Galactose Elimination Capacity 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.

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.

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 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

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.

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.

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.

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...

Critical flicker frequency and continuous reaction times for the diagnosis of minimal hepatic encephalopathy. A comparative study of 154 patients with liver disease

Minimal hepatic encephalopathy (MHE) is intermittently present in up to 2/3 of patients with chronic liver disease. It impairs their daily living and can be treated. However, there is no consensus on diagnostic criteria except that psychometric methods are required. We compared two easy-to-perform reproducible bedside methods: the critical flicker frequency (CFF) and continuous reaction times (CRT) tests. A CFF <39Hz and CRT-index <1.9 (index: the ratio 50/(90 minus 10) percentiles of reaction times) indicates cerebral dysfunction. 154 patients with acute or chronic liver disease with out overt hepatic encephalopathy (HE) underwent both tests at the same occasion. Both tests were abnormal in 20% of the patients and both tests were normal in 40% of the patients. In more than 1/3 the two tests were not in agreement as CFF classified 32% and CRT-index classified 48% of the patients as having MHE (p < 0.005). The two tests were weakly linearly correlated (r(2) = 0.14, p < 0.001) and neither test correlated with the metabolic liver function measured by the Galactose Elimination Capacity (GEC), nor with the blood ammonia concentration. Both tests identified a large fraction of the patients as having MHE and cleared only 40%. The two tests did not show concordant results, likely because they describe different aspects of MHE: the CFF gives a measure of astrocytic metabolic state and hence pathogenic aspects of MHE, whereas the CRT measures a composite key performance, viz. the ability of reacting appropriately to a sensory stimulus. The choice of test depends on the information needed in the clinical and scientific care and study of the patients.

Resting myocardial dysfunction in cirrhosis quantified by tissue Doppler imaging

Cirrhotic cardiomyopathy is described as latent cardiac failure. However, it remains to be investigated whether the myocardial dysfunction is present even at rest. The aim of the present study was to quantify left ventricular function at rest by means of tissue Doppler imaging in patients with cirrhosis and relate the findings to liver status and cirrhosis aetiology. Forty-four consecutive patients and 23 age-matched healthy controls were included. Conventional echocardiographic- and tissue Doppler-derived indices of systolic and diastolic function were obtained. Liver function was quantified by the galactose elimination capacity and clinical stage by the Child-Pugh and MELD scores. Both systolic and diastolic myocardial functions were compromised in the patients at rest. Left ventricular ejection fraction (56.4 ± 6.1 vs. 59.9 ± 3.9%, P<0.02), mean peak systolic tissue velocity (4.6 ± 0.9 vs. 5.6 ± 0.7 cm/s, P<0.001) and mean systolic strain rate (-1.23 ± 0.19 vs. -1.5 ± 0.14/s, P<0.001) were all reduced in cirrhosis patients. Thirty-four patients (54%) had diastolic dysfunction, 11 had impaired diastolic relaxation pattern (25%), 12 had the more severe pseudonormal filling pattern (27%) and one had restrictive filling or severe diastolic dysfunction (2%). None of the echocardiographic findings were related to the cirrhosis aetiology. Tissue Doppler imaging during rest detected substantial systolic and diastolic myocardial dysfunction in cirrhotic patients. This supports the existence of a distinct cirrhotic cardiomyopathy.

Quantitative Assessment of Hepatic Function During Liver Regeneration in a Standardized Rat Model

Reliable assessment of hepatic function during liver regeneration is crucial after liver surgery or liver transplantation. (99m)Tc-galactosyl human serum albumin ((99m)Tc-GSA) scintigraphy, (99m)Tc-mebrofenin hepatobiliary scintigraphy (HBS), the indocyanine green (ICG) clearance test, and the galactose elimination capacity (GEC) are common quantitative liver function tests. However, to our knowledge, comparative analysis between these tests has never been performed during liver regeneration. The aim of this study was therefore to compare (99m)Tc-GSA scintigraphy, (99m)Tc-mebrofenin HBS, the ICG clearance test, and GEC in the assessment of hepatic function during liver regeneration in rats. Rats were subjected to 70% partial hepatectomy (PHx). Liver function and functional volume were determined at predefined times after PHx and expressed as a percentage of baseline (pre-PHx) values. During liver regeneration, functional liver volume measured by (99m)Tc-GSA SPECT correlated strongly with conventional liver volume based on wet weight. One day after 70% PHx, conventional liver volume overestimated liver function as measured by (99m)Tc-mebrofenin uptake and excretion rates, (99m)Tc-GSA uptake rate, and ICG clearance. On days 5 and 7, (99m)Tc-mebrofenin uptake and ICG clearance had recovered to levels similar to conventional liver volume, whereas (99m)Tc-GSA uptake reflected a reduced liver function in relation to conventional liver volume and (99m)Tc-mebrofenin uptake. The GEC measurements consistently overestimated liver function during regeneration. Volumetric assessment of the liver should be complemented by liver function-specific assays. Functional regeneration is impaired, compared with volumetric regeneration, in the early phase of liver regeneration. In later stages of liver regeneration, (99m)Tc-GSA uptake underestimates hepatic regeneration in comparison to liver volume and (99m)Tc-mebrofenin uptake. GEC is of less value because it is only minimally affected by 70% PHx and is influenced by factors not related to liver function. (99m)Tc-mebrofenin HBS has the advantage of providing visual and quantitative information regarding both uptake and excretory liver function.

