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BACKGROUND: Progressive familial intrahepatic cholestasis (PFIC) encompasses a group of autosomal recessive disorders with high morbidity and mortality. Variants in the gene encoding tight junction protein-2 (TJP2) have been linked to PFIC type 4 (PFIC4), which predominantly presents in childhood. However, there are only limited data from adults with TJP2-related PFIC4. We report a family with an autosomal recessive disorder with a novel variant in the TJP2 gene in adults with very variable expression of PFIC4. CASE SUMMARY: The index patient presented at 19 years old with liver cirrhosis and variceal bleeding and was treated with endoscopic banding and beta-blockers. In 2018, he developed primary liver cancer that was treated with radiofrequency ablation followed by liver transplantation in 2019. Genetic testing revealed a novel homozygous TJP2 variant causing PFIC4 (TJP2([NM_004817.3]:c.[3334C>T]; [3334C>T])). The consanguineous family consists of the father and mother (both heterozygous) and their 12 children, of which five carry the variant in a homozygous state; however, these five siblings have highly variable expression of PFIC4. Two homozygous brothers had cirrhosis and portal hypertension at diagnosis at the ages of 19 and 36. Two other homozygous brothers, age 23 and 19, and the homozygous sister, age 21, have elevated liver enzymes but presently no cirrhosis, which may suggest an age-dependent penetrance. In addition, five sisters had severe and mild intrahepatic cholestasis of pregnancy and carry the TJP2 variant in a homozygous and heterozygous state, respectively. CONCLUSION: This novel TJP2 variant is associated with PFIC4 causing severe liver disease with cirrhosis and primary liver cancer in adolescents/adults.

To the Editor,In this study, we examined pathogens and resistance in a large Danish cohort of patients with spontaneous bacterial peritonitis (SBP). Recent international studies report of a shift t...

Objectives: A few adult and adolescent patients with even severe cholestatic liver disease remain unexplained after standard diagnostic work-up. We studied the value of genetic examination in such patients and developed a panel of eight genes with known cholestatic associations. Materials and methods: Thirty-three patients with unexplained cholestasis despite a thorough clinical work-up were examined for sequence variations in the coding regions of the ABCB4, ABCB11, ABCC2, ABCG5, ATP8B1, JAG1, NOTCH2, and UGT1A1 genes and the promoter region of UGT1A1 by massive parallel sequencing of DNA extracted from whole blood. Hepatologists and clinical geneticists evaluated the causal potential of genetic variants. Results: In 9/33 patients (27%), we identified genetic variants as a certain causal factor and in further 9/33 (27%) variants as a possible contributing factor. In most cases, a detailed family history was necessary to establish the importance of genetic variants. Genetic causes were identified in 6/13 women (46%) with intrahepatic cholestasis during pregnancy and persisting abnormal biochemistry after delivery. Conclusions: Our study suggests that a small number of well-known genetic variants are involved in at least 27–54% of patients with unexplained cholestasis. An expanded panel will likely explain more cases. This motivates genetic testing of these patients. Genetic testing, however, cannot stand alone but should be combined with a clinical genetic work-up in collaboration between hepatologists and clinical geneticists.

BACKGROUND: Biliary complications (BC) are frequently observed following liver transplantation. The aim of the present retrospective study, conducted at an outpatients' tertiary care hospital, was to determine the incidence of biliary complications and risk factors associated with their development in liver transplantation (lT) patients.MATERIALS AND METHODS: The medical records were reviewed for all patients who underwent liver transplantation at the Rigshospitalet, Copenhagen, Denmark, from 2000 to 2011 and were referred to the Aarhus University Hospital for follow-up. Patients who died within 3 months of surgery or had incomplete clinical information were excluded. All data for demographic characteristics and possible risk factors for development of biliary stricture were collected. Fifty-one patients were included.RESULTS: The median age at transplantation was 40 (range=7-64) years, and 53% of patients were males. Biliary complications occurred in 18 patients (35%), the majority of whom developed strictures (12 patients, 24%). Univariate and multivariate analyses revealed that cytomegalovirus infection (p=0.008), hepatic artery obstruction (p=0.03) and hepatic artery graft abnormalities (p=0.03) were independent risk factors for the development of biliary strictures.CONCLUSION: One-third of patients presented biliary complications after liver transplantation, among which biliary strictures were the most common. Cytomegalovirus infection, hepatic artery stenosis and anatomical abnormality of the graft's hepatic artery are independent risk factors for the development of biliary stricture.

Human newborns spend up to 18 hours sleeping. The organization of their sleep differs immensely from adult sleep, and its quick maturation and fundamental changes correspond to the rapid cortical development at this age. Manual sleep classification is specifically challenging in this population given major body movements and frequent shifts between vigilance states; in addition various staging criteria co-exist. In the present study we utilized a machine learning approach and investigated how EEG complexity and sleep stages evolve during the very first weeks of life. We analyzed 42 full-term infants which were recorded twice (at week two and five after birth) with full polysomnography. For sleep classification EEG signal complexity was estimated using multi-scale permutation entropy and fed into a machine learning classifier. Interestingly the baby’s brain signal complexity (and spectral power) revealed huge developmental changes in sleep in the first 5 weeks of life, and were restricted to NREM (“quiet”) and REM (“active sleep”) states with little to no changes in state wake. Data demonstrate that our classifier performs well over chance (i.e., >33% for 3-class classification) and reaches almost human scoring accuracy (60% at week-2, 73% at week-5). Altogether, these results demonstrate that characteristics of newborn sleep develop rapidly in the first weeks of life and can be efficiently identified by means of machine learning techniques.Author summaryThe organization of newborn sleep differs from adult sleep, and its ongoing maturation over time corresponds with cortical development. However, sleep scoring in this population is challenging given frequent artifacts in polysomnography (PSG) and absence of established staging criteria which results in low inter-scorer reliability. To investigate changes in the early brain activity, we analyzed large sample of newborn data at week 2 and 5 after birth. First we evaluated sleep that was previously scored visually, in terms of both entropy and oscillatory power. Next we accessed the performance of automatic sleep scoring based on machine learning compared with conventional, manual scoring. We observed clear developmental changes on the brain-level in the first 5 weeks of life in human newborns. These changes were limited to “quiet” NREM and “active” REM sleep. Also our classifier data demonstrated that we can classify well above chance and similar to human scorers using multi-scale permutation entropy (and just 6 EEG and 5 physiological channels).

Purpose:The purpose of this study was to investigate the use of anterior segment imaging in diagnosing Kayser-Fleischer rings in patients with Wilson disease.Methods:In a tertiary center for Wilson disease, patients were examined with a Pentacam HR Scheimpflug-based tomography device in addition to conventional slit-lamp examination. The inferior part of the cornea was analyzed using both a built-in densitometry module and ImageJ.Results:Thirty-one patients with Wilson disease (78% of all Danish patients) were included, resulting in 83 examinations over a 5-year period. Ten had a manifest Kayser-Fleischer ring in the inferior part of the cornea on at least 1 examination, 5 had other causes of peripheral corneal scatter, and 16 had normal examinations. The built-in densitometry module performed poorly in discriminating between the presence and absence of a Kayser-Fleischer ring. However, analysis of the images in ImageJ and calculation of a normalized signal (peak posterior value/peak anterior value) with a cutoff value set to 1 detected 28 of 31 Kayser-Fleischer rings and resulted in 96% sensitivity and 95% specificity. In 12 patients who underwent 3 or more examinations during the period, changes in the normalized signal seemed to reflect the efficiency of the treatment, although more studies are needed for this conclusion.Conclusions:ImageJ-based analysis of Pentacam images has a high sensitivity in detecting Kayser-Fleischer rings and can be used as a diagnostic procedure for Wilson disease and may be a tool to monitor the disease in an objective manner.

