-d-Galactose PET/CT

Accurate quantification of regional liver function is needed, and PET of specific hepatic metabolic pathways offers a unique method for this purpose. Here, we quantify hepatic galactose elimination in humans using PET and the galactose analog 2-(18)F-fluoro-2-deoxy-d-galactose ((18)F-FDGal) as the PET tracer. Eight healthy human subjects underwent (18)F-FDGal PET/CT of the liver with and without a simultaneous infusion of galactose. Hepatic systemic clearance of (18)F-FDGal was determined from linear representation of the PET data. Hepatic galactose removal kinetics were determined using measurements of hepatic blood flow and arterial and liver vein galactose concentrations at increasing galactose infusions. The hepatic removal kinetics of (18)F-FDGal and galactose and the lumped constant (LC) were determined. The mean hepatic systemic clearance of (18)F-FDGal was significantly higher in the absence than in the presence of galactose (0.274 ± 0.001 vs. 0.019 ± 0.001 L blood/min/L liver tissue; P < 0.01), showing competitive substrate inhibition of galactokinase. The LC was 0.13 ± 0.01, and the (18)F-FDGal PET with galactose infusion provided an accurate measure of the local maximum removal rate of galactose (V(max)) in liver tissue compared with the V(max) estimated from arterio-liver venous (A-V) differences (1.41 ± 0.24 vs. 1.76 ± 0.08 mmol/min/L liver tissue; P = 0.60). The first-order hepatic systemic clearance of (18)F-FDGal was enzyme-determined and can thus be used as an indirect estimate of galactokinase capacity without the need for galactose infusion or knowledge of the LC. (18)F-FDGal PET/CT provides an accurate in vivo measurement of human galactose metabolism, which enables the quantification of regional hepatic metabolic function.

Kupffer cells are activated in cirrhotic portal hypertension and not normalised by TIPS

IntroductionHepatic macrophages (Kupffer cells) undergo inflammatory activation during the development of portal hypertension in experimental cirrhosis; this activation may play a pathogenic role or be an epiphenomenon. Our objective was...