Could metabolic liver function tests predict mortality on waiting list for liver transplantation? A study on 560 patients

Allocation of graft in liver transplantation (LT) depends mainly on Model for End Stage Liver Disease (MELD) score. We studied the prognostic ability of three metabolic liver function tests in 560 cirrhotic patients listed for transplantation, in comparison with MELD and Child-Turcotte-Pugh (CTP) scores. Indocyanine green retention rate (ICG), aminopyrine breath test (ABT), and galactose elimination capacity were performed at the time of listing in addition to standard biological parameters. Seventy-three patients died on waiting list, 438 were transplanted, and 73 died after LT. Cox regression analysis and receiver operating characteristic curves with c-statistics were calculated after stratification according to CTP and MELD score. For the mortality before transplantation, c-statistics showed that ICG and ABT had a slightly better prognostic ability (0.73 and 0.68, respectively) than MELD score (0.66), and similar to CTP score (0.70). ABT's prognostic ability remained significant once the MELD score (below and above 20) had already been taken into account. Only ICG had a prognostic ability to predict the survival after LT, even after stratification according to MELD and CTP score. Our results strongly support that ABT and ICG may be useful in the ranking of the patients in LT list, adding prognosis information in association with MELD score.

Age-dependency of galactose elimination capacity in healthy children and children with chronic liver disease

Objective. Galactose elimination capacity (GEC) is used as a quantitative measure of liver metabolic function with prognostic value in adults with acute and chronic liver failure. Almost no data are available regarding GEC in children, however. This study thus aims to meet the previously unmet clinical need for age-related data on GEC in children. Material and methods. We studied galactose elimination in 10 healthy children (median age 10.7 years; range 7 months to 16 years) and 30 children with chronic liver disease (median age 8.6 years; range 3 months to 16 years). GEC was estimated from the linear decrease in concentration of galactose in arterialized capillary blood from the ear following intravenous infusion of galactose. Results. In both groups of children, GEC (μmol/min/kg body weight) was highest in the youngest children and decreased with age, although at a significantly lower level in the children with liver disease (p = 0.05). GEC was significantly higher in healthy children than in healthy adults, diminishing to the adult level by the age of 16 years. Conclusions. GEC was found to be higher in children than in adults until the age of 16 years. Moreover, GEC was significantly lower in children with chronic liver disease than in healthy children, underlining that GEC testing also has potential clinical usefulness as a quantitative measure of liver metabolic function in children.

Determination of hepatic galactose elimination capacity using 2-[18F]fluoro-2-deoxy-d-galactose PET/CT: reproducibility of the method and metabolic heterogeneity in a normal pig liver model

Objective. A PET method is developed for non-invasive measurement of regional metabolic liver function using the galactose analog 2-[18F]fluoro-2-deoxy-d-galactose, FDGal. The aim of the present study was to determine the reproducibility of the method in pigs before translating it to human studies. Material and methods. Five anesthetized pigs were studied twice within an interval of three days. A dynamic PET recording was performed with an injection of 100 MBq FDGal. Non-radioactive galactose was administered throughout the PET recordings to achieve near-saturated elimination kinetics. Arterial blood samples were collected for determination of blood concentrations of FDGal and galactose (cgal). Net metabolic clearance of FDGal, KFDGal, was calculated from linear representation of data. The approximate maximal hepatic removal rate, Vmax, of galactose (mmol/l tissue/min) was calculated as KFDGal cgal. The estimates from Day 1 and Day 2 were compared and the coefficient of variation, COV, of the estimates calculated. Functional heterogeneity in normal pig liver was evaluated as COV of the tissue concentration of radioactivity during quasi steady-state metabolism. Results. There was no significant difference between Vmax from Day 1 and Day 2 (p = 0.38), and the reproducibility was good with a COV of 14% for the whole liver. In normal pig liver tissue, mean COV after an injection of FDGal was on average 15.6% with no day-to-day variation (p = 0.7). Conclusions. The novel FDGal PET method for determination of hepatic metabolic function has a good reproducibility and is promising for future human studies of regional liver function.