Background & Aims: In 2009, the Danish Government instituted “Fast Track Clinical Pathways” (FTCP) to accelerate diagnosis and treatment of cancers including hepatocellular carcinoma (HCC). We examined how the implementation of FTCP affected the time from referral to diagnosis and treatment as well as the patient survival.Methods: 309 consecutive patients with suspected HCC were included, 79 referred during the period 2007- 2008 (before FTCP) and 230 during 2009-2011. Of those, 271 (88%) were diagnosed with HCC and 161 (60%) had cirrhosis, in most cases caused by alcohol.Results: The time from referral to the first visit was reduced from a mean 16.4 (11.5) to 5.4 (6) days (p

This report presents the case of a patient with complex, post-operative congenital heart disease who required an atypical approach for placement of a left ventricular pacing lead to establish biventricular pacing after developing pacemaker-mediated cardiomyopathy. A 42-year-old man with upstairs

Observational studies have explored the safety of magnetic resonance (MR) scanning of patients with cardiac implantable electronic devices (CIEDs) that are not Food and Drug Administration approved for MR scanning ("nonconditional"). However, concern has been raised that MR scanning that includes the thoracic region may pose a higher risk. This study examines the safety of MR scanning of thoracic versus nonthoracic regions of patients with CIEDs.Patients underwent MR scanning utilizing an institutional protocol. CIED variables examined included sensing value, pacing capture threshold, lead impedance, and battery voltage. Regression analysis of the CIED variable differences (pre- to immediately post-MR and pre-MR to long-term follow-up) was performed to determine if CIED variable differences were dependent on region scanned (thoracic vs nonthoracic), time from CIED implant to MR scanning, or CIED type (pacemaker vs implantable cardioverter defibrillator).238 patients (38% female, age 65 ± 15 years) underwent 339 MR scans, including 99 MR scans of the thoracic region. CIED variable differences to immediately post-MR or to long-term follow-up were not significantly different from zero (P 0.05) and there was no dependence upon region scanned (thoracic vs nonthoracic), time from CIED implant to MR scan, or CIED type. One power-on reset occurred in a patient that underwent a cardiac MR and the CIED was successfully reprogrammed. There were no clinical adverse effects.CIED variable differences following MR scan were not dependent on the region scanned (thoracic vs nonthoracic) and there were no clinical adverse effects in this prospective cohort.

Cardiac implanted electronic devices (CIEDs) have historically been regarded as a contraindication for performing magnetic resonance imaging (MRI), limiting the availability of this exam for large numbers of patients who may have otherwise benefited from the unique diagnostic capabilities of MRI. Interactions between CIEDs and the magnetic field associated with MRI systems have been documented, and include potential effects on CIED function, lead heating, and force/torque on the generator. Several device manufacturers have developed "MR-Conditional" CIEDs with specific hardware and software design changes to optimize the device for the MR environment. However, a substantial body of evidence has been accumulating that suggests that MRI may be safely performed in patients with either conditional or nonconditional CIEDs. Institutional policies and procedures, including preexam screening and assessment by skilled electrophysiology personnel and intraexam monitoring, allow MRI to be safely performed in CIED patients, as evidenced by at least two, large multicenter prospective studies and multiple smaller, single-institution studies. Cross-departmental collaboration and a robust safety infrastructure at sites that perform MRI should allow for the safe imaging of CIED patients who have a clinical indication for the study, regardless of the conditionality status of the device.5 Technical Efficacy: Stage 5 J. Magn. Reson. Imaging 2018;47:595-603.

Hepatobiliary secretion of bile acids is an important liver function. Here, we quantified the hepatic transport kinetics of conjugated bile acids using the bile acid tracer [N-methyl-Nine healthy participants and eight patients with varying degrees of cholestasis were examined withResults are presented as median (range). The hepatic intrinsic clearance was 1.50 (1.20-1.76) ml blood/min/ml liver tissue in healthy participants and 0.46 (0.13-0.91) in patients. In healthy participants, the rate constant for secretion ofThis first in vivo quantification of individual steps involved in the hepatobiliary secretion of a conjugated bile acid in humans provided new insight into cholestatic disease.Positron emission tomography (PET) using the radiolabelled bile acid (The trial is registered at ClinicalTrials.gov (NCT01879735).

BACKGROUND & AIMS: There are no recent data on incidence or survival of hepatocellular carcinoma (HCC) in Denmark. We examined current HCC epidemiology.METHODS: We used data from nationwide registries to identify all Danish citizens diagnosed with HCC in 1994-2016. We computed annual standardized incidence rates for the entire 1994-2016 period, and we compared survival for patients diagnosed in 2004-2014; data on HCC stage were available for that period alone and coded according to the TNM classification.RESULTS: The incidence rate for 1994-2016 was 3.7 (95% CI 3.6-3.8) per 100 000 population per year. It was stable around 3.0 in 1994-2007, climbed steadily to 5.7 in 2008-2011, and remained high in 2012-2016. The proportion of non-cirrhotic patients with HCC was 21%, with a slightly decreasing time trend. Median survival time rose from 2.7 months in 2004-2006 to 7.7 months in 2013-2014, but only patients with early HCC (stage I or II HCC or a "probably early HCC") saw improvements after 2007 (confounder-adjusted mortality hazard ratio for 2013-2014 vs 2007-2009=0.67, 95% 0.50-0.90). The proportion of patients with early HCC rose from 17% in 2004-2006 to 30% in 2013-2014.CONCLUSIONS: HCC incidence increased between 2007 and 2011. Concurrently, the HCC stage at diagnosis and patient survival improved. The likely reasons for the changes include easier access to HCC workup, changing diagnostic criteria for HCC, increased prevalence of risk factors for HCC, and improved treatment of patients with HCC.

Branched-chain amino acids (BCAA) are used in attempts to reduce blood ammonia in patients with cirrhosis and intermittent hepatic encephalopathy based on the hypothesis that BCAA stimulate muscle ammonia detoxification. We studied the effects of an oral dose of BCAA on the skeletal muscle metabolism of ammonia and amino acids in 14 patients with cirrhosis and in 7 healthy subjects by combining [13N]ammonia positron emission tomography (PET) of the thigh muscle with measurements of blood flow and arteriovenous (A-V) concentrations of ammonia and amino acids. PET was used to measure the metabolism of blood-supplied ammonia and the A-V measurements were used to measure the total ammonia metabolism across the thigh muscle. After intake of BCAA, blood ammonia increased more than 30% in both groups of subjects (both P < 0.05). Muscle clearance of blood-supplied ammonia (PET) was unaffected ( P = 0.75), but the metabolic removal rate (PET) increased significantly because of increased blood ammonia in both groups (all P < 0.05). The total ammonia clearance across the leg muscle (A-V) increased by more than 50% in both groups, and the flux (A-V) of ammonia increased by more than 45% (all P < 0.05). BCAA intake led to a massive glutamine release from the muscle (cirrhotic patients, P < 0.05; healthy subjects, P = 0.12). In conclusion, BCAA enhanced the intrinsic muscle metabolism of ammonia but not the metabolism of blood-supplied ammonia in both the patients with cirrhosis and in the healthy subjects.

Udgivelsesdato: 2010 The clinical course of alcoholic cirrhosis, a condition with a high mortality, has not been well described. We examined prevalence, risk, chronology, and mortality associated with three complications of cirrhosis: ascites, variceal bleeding, and hepatic encephalopathy. We followed a population-based cohort of 466 Danish patients diagnosed with alcoholic cirrhosis in 1993-2005, starting from the date of hospital diagnosis and ending in August 2006. Data were extracted from medical charts during the follow-up period. Risk and mortality associated with complications were calculated using competing-risks methods. At diagnosis of alcoholic cirrhosis, 24% of patients had no complications, 55% had ascites alone, 6% had variceal bleeding alone, 4% had ascites and variceal bleeding, and 11% had hepatic encephalopathy. One-year mortality was 17% among patients with no initial complications, 20% following variceal bleeding alone, 29% following ascites alone, 49% following ascites and variceal bleeding (from the onset of the later of the two complications), and 64% following hepatic encephalopathy. Five-year mortality ranged from 58% to 85%. The risk of complications was about 25% after 1 year and 50% after 5 years for all patients without hepatic encephalopathy. The complications under study did not develop in any predictable sequence. Although patients initially without complications usually developed ascites first (12% within 1 year), many developed either variceal bleeding first (6% within 1 year) or hepatic encephalopathy first (4% within 1 year). Subsequent complications occurred in an unpredictable order among patients with ascites or variceal bleeding. Conclusion: Patients with alcoholic cirrhosis had a high prevalence of complications at the time of cirrhosis diagnosis. The presence and type of complications at diagnosis were predictors of mortality, but not of the risk of subsequent complications. (HEPATOLOGY 2010.).

The exponential rise in blood lactate with exercise intensity may be influenced by hepatic lactate uptake. We compared muscle-derived lactate to the hepatic elimination during 2 h prolonged cycling (62 ± 4% of maximal O2uptake, V̇o2max) followed by incremental exercise in seven healthy men. Hepatic blood flow was assessed by indocyanine green dye elimination and leg blood flow by thermodilution. During prolonged exercise, the hepatic glucose output was lower than the leg glucose uptake (3.8 ± 0.5 vs. 6.5 ± 0.6 mmol/min; mean ± SE) and at an arterial lactate of 2.0 ± 0.2 mM, the leg lactate output of 3.0 ± 1.8 mmol/min was about fourfold higher than the hepatic lactate uptake (0.7 ± 0.3 mmol/min). During incremental exercise, the hepatic glucose output was about one-third of the leg glucose uptake (2.0 ± 0.4 vs. 6.2 ± 1.3 mmol/min) and the arterial lactate reached 6.0 ± 1.1 mM because the leg lactate output of 8.9 ± 2.7 mmol/min was markedly higher than the lactate taken up by the liver (1.1 ± 0.6 mmol/min). Compared with prolonged exercise, the hepatic lactate uptake increased during incremental exercise, but the relative hepatic lactate uptake decreased to about one-tenth of the lactate released by the legs. This drop in relative hepatic lactate extraction may contribute to the increase in arterial lactate during intense exercise.

Background— Implantable cardioverter-defibrillators and cardiac resynchronization therapy defibrillators have relied on multiple ventricular fibrillation (VF) induction/defibrillation tests at implantation to ensure that the device can reliably sense, detect, and convert VF. The ASSURE Study (Arrhythmia Single Shock Defibrillation Threshold Testing Versus Upper Limit of Vulnerability: Risk Reduction Evaluation With Implantable Cardioverter-Defibrillator Implantations) is the first large, multicenter, prospective trial comparing vulnerability safety margin testing versus defibrillation safety margin testing with a single VF induction/defibrillation. Methods and Results— A total of 426 patients receiving an implantable cardioverter-defibrillator or cardiac resynchronization therapy defibrillator underwent vulnerability safety margin or defibrillation safety margin screening at 14 J in a randomized order. After this, patients underwent confirmatory testing, which required 2 VF conversions without failure at ≤21 J. Patients who passed their first 14-J and confirmatory tests, irrespective of the results of their second 14-J test, had their devices programmed to a 21-J shock for ventricular tachycardia (VT) or VF ≥200 bpm and were followed up for 1 year. Of 420 patients who underwent 14-J vulnerability safety margin screening, 322 (76.7%) passed. Of these, 317 (98.4%) also passed 21-J confirmatory tests. Of 416 patients who underwent 14-J defibrillation safety margin screening, 343 (82.5%) passed, and 338 (98.5%) also passed 21-J confirmatory tests. Most clinical VT/VF episodes (32 of 37, or 86%) were terminated by the first shock, with no difference in first shock success. In all observed cases in which the first shock was unsuccessful, subsequent shocks terminated VT/VF without complication. Conclusions— Although spontaneous episodes of fast VT/VF were limited, there was no difference in the odds of first shock efficacy between groups. Screening with vulnerability safety margin or defibrillation safety margin may allow for inductionless or limited shock testing in most patients.

OBJECTIVE: Branched-chain amino acids (BCAA) are used in liver cirrhosis to promote protein synthesis, support ammonia detoxification, and treat hepatic encephalopathy. Cirrhosis leads to subnormal BCAA plasma concentrations and studies indicate that levels are decreased due to their role in muscle ammonia removal. Muscle contribution has not been fully elucidated. We studied muscle amino acid metabolism in six healthy subjects, 13 cirrhosis patients and six patients with an episode of alcoholic hepatitis.METHODS: Subjects had catheters inserted into the femoral artery and vein to obtain arterial (A) and venous (V) concentrations of amino acids (μmol/L blood).RESULTS: BCAA concentrations were lower in patients with cirrhosis compared to healthy subjects (p < 0.05) with no difference between patients with alcoholic hepatitis and the other groups. Muscle BCAA uptake was variable and on average higher in patients with alcoholic hepatitis and patients with stable cirrhosis compared to healthy subjects (mean A-V difference 0.5 and 32 vs. - 12 μmol/L blood) (p = 0.22). The release of aromatic amino acids (AAA) was comparable in the three groups (P > 0.30). The BCAA/AAA (Fischer's ratio) was lower in patients with cirrhosis and patients with alcoholic hepatitis compared to healthy subjects (mean 1.65, 1.17 and 2.73, both p < 0.05) and it was negatively correlated to the Child-Pugh score (p < 0.05).CONCLUSIONS: Patients with liver disease have lower BCAA and higher AAA blood concentrations compared to healthy subjects. The trend towards an increased muscle uptake of BCAA may have contributed but this was not significant.

Patients with acetaminophen-induced fulminant hepatic failure may have the capacity for recovery if sufficient liver cell mass remains to allow regeneration. We investigated the prognostic potential of the galactose elimination capacity (GEC) as a noninvasive measurement of functioning liver cell mass in severe acetaminophen-induced hepatotoxicity.All patients admitted with acetaminophen poisoning during a 10-year period were studied retrospectively. A total of 220 patients who had at least one GEC performed were included in the study.The GEC was lower in patients with than without hepatic encephalopathy (14.5 +/- 5.6 micromol/min/kg vs. 23.2 +/- 6.7 micromol/min/kg; P0.0001). Among patients with hepatic encephalopathy, the GEC was significantly higher in spontaneous survivors than in nonsurvivors (16.8 +/- 5.6 micromol/min/kg vs. 12.2 +/- 4.7 micromol/min/kg; P0.0001). In a logistic regression analysis, GEC was associated independently with mortality (odds ratio: 1.28 per 1 micromol/min/kg decrease in GEC; 95% confidence interval: 1.14-1.45). A threshold GEC of 16.5 micromol/min/kg to identify nonsurvivors had a sensitivity of 90%, a specificity of 72%, a positive predictive value of 49%, and a negative predictive value of 96%. None of 14 patients with hepatic encephalopathy and a GEC less than 10 micromol/min/kg survived.The GEC was strongly associated with development of hepatic encephalopathy and death from acetaminophen-induced fulminant hepatic failure. The GEC was too unspecific to be used alone for identification of transplantation candidates, but it may be useful as a supplement to other selection criteria.