Body composition changes after transjugular intrahepatic portosystemic shunt in patients with cirrhosis

To investigate the effect of transjugular intrahepatic porto-systemic shunt (TIPS) on malnutrition in portal hypertensive cirrhotic patients. Twenty-one patients with liver cirrhosis and clinical indications for TIPS insertion were investigated before and 1, 4, 12, 52 wk after TIPS. For each patient we assayed body composition parameters [dry lean mass, fat mass, total body water (TBW)], routine liver and kidney function tests, and free fatty acids (FFA). Glucose and insulin were measured for the calculation of the homeostasis model assessment insulin resistance (HOMA-IR); liver function was measured by the galactose elimination capacity (GEC); the severity of liver disease was graded by model for end-stage liver disease (MELD). Porto-systemic gradient decreased after TIPS (6.0 +/- 2.1 mmHg vs 15.8 +/- 4.8 mmHg, P < 0.001). Patients were divided in two groups according to initial body mass index. After TIPS, normal weight patients had an increase in dry lean mass (from 10.9 +/- 5.9 kg to 12.7 +/- 5.6 kg, P = 0.031) and TBW (from 34.5 +/- 7.6 L to 40.2 +/- 10.8 L, P = 0.007), as well as insulin (from 88.9 +/- 49.2 pmol/L to 164.7 +/- 107.0 pmol/L, P = 0.009) and HOMA-IR (from 3.36% +/- 2.18% to 6.18% +/- 4.82%, P = 0.023). In overweight patients only FFA increased significantly (from 0.59 +/- 0.24 mmol/L to 0.93 +/- 0.34 mmol/L, P = 0.023). TIPS procedure is effective in lowering portal pressure in patients with portal hypertension and improves body composition without significant changes in metabolic parameters.

Soluble membrane attack complex in ascites in patients with liver cirrhosis without infections

To study complement activation in 46 patients with alcoholic cirrhosis and ascites but no spontaneous bacterial peritonitis (SBP) and 10 healthy controls. Complement activation was determined by the measurement of soluble membrane attack complex (sMAC) concentrations in ascites and plasma. In patients, metabolic liver function was determined by the galactose elimination capacity and the clinical status assessed by the Model of End-Stage Liver Disease and Child-Pugh scores. Ascites sMAC levels were markedly higher than in the corresponding plasma sample (median (range): 596 (170 - 1519) vs 160 (77 - 848) μg/L; P < 0.01). Ascites sMAC levels correlated positively with liver status. There was no relationship between ascites sMAC and leukocyte count. No relationship between ascites sMAC and blood C-reactive protein, albumin or neutrophile count was found. Plasma sMAC concentrations were slightly higher in patients than in controls [130 μg/L (70 - 204); P = 0.04]. Neither sMAC in ascites nor plasma was related to mortality. The increased sMAC concentration in ascites and plasma indicate an activation of the complement system in cirrhosis even in the absence of SBP. This was particularly evident in the peritoneal fluid and most marked in patients with preserved liver status. The high ascites sMAC levels may reflect transudation of membrane attack complexes from the liver. Whether this complement activation has any clinical implications remains to be clarified.

A Clinical Perspective on the Criteria for Liver Resection and the Use of Liver Function Tests