Clinical and experimental studies suggest that the proteins of the extracellular actin scavenger system have a role in the pathophysiological processes taking place in critically ill and injured patients. Circulating levels of Gc-globulin and gelsolin are reduced shortly after severe trauma, and admission levels of Gc-globulin are associated with survival. Herein, we sought to measure the association between admission levels of Gc-globulin and postinjury organ dysfunction and infection. We also wanted to describe the serial changes in Gc-globulin in these severely injured patients.Prospective cohort.Intensive care unit at a county hospital that serves as a level one trauma center.Ninety-eight consecutive trauma victims admitted to the intensive care unit for24 hrs during a 4-month period.Circulating levels of Gc-globulin were measured by using immunonephelometry. All patients were evaluated daily to obtain the necessary data for assessment of organ dysfunction and sepsis. The median Gc-globulin concentration at admission was 127 mg/L in patients who developed severe multiple organ dysfunction compared with 184 mg/L in patients who did not (p =.001). The admission level of Gc-globulin was comparable to known risk factors such as age and injury severity score, regarding development of organ dysfunction. Plasma concentrations of Gc-globulin remained significantly lower in patients who developed respiratory failure and sepsis, compared with patients who did not develop these complications (p =.02 and p=.015, respectively).Admission plasma concentration of Gc-globulin is lower in patients who develop organ dysfunction and sepsis after traumatic injury. These data, combined with the work of others, support the hypothesis that actin release and depletion of the extracellular actin scavenger system proteins are associated with, and may contribute in part to, the complications of sepsis and organ dysfunction, particularly respiratory failure and thrombocytopenia.

Fulminant hepatic failure (FHF) is often complicated by high intracranial pressure (ICP) and fatal brain damage. In this study, we determined if a rise in [glutamate]ec and [lactate]ec preceded surges of high ICP in patients with FHF (median age, 42; range, 20-55 years; 7 women; 3 men) by inserting a microdialysis catheter into the brain-cortex together with an ICP catheter. The microdialysis catheter was perfused with artificial cerebrospinal-fluid at a rate of 0.3 microL/min. Dialysate was collected approximately every 30 minutes or when ICP increased. A total of 352 microdialysis samples were collected during a median of 3 days and allowed for approximately 1,760 bedside analyses of the collected dialysate. In 5 patients that later developed surges of high ICP, the initial values of [glutamate]ec and [lactate]ec were 2 to 5 times higher compared with patients with normal ICP. [Glutamate]ec then tended to vanish with time in both groups of patients. An increase in [glutamate]ec did not precede high ICP in any of the cases. In contrast, [lactate]ec was high throughout the study in the high ICP group and increased further before surges of high ICP. We conclude that in patients with FHF, cerebral [glutamate]ec and [lactate]ec are elevated. However, the elevated [glutamate]ec is not correlated to high ICP. In contrast, elevations in [lactate]ec preceded surges of high ICP. In conclusion, accelerated glycolysis with lactate accumulation is implicated in vasodilatation and high ICP in patients with FHF. The data suggest that bedside cerebral microdialysis is a valuable tool in monitoring patients with FHF and severe hyperammonemia.

This report describes a case of syncope with an initial ECG that showed ST-segment elevation in the right precordial leads suggestive of Brugada syndrome. Procainamide infusion induced a significant increase in the ST-segment abnormalities, further increasing the suspicion for this syndrome. Cardiac catheterization showed lesions in the proximal left anterior descending artery and distal right coronary artery. Following percutaneous coronary intervention at these sites, the ST-segment abnormalities resolved and a repeat procainamide challenge was negative. Electrophysiological study did not provoke any ventricular arrhythmias. Silent myocardial ischemia may result in ECG changes that resemble those seen in patients with Brugada syndrome.

A plasma acetaminophen (INN, paracetamol) half-life of more than 4 hours has been correlated with hepatotoxicity in acetaminophen overdosing not treated with an antidote. Acetaminophen half-life has not been studied in patients receiving the antidote N -acetylcysteine.Prospectively, 112 patients with acetaminophen overdosage all treated with intravenous N -acetylcysteine were studied. A minimum of 2 plasma acetaminophen values20 micromol/L were available for calculation of acetaminophen half-life, assuming first-order kinetics.Overall, the median acetaminophen half-life was 5.4 hours (range, 0.8-119.7 hours). Forty-eight patients with no or little hepatotoxicity (ALT1000 U/L), 43 patients with hepatotoxicity without encephalopathy, and 21 patients with hepatotoxicity and encephalopathy had acetaminophen half-lives of 3.0 hours (range, 0.8-10.0 hours), 6.4 hours (range, 1.3-19.0 hours), and 18.4 hours (range, 4.6-119.7 hours), respectively (P.001). An acetaminophen half-life4 hours was observed in 71 patients, and 56 of those (79%) had hepatotoxicity (ALT1000 U/L or coma). Thirty-three of 41 patients (81%) with an acetaminophen half-life4 hours had no hepatotoxicity. A receiver operating characteristic curve analysis showed that an acetaminophen half-life of 5.5 hours provided better discrimination; hepatotoxicity was therefore present in 49 of 54 patients with an acetaminophen half-life5.5 hours (positive predictive value, 91%) and in 15 of 58 patients with a half-life below this limit (negative predictive value, 74%) despite treatment with N -acetylcysteine.Acetaminophen half-life correlates well with the degree of liver damage in patients treated with the antidote N-acetylcysteine. Longer half-lives reflect a greater toxic effect on the liver.

We evaluated whether the increase in blood lactate with intense exercise is influenced by a low hepatosplanchnic blood flow as assessed by indocyanine green dye elimination and blood sampling from an artery and the hepatic vein in eight men. The hepatosplanchnic blood flow decreased from a resting value of 1.6 ± 0.1 to 0.7 ± 0.1 (SE) l/min during exercise. Yet the hepatosplanchnic O2uptake increased from 67 ± 3 to 93 ± 13 ml/min, and the output of glucose increased from 1.1 ± 0.1 to 2.1 ± 0.3 mmol/min ( P < 0.05). Even at the lowest hepatosplanchnic venous hemoglobin O2 saturation during exercise of 6%, the average concentration of glucose in arterial blood was maintained close to the resting level (5.2 ± 0.2 vs. 5.5 ± 0.2 mmol/l), whereas the difference between arterial and hepatic venous blood glucose increased to a maximum of 22 mmol/l. In arterial blood, the concentration of lactate increased from 1.1 ± 0.2 to 6.0 ± 1.0 mmol/l, and the hepatosplanchnic uptake of lactate was elevated from 0.4 ± 0.06 to 1.0 ± 0.05 mmol/min during exercise ( P < 0.05). However, when the hepatosplanchnic venous hemoglobin O2 saturation became low, the arterial and hepatosplanchnic venous blood lactate difference approached zero. Even with a marked reduction in its blood flow, exercise did not challenge the ability of the liver to maintain blood glucose homeostasis. However, it appeared that the contribution of the Cori cycle decreased, and the accumulation of lactate in blood became influenced by the reduced hepatosplanchnic blood flow.

Liver damage activates processes aimed at repairing damage; simultaneously, liver functions required for survival must be maintained. The expression of genes responsible for both in rat models of lethal (lipopolysaccharide, 90% hepatectomy, and d-galactosamine) and nonlethal (turpentine, 70% hepatectomy, and acetaminophen) liver damage and stress was measured at 3, 6, 12, and 24 h after the intervention and quantitated as the area between the control curves and the test curves (AUC). The expression of genes for cell division and remodeling was upregulated most in the lethal models. The expression of most liver-specific function genes was reduced. Positive AUC was found for ARG, ASL, CPT1, Mdr1b, Mdr2, and PEPCK. It is concluded that a high expression of genes for repair of liver damage is associated with reduced expression of genes for several liver-specific functions, possibly reflecting a limited capacity for transcriptional activity. Maintained or increased expression of selected function genes indicates that the corresponding functions have high priority. The liver sustains metabolic homeostasis ensuring that other organs in the body function normally. Simultaneously, the processes required for the integrity of its own structure and function are maintained as a result of regulated expression of the genes that produce the proteins needed to perform both set of functions.

Cyclosporine A and sirolimus are used alone or in combination as immunosuppressants in organ transplantation. To elucidate hepatic side effects, we examined hepatic mRNA of proteins involved in biliary and hepatocellular transport of drugs, formation of glutathione (GSH) and drug metabolising cytochrome P-450 enzymes (CYPs) in rats treated orally for 2 weeks with cyclosporine A (15 mg/kg/day), sirolimus (0.4 mg/kg/day), their combination (same doses), or vehicle. Liver function tests (alanine aminotransferase, alkaline phosphatase, gamma-glutamyl transferase and bilirubin) in blood were then analysed as were hepatic mRNA levels of canalicular transport proteins (Mrp2, Bsep, Mdr1b and Mdr2), sinusoidal transport proteins (Ntcp, Oatp1 and Oatp2), GSH related enzymes (gamma-glutamylcysteine synthetase light (GCSlc) and heavy (GCShc) chain subunits and glutathione-S-transferase) and CYPs (CYP3A9, CYP1A2, CYP2E1 and CYP2BI/II). Cyclosporine A caused moderate cholestatic changes in liver enzymes, which was synergistically exacerbated by sirolimus. The data suggest that the underlying mechanisms behind cholestasis were not totally identical in the different treatment regimens. Cholestasis secondary to cyclosporine A could be related to reduction in mRNA expression of GSH synthesising enzymes and Mrp2, leading to reduced protection against oxidative stress and reduced bile acid-independent bile flow. After sirolimus treatment, Mrp2 mRNA was also reduced together with reduced levels of most CYPs and increased Oatp2, possibly leading to accumulation of toxic metabolites in the hepatocytes. The enhanced cholestatic effect of the combination treatment could be related to reduced GSH synthesising enzymes and even more pronounced reduction in Mrp2 mRNA and increase of Oatp2 mRNA.

We describe the occurrence of Mahaim syndrome in a mother and her son. The occurrence of such a rare disorder in two members of a family is noteworthy, has not been reported before, and suggests the possibility of genetic transmission. A genetic transmission of supraventricular tachycardia has been described only in rare cases for the Wolff‐Parkinson‐White syndrome. No such data is available for the Mahaim syndrome. A.N.E. 2001; 6(3):272–275

Objective: Actin is the dominating intracellular protein and is released to the circulation after tissue injury. Gc-globulin is one of the plasma proteins responsible for removal of actin from the circulation. Recent studies have shown that the level of Gc-globulin is reduced shortly after trauma. Serial changes in Gc-globulin after severe injury have not been studied so far and could provide additional information about the role of Gc-globulin in the pathophysiological response to trauma. Design: Prospective, observational. Setting: Surgical intensive care unit in a university hospital. Patients: Thirty-eight patients were included in the study: 12 women and 26 men with a median age of 38 years (range 19–86) and a median Injury Severity Score (ISS) of 18 (range 6–45). Seven patients died, on day 5, 8, 8, 10, 10, 13 and 21, respectively. Interventions: None. Measurements and main results: The serum concentration of Gc-globulin (Gctotal) and the percentage of Gc-globulin bound to actin (Gc%complexed) were measured daily for 1 week using rocket immunoelectrophoresis. Concentrations of free Gc-globulin (Gcfree) and Gc-globulin bound to actin (Gcbound) were calculated from these analytical results. The concentration of Gctotal and Gccomplexed correlated significantly (r=–0.99, p

Transarterial chemoembolization (TACE) is used as palliative treatment of hepatocellular carcinoma (HCC). Most publications are from HCC patient populations where viral hepatitis is the primary cause of liver disease. In the Nordic countries, most patients have either alcohol-induced cirrhosis or are noncirrhotic. The aim of this single-center study was to evaluate patient characteristics, survival, and side effects of TACE in a Danish referral center for HCC treatment.Fifty-nine consecutive patients with HCC, treated with TACE, either chemoembolization with drug-eluting beads or conventional-TACE with Lipiodol, were included in the study. Their medical records were retrospectively reviewed, computed tomography images analyzed, and biochemical markers recorded. The primary endpoint was overall survival. Analyses were by intention to treat.Thirty-five patients (59 %) had HCC on a background of liver cirrhosis most often caused by alcohol (60 % of cirrhotics or 35 % overall). Before the first chemoembolization, the patients had a median Child-Pugh score of 6 (5-7) and a median MELD score of 10 (6-21). Median survival after chemoembolization was 18.9 months (13.1-24.7). TACE patients were hospitalized for an average of 3 days (2-30). Prolonged stay was most often due to side effects-eg. pain (31 %), fever (14 %), nausea (10 %), and infection (10 %). Thirty-three patients (56 %) did not have any side effects.In this cohort, we observed an acceptable survival following TACE without significant side effects.

The calculated fraction of receptor ligands available for blood–brain barrier passage in vivo (favail) may differ from in vitro (feq) measurements. This study evaluates the protein–ligand interaction for iomazenil and flumazenil in rats by comparing feq and favail. Repeated measurements of blood–brain barrier permeability for two benzodiazepine antagonists were performed in 44 rats by the double-indicator technique. Cerebral blood flow was measured by intracarotid Xe-injection. The apparent permeability–surface product (PSapp) was measured while CBF or bolus composition was changed. Comparison of PSapp obtained in the absence and presence of 5% albumin in the injectate yielded favail, whereas feq was measured by equilibrium dialysis. Iomazenil and flumazenil favail was 62% and 82%, respectively, whereas feq was significantly lower, 42% and 61%. The PSapp for iomazenil and flumazenil increased significantly by 89% and 161% after relative CBF increases of 259% and 201%, respectively. The results demonstrate that application of feq in neuroreceptor studies underestimates the plasma input function to the brain. Model simulations render possible that the differences between favail and feq as well as the effect of CBF on PSapp can be caused by capillary heterogeneity.

Background: Actin is the dominating protein in mammalian cells. Release of excessive amounts of actin into the circulation may result in a condition resembling multiple organ failure. The purpose of this study was to determine if admission levels of Gc-globulin can predict survival after multiple trauma. Also, we wanted to compare the predictive ability of Gc-globulin with that of the TRISS–Like scoring system. Methods: Fifty-seven patients with a median ISS 18 (16–75) were included. All patients had a blood sample taken median 42 min after the injury (19–110 min). Serum Gc-globulin was measured by rocket immunoelectrophoresis. Results: On admission, all patients had significantly reduced levels of Gc-globulin compared with normal controls. Gc-globulin was significantly higher in the group of survivors (n=41), compared with non-survivors (n=16). Median 237 mg/l vs. 188 mg/l (P

BACKGROUND: Arterial hypotension occurs frequently in patients with acute liver failure (ALF). Treatment with epinephrine and norepinephrine in patients with ALF has been associated with a decrease in whole-body (systemic) oxygen consumption. We aimed to investigate the effect of increasing blood pressure with dopamine on whole-body (systemic), splanchnic, and lower extremity hemodynamics and oxygen consumption in patients with acute liver failure and hepatic encephalopathy grade III or IV. METHODS: In seven patients with ALF cardiac output (CO) was measured with the thermodilution technique, and hepatic blood flow (HBF) was estimated with infusion of sorbitol as test compound, liver vein catheterization, and calculations on the basis of Fick's principle. Lower-extremity blood flow was measured with strain-gauge plethysmography. RESULTS: During infusion of dopamine (5 +/- 2 microg kg(-1) min(-1)) mean arterial pressure (MAP) increased from 68 +/- 5 to 85 +/- 8 mmHg. CO increased from 6.8 +/- 0.8 to 9.0 +/- 2.4 l/min (P < 0.05), systemic oxygen delivery from 45 +/- 7 to 63 +/- 19 mmol/min (P < 0.05), systemic oxygen consumption from 10.2 +/- 2.0 to 11.5 +/- 3.3 mmol/min (NS). HBF increased from 2.2 +/- 0.7 to 2.7 +/- 1.0 l/ min (P < 0.05), splanchnic oxygen delivery from 14.4 +/- 5.3 to 18.5 +/- 7.2 mmol/min (P < 0.01), and splanchnic oxygen consumption decreased from 3.9 +/- 1.1 to 2.9 +/- 0.6 mmol/min (P < 0.05). No significant changes in lower extremity flow and oxygenation variables were found. CONCLUSIONS: The use of dopamine in patients with ALF to increase MAP was associated with increases in systemic and splanchnic oxygen delivery. A concomitant decrease in splanchnic oxygen consumption was observed.