To the Editor, In a recently published survey of 100 liver centers, Breitenstein et al. [1] reported that on a global scale, (1) the average minimal remnant liver volume for resection is 25% (range = 15-40%) for normal liver parenchyma and 50% (range = 25–90%) for cirrhotic livers, (2) portal vein occlusion is employed in 89% of the centers for purposes of augmenting liver volume before surgery, and that (3) 38% of the centers employed liver function tests as part of their clinical routine, of which 76% used the ICG clearance test. The interesting survey provoked a few issues that we feel obliged to address. The authors contend that “below a certain volume, a remnant liver cannot sustain metabolic, synthetic, and detoxifying functions” [1]—a statement that is unequivocal and uncontested. However, it should be born in mind that liver volume is not a directly proportional measure of liver function. We have demonstrated a few fundamental aspects of the volume-function relationship that support this notion: (i) Whereas liver function correlates with volume in uncompromised livers [2], there is significantly less correlation between liver volume and function in patients with coexisting parenchymal liver disease [3, 4]. (ii) This discrepancy also applies to the regenerating liver [3]. (iii) The liver often exhibits functional heterogeneity [3]. These findings have been corroborated to some extent by others [5]. Consequently, a marginal remnant liver volume (e.g., 25% for cirrhotic livers [1]) may translate to functional deficiencies following resection and hence predisposes the organ to the “small-for-size” or, rather, the “small-for-function” syndrome. Likewise, allowing the organ to regenerate to a predetermined volume before resection bears comparable implications and strongly pleads for the use of dynamic liver function tests rather than CT volumetry as the gold standard, particularly for borderline surgical decisions. We emphasize specifically the use of quantitative dynamic liver function tests [i.e., ICG clearance, 99mTc-mebrofenin hepatobiliary scintigraphy (HBS) [2–4], galactose elimination capacity (GEC) [5], and 99mTc-labeled galactosyl human serum albumin scintigraphy (GSAS)] inasmuch as conventional liver function tests such as prothrombin time, serum bilirubin, and the Child-Pugh score are relatively insensitive and are thus lagging indicators for determining whether a liver resection can be safely performed. It is well known that there are notable discrepancies between the above-mentioned dynamic liver function tests in the assessment of liver function. In our patient population, ICG and 99mTc-mebrofenin uptake exhibited similar pharmacokinetics in regenerating rat livers (that also corresponded well to the extent of hepatic damage), whereas the GSAS and GEC tests displayed an underestimation and an overestimation, respectively, of liver function in comparison to ICG and 99mTc-mebrofenin uptake (unpublished). This is because liver function encompasses a broad spectrum of processes, ranging from uptake, synthesis, biotransformation, and systemic and canalicular secretion, whereby each test measures a different component of that spectrum. In summary, criteria on the basis of which extended liver resections are performed should preferably be dictated by functional parameters rather than volume alone, especially when livers are resected to a minimally accepted remnant volume. Furthermore, we advocate the use of dynamic liver function tests such as ICG or 99mTc-mebrofenin uptake for testing liver function due to their sensitivity and prognostic strength. We acknowledge that each of these tests reflects a limited aspect of liver function only. However, currently no better, clinically viable alternatives are available.

Pulmonary dysfunction and hepatopulmonary syndrome in cirrhosis and portal hypertension

Pulmonary dysfunction including the hepatopulmonary syndrome (HPS) is an important complication to cirrhosis and portal hypertension. However, the precise relation to liver dysfunction and the prevalence of HPS are unclear. We therefore aimed to assess (i) the prevalence of HPS in consecutive alcoholic cirrhotic patients, (ii) the degree of pulmonary dysfunction in relation to liver function and (iii) the response of a 100% oxygen test on cardiopulmonary and peripheral oxygenation. Fifty patients with cirrhosis and 12 matched healthy controls were entered in this study. All underwent haemodynamic and pulmonary investigations [lung diffusing capacity for carbon monoxide (DLCO), contrast-enhanced echocardiography and detection of extrapulmonary shunt fraction]. A 100% oxygen test was performed with the assessment of arterial oxygen tension (PaO(2)), the alveolar-arterial oxygen gradient (AaPO(2)) and peripheral transcutaneous oxygen tension (tcPO(2)). The prevalence of HPS was 10%. PaO(2) and DLCO were reduced in 32 and 72% and AaPO(2), was increased in 60% of the patients respectively. DLCO correlated with indicators of liver dysfunction (galactose elimination capacity, P<0.01, indocyanine green clearance, P<0.001), portal hypertension (post-sinusoidal resistance, P<0.01) and central hypovolaemia (central and arterial blood volume, P<0.01). After 100% oxygen inhalation, the changes in PaO(2), AaPO(2), tcPO(2) and heart rate were abnormal in the patients compared with controls (P<0.02). Pulmonary dysfunction in alcoholic cirrhosis is common and relates to different aspects of liver dysfunction, whereas the prevalence of HPS is low. The haemodynamic response to oxygen inhalation is clearly impaired and HPS and pulmonary dysfunction seem to be caused by different pathophysiological mechanisms.