Ventricular Dilatation and DFT. Introduction: Ventricular dilatation has Important electrophysiologic effects, but its effect on ventricular defibrillation threshold (DFT) is unknown. Methods and Results: A fluid-filled, latex balloon was placed in the left ventricular cavity of 19 isolated rabbit hearts. In each experiment, an undilated volume (equivalent to a left ventricular end-diastolic pressure of approximately 0 mmHg) was compared to a dilated volume achieved by adding 1.0 mL of saline (n = 10) or 5% dextrose (n = 9) to the intracavitary balloon. Left ventricular effective refractory period (ERP) and DFT were determined at each volume. Defibrillation was attempted with a monophasic shock delivered between a patch electrode positioned over the posterior left ventricle (cathode) and a metallic aortic cannula (anode). DFT was determined using a modified “down/up” protocol with 10-V steps. Ventricular dilatation increased the left ventricular end-diastolic pressure from 0 ± 0.5 mmHg to 35 ± 3 mmHg (P < 0.001), decreased the average left ventricular ERP 15% (from 116 ± 3 msec to 99 ± 3 msec; P < 0.001), and increased the average DFT 30% (from 96 ± 4 V to 125 ± 7 V; P < 0.001). In one third of experiments, the dilated DFT was ≥ 150% of the DFT at zero volume. The mechanism of the observed increase in DFT is unknown but may be related to the decrease in refractoriness observed with ventricular dilatation. Conclusion: Acute ventricular dilatation in this model increased DFT an average of 30%, an effect not previously described. This observation may have implications for patients with implantable cardioverter defibrillators.

Studies have shown decreased cerebral oxygen metabolism (CMRO2) and blood flow (CBF) in patients with cirrhosis with hepatic encephalopathy (HE). It remains unclear, however, whether these disturbances are associated with HE or with cirrhosis itself and how they may relate to arterial blood ammonia concentration and cerebral metabolic rate of blood ammonia (CMRA). We addressed these questions in a paired study design by investigating patients with cirrhosis during and after recovery from an acute episode of HE type C. CMRO2, CBF, and CMRA were measured by dynamic positron emission tomography (PET)/computed tomography (CT). Ten patients with cirrhosis were studied during an acute episode of HE; nine were reexamined after recovery. Nine patients with cirrhosis with no history of HE served as controls. Mean CMRO2 increased from 0.73 μmol oxygen/mL brain tissue/min during HE to 0.91 μmol oxygen/mL brain tissue/min after recovery (paired t test; P 0.30); both values were higher than in the control patients (both P < 0.05). Conclusion: The low values of CMRO2 and CBF observed during HE increased after recovery from HE and were thus associated with HE rather than the liver disease as such. The changes in CMRO2 and CBF could not be linked to blood ammonia concentration or CMRA. (HEPATOLOGY 2013)

Summary. We studied a large Swiss family with dominantly inherited hereditary spherocytosis and band 3 (anion exchanger 1, AE1) deficiency. Band 3 cDNA was analysed by single-strand conformation polymorphism analysis and nucleotide sequencing. A new point mutation was found: G771D (GGC→GAC). This change was present in all eight investigated patients but absent in four healthy members of the family. It is located at a highly conserved position in the middle of transmembrane segment 11, introducing a negative charge in a stretch of 16 apolar or neutral residues. None of the six amino-acid substitutions already known in this region as being associated with band 3 deficiency were recorded. To rule out any major transcriptional or post-transcriptional defect, we evaluated the amount of band 3 mRNA by RNase mapping using a band 3-protein 4.1 chimaeric probe. Similar mRNA amounts were present in patients and controls. Our results strengthen the view that some amino-acids, that are well conserved throughout the AE family, may be crucial for the insertion and/or the stabilization of band 3 within the lipid bilayer. At the present time, most of the mutations altering such residues are located in the C-terminal region of band 3.

Background The cirrhosis complications hepatic encephalopathy, ascites, and variceal bleeding increase mortality but develop in random sequence. Therefore prognoses based on the presence or absence of these clinical complications are inherently inaccurate, and other determinants of the clinical course should be identified. Here we present our study of patho-etiological factors that may be causally involved in the development of specific complications to alcoholic cirrhosis; it was based on a model of cirrhosis pathophysiology encompassing hepatic metabolic capacity, continued alcohol consumption, and circulatory dysfunction. Methods We followed a Danish community-based cohort of 466 patients with alcoholic cirrhosis. Stratified Cox regression was used to examine the effects of GEC (a measure of hepatic metabolic capacity), alcohol consumption, and plasma sodium concentration (a measure of circulatory dysfunction) on the hazard rates of first-time hepatic encephalopathy, first-time ascites, first-time variceal bleeding, and mortality. We adjusted for confounding by comorbidity, gender, and age. Data on risk factors and confounders were updated during follow-up. Results A low GEC increased the risk of first-time hepatic encephalopathy (hazard ratio [HR] 1.21 per 0.1 mmol/min GEC loss, 95% CI 1.11-1.31), but was unassociated with other adverse events. Alcohol consumption increased the risk of first-time ascites (HR 3.18, 95% CI 1.19-8.47), first-time variceal bleeding (HR 2.78, 95% CI 1.59-4.87), and mortality (HR 2.45, 95% CI 1.63-3.66), but not the risk of first-time hepatic encephalopathy. Hyponatremia increased the risk of all adverse events. Conclusions Reduced hepatic metabolic capacity, alcohol consumption, and hyponatremia were causally involved in the development of specific complications to alcoholic cirrhosis.

BACKGROUND AND AIM Patients with cystic fibrosis (CF) have low levels of n-3 long-chain polyunsaturated fatty acids (n-3 LCPUFA) in plasma or red blood cells (RBC), as also seen in other chronic and acute liver diseases. The differences may be more pronounced in CF transmembrane conductance regulator protein (CFTR)-regulated tissues such as granulocytes, monocytes, and lymphocytes. The aim of the present study was to investigate whether patients with CF-related liver disease have lower n-3 LCPUFA level than patients with CF without liver disease. METHODS Twenty patients with known CF-related liver disease were matched with 20 CF patients without. Blood samples were analysed for liver biochemistry and haematology. Granulocytes, mononuclear cells, and RBC were separated by density gradient centrifugation, and fatty acid composition was measured by gas chromatography. Hepatic ultrasound was scored according to Williams et al. Hepatic transit time (HTT) was measured with the ultrasound contrast agent SonoVue. RESULTS No significant differences were seen in either n-6 or n-3 LCPUFAs in any cell line when the 2 groups were compared. In a multiple regression analysis including HTT, age, Pseudomonas aeruginosa infection, diabetes mellitus, treatment with ursodeoxycholic acid, forced expiratory volume in 1 second (% of predicted value), and Williams' ultrasound scoring scale, only n-3 LCPUFA docosahexaenoic acid in mononuclear cell membranes was positively associated with HTT (P = 0.02). The arachidonic acid/docosahexaenoic acid ratio within the mononuclear cells was negatively associated with both HTT (P = 0.003) and Williams' ultrasound scoring scale (P = 0.03). For RBC-LCPUFAs, no significant associations were seen. CONCLUSIONS These findings indicate that in patients with CF, the degree of liver disease was negatively associated with LCPUFA n-3 levels in CFTR-expressing white blood cells but unrelated to those levels in CFTR-negative RBC.

The goal of this study was to examine the effects of a single oral dose of 300,000 international units of either ergocalciferol (D₂) or cholecalciferol (D₃) on the plasma levels of 25-hydroxyvitamin D in patients with alcoholic liver cirrhosis.Inclusion criteria for this study were diagnosis of alcoholic liver cirrhosis and plasma levels of 25-hydroxyvitamin D less than 25 nmol/l. At baseline, patients were divided into Child-Pugh groups A, B, or C and were given one oral dose of 300,000 international units of ergocalciferol (D₂ group, N=23) or cholecalciferol (D₃ group, N=13). Plasma concentrations of 25(OH) vitamin D and vitamin D-binding protein were measured on days 0, 7, 30, and 90.On days 7 and 30, patients from the D₃ group had higher vitamin D levels than patients from the D₂ group (P0.05). On day 7, vitamin D levels were found to correlate with Child-Pugh scores from patients in the D₃ group. For patients in the D₂ group, there was a positive correlation between vitamin D and vitamin D-binding protein as indicated by the area under the concentration versus time curves (Spearmen's ρ=0.64 P0.001).In patients with alcoholic liver cirrhosis, a single oral megadose of cholecalciferol was more effective than ergocalciferol in the treatment of vitamin D deficiency. Severe liver disease and low levels of vitamin D-binding protein were predictors for poor treatment outcomes.

This study describes the clinical presentation and diagnosis in all Danish patients (49, 41 unrelated) with Wilson disease (WND). On the basis of the number of diagnosed patients from 1990–2008, the prevalence was estimated to be 1:49 500. Among routinely used diagnostic tests, none were consistently indicative of WND, with the exception of the 24-h urine-Cu test, which is always outside the normal range. Mutations were identified in 100% of the screened ATP7B alleles (70 unrelated), including five novel mutations: p.1021K; p.G1158V; p.L1304F; IVS20-2A>G; Ex5_6del. In all, 70% of mutations were found in exons 8, 14, 17, 18, and 20. The most frequent mutation, p.H1069Q, comprised 18%. We propose a new and simple model that correlates genotype and age of onset. By assuming that the milder of two mutations is ‘functionally dominant' and determines the age of onset, we classified 25/27 mutations as either severe (age of onset 20 years), and correctly predicted the age of onset in 37/39 patients. This method should be tested in other Wilson populations.

Background & Aims Cirrhosis patients with symptomatic portal hypertension might be effectively treated with a transjugular intrahepatic portosystemic shunt stent (TIPS). The intervention, however, carries a risk of debilitating portosystemic hepatic encephalopathy (HE). HE in cirrhosis might be associated with decreased cerebral blood flow (CBF), and CBF might decrease after TIPS. Methods We measured CBF by [ 15 O]-water positron emission tomography (PET) in 9 nonencephalopathic cirrhosis patients before and median 11 days after the insertion of TIPS. The PET images were co-registered to magnetic resonance images for region-based analysis. Results Pre-TIPS whole-brain CBF varied markedly from very low to high-normal values of 0.28–0.58 mL blood/mL of brain tissue/min. There were no systematic changes in whole-brain or regional CBF after the TIPS treatment ( P > .1). No patient had HE after TIPS. Conclusions Treating portal hypertension by TIPS in patients with advanced cirrhosis and without HE had no effect on their CBF and seemed not to entail a risk of cerebral hypoperfusion.

Indocyanine green is used to estimate liver blood flow rate and hepatic intrinsic clearance. However, its use as a test substance for studies of liver function has been limited by two puzzling kinetic observations: a biexponential plasma decay after bolus injection with an extremely slow late phase and an apparently steadily decreasing clearance value during constant infusion. These observations have been made with spectrophotometric concentration analysis. In anesthetized 30‐to 40‐kg pigs, we examined plasma concentration curves of indocyanine green after intravenous bolus injection and during long‐term infusion. We compared spectrophotometry with high‐pressure liquid chromatography for measurement of plasma indocyanine green concentration. In freshly prepared commercially available indocyanine green, highpressure liquid chromatography could separately measure two fractions, the genuine indocyanine green (97% to 99% of total) and an in vitro degradation product (1% to 3%). Because their spectra were nearly identical, these fractions could not be distinguished by spectrophotometry. After intravenous administration both fractions were identified in the plasma by highpressure liquid chromatography. In the first series (n = 6) 25 mg of indocyanine green was injected intravenously for 5 min. When analyzed by high‐pressure liquid chromatography, the genuine indocyanine green plasma concentration decay was biexponential with rate constants 0.196 ± 0.021 (mean ± S.E.M., n = 6) and 0.0372 ± 0.0064 min. The degradation product of indocyanine green decayed almost monoexponentially, with a rate constant of 0.0093 ± 0.0002 min. With spectrophotometry a biexponential decay was observed with rate constants 0.130 ± 0.012 and 0.0095 ± 0.0001 min. The biexponential decay of indocyanine green after spectrophotometry was the result of codetermination of the two fractions: genuine indocyanine green was responsible for initial phase, and the degradation product of indocyanine green was responsible for the late phase. In the second series (n = 9), indocyanine green was administered as a constant intravenous infusion. From 90 to 240 min the intrinsic hepatic clearance of genuine indocyanine green did not change detectably with time. In contrast, the degradation product of indocyanine green never reached steady‐state concentrations. Because of codetermination of these two indocyanine green fractions, the apparent intrinsic hepatic clearance of indocyanine green estimated from spectrophotometry was steadily decreasing by 8.9% ± 1% per hour of its initial value. At the same time estimation of liver plasma flow rate based on Fick's principle was not affected by the choice of analytical methodology. These observations indicate that high‐pressure liquid chromatography is superior to spectrophotometry for kinetic analysis of indocyanine green elimination. (HEPATOLOGY 1993;18:1504–1515.) Copyright

The kinetics of hepatic removal of protein-bound substances were studied in nine human subjects with various liver diseases by the use of indocyanine green as a model substance. Intrinsic hepatic clearance of indocyanine green was measured by means of a constant infusion of indocyanine green and concentration measurements of indocyanine green in arterial and hepatic venous plasma samples. During the indocyanine green infusion, 1-1.51 of dextran-70 was given whereby a stable dilution of the plasma protein concentration by a factor of 0.6-0.8 was obtained. In each of the subjects, the intrinsic clearance of indocyanine green increased after the protein dilution (range 11-64%). Elimination of ethanol (not protein bound), similarly assessed, was not significantly changed. The traditional hypothesis that unbound clearance (intrinsic clearance divided by the free fraction of the ligand) is independent of protein concentration was refuted since in each of the subjects the protein dilution was followed by a reduction of the unbound clearance of ICG (P0.005, n = 9). We examined whether these observations imply some special mechanism (e.g. a hepatocyte protein receptor) by which the unbound clearance is enhanced by the binding protein(s). The previously developed pseudofacilitation model--describing the effects of ligand-protein diffusion and dissociation in an unstirred plasma layer near the hepatocyte--was extended to the case of a mixture of binding proteins, and parameter-free bounds were derived to predict the response of intrinsic clearance to protein dilution. The observed changes of the intrinsic clearance values did not violate these bounds (P0.002, n = 9). Thus no facilitating mechanisms are necessary to account for the observed deviations from the traditional hypothesis.

Magnesium is an essential element for the proper functioning of many enzyme systems, and numerous studies indicate that alterations in magnesium homeostasis are associated with cardiovascular disease. Epidemiologic studies have correlated an increased incidence of ischemic heart disease and myocardial infarction with a decrease in drinking water magnesium concentrations in certain geographic areas.’ An animal study2 suggested a link between magnesium deficiency and the formation of atherosclerotic plaques. Increased peripheral vascular tone and coronary artery spasm were found to correlate with hypomagnesemia in animal models3 Myocardial cells in patients who died from a myocardial infarction had a lower magnesium content than myocardial cells in a comparison group of patients who died from trauma.4 Lowered serum magnesium concentrations were found in patients with acute myocardial infarction and were thought to correlate with the risk of arrhythmias and death.” Magnesium was found to be therapeutically beneficial in the treatment of certain ventricular arrhythmias, specifically torsade de pointes and arrhythmias caused by digoxin toxicity.6 Studies such as these suggest that hypomagnesemia may be a significant factor in acute and chronic coronary artery disease. This review examines the rationale for and the effects of supplemental magnesium administration in the treatment of acute myocardial infarction. Magnesium homeostasis and biologic role. In healthy adults, approximately 300 mg of magnesium is ingested daily. Approximately 200 mg is excreted in the feces and 100 mg is excreted in the urine. The most common causes of magnesium deficiency are excessive urinary loss because of diuretics, diabetes, or al

Background Despite its biologic plausibility, the association between liver function and mortality of patients with chronic liver disease is not well supported by data. Therefore, we examined whether the galactose elimination capacity (GEC), a physiological measure of the total metabolic capacity of the liver, was associated with mortality in a large cohort of patients with newly-diagnosed cirrhosis. Methods By combining data from a GEC database with data from healthcare registries we identified cirrhosis patients with a GEC test at the time of cirrhosis diagnosis in 1992–2005. We divided the patients into 10 equal-sized groups according to GEC and calculated all-cause mortality as well as cirrhosis-related and not cirrhosis-related mortality for each group. Cox regression was used to adjust the association between GEC and all-cause mortality for confounding by age, gender and comorbidity, measured by the Charlson comorbidity index. Results We included 781 patients, and 454 (58%) of them died during 2,617 years of follow-up. Among the 75% of patients with a decreased GEC ( Conclusion Among patients with newly-diagnosed cirrhosis and a decreased GEC, the GEC was a strong predictor of short- and long-term all-cause and cirrhosis-related mortality. These findings support the expectation that loss of liver function increases mortality.

Udgivelsesdato: 2008-Oct-28 AIM: To investigate if sildenafil increases splanchnic blood flow and changes the hepatic venous pressure gradient (HVPG) in patients with cirrhosis. Phosphodiesterase type-5 inhibitors are valuable in the treatment of erectile dysfunction and pulmonary hypertension in patients with end-stage liver disease. However, the effect of phosphodiesterase type-5 inhibitors on splanchnic blood flow and portal hypertension remains essentially unknown. METHODS: Ten patients with biopsy proven cirrhosis (five females/five males, mean age 54 +/- 8 years) and an HVPG above 12 mmHg were studied after informed consent. Measurement of splanchnic blood flow and the HVPG during liver vein catheterization were done before and 80 min after oral administration of 50 mg sildenafil. Blood flow was estimated by use of indocyanine green clearance technique and Fick's principle, with correction for non-steady state. RESULTS: The plasma concentration of sildenafil was 222 +/- 136 ng/mL 80 min after administration. Mean arterial blood pressure decreased from 77 +/- 7 mmHg to 66 +/- 12 mmHg, P = 0.003, while the splanchnic blood flow and oxygen consumption remained unchanged at 1.14 +/- 0.71 L/min and 2.3 +/- 0.6 mmol/min, respectively. Also the HVPG remained unchanged (18 +/- 2 mmHg vs 16 +/- 2 mmHg) with individual changes ranging from -8 mmHg to +2 mmHg. In seven patients, HVPG decreased and in three it increased. CONCLUSION: In spite of arterial blood pressure decreases 80 min after administration of the phosphodiesterase type-5 inhibitor sildenafil, the present study could not demonstrate any clinical relevant influence on splanichnic blood flow, oxygen consumption or the HVPG.

Udgivelsesdato: 2008-Oct-30 BACKGROUND & AIMS: It is unclear whether patients with hepatic encephalopathy (HE) have disturbed brain oxygen metabolism and blood flow. METHODS: We measured cerebral oxygen metabolism rate (CMRO(2)) by using (15)O-oxygen positron emission tomography (PET), and cerebral blood flow (CBF) by using (15)O-water PET in 6 patients with liver cirrhosis and an acute episode of overt HE, 6 cirrhotic patients without HE, and 7 healthy subjects. RESULTS: Neither whole-brain CMRO(2) nor CBF differed significantly between cirrhotic patients without HE and healthy subjects, but were both significantly reduced in cirrhotic patients with HE (P < .01). CMRO(2) was 0.96 +/- 0.07 mumol oxygen/mL brain tissue/min (mean +/- SEM) in cirrhotic patients with HE, 1.34 +/- 0.08 in cirrhotic patients without HE, and 1.35 +/- 0.05 in healthy subjects, and CBF was 0.29 +/- 0.01 mL blood/mL brain tissue/min in patients with HE, 0.47 +/- 0.02 in patients without HE, and 0.49 +/- 0.03 in healthy subjects. CMRO(2) and CBF were correlated, and both variables correlated negatively with arterial ammonia concentration. Analysis of regional values, using individual magnetic resonance co-registrations, showed that the reductions in CMRO(2) and CBF in patients with HE were essentially generalized throughout the brain. CONCLUSIONS: The observations imply that reduced cerebral oxygen consumption and blood flow in cirrhotic patients with an acute episode of overt HE are associated with HE and not cirrhosis as such, and that the primary event in the pathogenesis of HE could be inhibition of cerebral energy metabolism by increased blood ammonia.

Changes due to biventricular pacing have been documented by shortening of QRS duration and echocardiography. Compared to normal ventricular activation, the presence of left bundle branch block (LBBB) results in a significant change in cardiac cycle time intervals. Some of these have been used to quantify the underlying cardiac dyssynchrony, assess the effects of biventricular pacing, and guide programming of ventricular pacing devices. This study evaluates a simple noninvasive method using accelerometers attached to the skin to measure cardiac time intervals in biventricularly paced patients.Ten patients with biventricular pacemakers previously implanted for congestive heart failure were paced in the AAI mode, then in atrioventricular (AV) sequential mode from the right and left ventricles followed by biventricular pacing. Simultaneous recordings were obtained by 2D, Doppler echocardiography as well as by accelerometers. Similar recordings were obtained from 10 gender, aged matched, normal controls during sinus rhythm.Compared to normals, heart failure patients paced in AAI mode had prolonged isovolumetric contraction time (IVCT), shorter ventricular ejection time (LVET), and prolonged isovolumetric relaxation (IVRT). With biventricular pacing the IVCT decreased, but the LVET and IVRT did not change significantly. There was excellent correlation between the echo and accelerometer-measured intervals.Shortening of the IVCT measured by an accelerometer is a consistent time interval change due to biventricular pacing that probably reflects more rapid acceleration of left ventricular ejection. The accelerometer may be useful to assess immediate efficacy of biventricular pacing during device implantation and optimize programmable time intervals such as AV and interventricular (VV) delays.

Pruritus is a key symptom of hepatic disease. In severe cases, this symptom ruins the patient's quality of life. Most likely it is caused by a protein-bound bile acid (metabolite) that stimulates opioid receptors in the brain. Symptomatic treatments that can reduce pruritus in selected patients include opioid receptor antagonists, biliary diversion, cholestyramine, ursodeoxycholic acid, rifampicin and phenobarbitone. Plasmapheresis or albumin dialysis may be useful when other treatment fails.