ABSTRACT
Minimal hepatic encephalopathy (MHE) is common in liver cirrhosis and is identified by psychometric tests. The portosystemic hepatic encephalopathy score (PHES) is the most widely used and serves as an inter-study comparator. PHES has not been standardised for use in the Danish population, where German normal values have been applied until now based on the notion that the populations are comparable. This study aimed to evaluate if German PHES normal values can be applied in the Danish population and establish Danish normal values if needed. 200 Danish and 217 German healthy persons underwent Number Connection Test A and B (NCT), Line Tracing Test (LTT), Digit Symbol Test (DST), and Serial Dotting Test (SDT), and based on performance, PHES was calculated. German and Danish PHES performance declined with age in all subtests but more rapidly in Danes. Both German and Danish norms were impacted by gender and education, but to a different extent in the single tests of the test battery. Accordingly, there was a need for specific Danish normal values, which are presented here. Applying the new Danish normal values instead of the German in patients with cirrhosis yielded a lower percentage of out-of-norm performances (58% vs. 66%) and, hence, a lower prevalence of MHE. Danes and Germans perform differently on PHES, and therefore, normal German values cannot be used in Danish patients. Danish normal values are presented here and yield a lower number of 'out of norm' performances.
Subject(s)
Hepatic Encephalopathy , Humans , Hepatic Encephalopathy/diagnosis , Hepatic Encephalopathy/psychology , Hepatic Encephalopathy/epidemiology , Male , Denmark/epidemiology , Female , Germany/epidemiology , Middle Aged , Adult , Aged , Neuropsychological Tests , Young Adult , Reference Values , Liver Cirrhosis/diagnosis , Psychometrics , Cross-Cultural ComparisonABSTRACT
BACKGROUND & AIMS: Hyperammonaemia is a key pathological feature of liver disease and the primary driver of hepatic encephalopathy (HE). However, the relative roles of increased ammonia production and reduced clearance are poorly understood as is the action of ammonia-targeting drugs for HE. We aimed to quantify whole-body ammonia metabolism in healthy persons and patients with cirrhosis and to validate our method by examining the effects of glycerol phenylbutyrate and lactulose + rifaximin treatment. METHODS: Ten healthy men and ten male patients with cirrhosis were investigated by 90-minute constant ammonia infusion to achieve steady-state plasma ammonia. Whole-body ammonia clearance was calculated as infusion rate divided by steady-state concentration increase and ammonia production was calculated as clearance multiplied by baseline ammonia concentration. Participants were re-investigated after the ammonia-targeting interventions. RESULTS: In healthy persons, ammonia clearance was 3.5 (3.1-3.9) L/min and ammonia production was 49 (35-63) µmol/min. Phenylbutyrate increased clearance by 11% (4-19%, p = 0.009). In patients with cirrhosis, ammonia clearance was 20% lower at 2.7 (2.1-3.3) L/min (p = 0.02) and production was nearly threefold higher at 131 (102-159) µmol/min (p <0.0001). Lactulose + rifaximin reduced production by 20% (2-37%, p = 0.03). The infusion was generally well-tolerated apart from in one hyperammonaemic patient, with cirrhosis and possible bleeding unrelated to the infusion, who developed clinical HE that reverted when infusion was discontinued. CONCLUSIONS: Whole-body ammonia clearance and production may be measured separately using the described technique. This technique identified a lower clearance and a higher production of ammonia in patients with cirrhosis, and showed that phenylbutyrate increases clearance, whereas lactulose + rifaximin reduces production. IMPACT AND IMPLICATIONS: High blood ammonia plays a key role in cirrhosis-related brain dysfunction. However, the relative roles of reduced ammonia clearance and increased ammonia production are poorly understood as is the action of ammonia-targeting treatments. This study presents a relatively simple test to measure ammonia metabolism. By using this test, it was possible to show that patients with cirrhosis exhibit decreased ammonia clearance and increased ammonia production compared to healthy persons, and to quantify the unique effects of different ammonia-targeting treatments. The test described herein may be used to examine a range of questions related to normal physiology, pathophysiology and the mechanisms of action of ammonia-targeting treatments. CLINICAL TRIAL NUMBER: ClinicalTrials.gov (1-16-02-297-20).
Subject(s)
Hepatic Encephalopathy , Hyperammonemia , Humans , Male , Ammonia/metabolism , Hepatic Encephalopathy/drug therapy , Hepatic Encephalopathy/etiology , Hepatic Encephalopathy/metabolism , Hyperammonemia/drug therapy , Hyperammonemia/etiology , Lactulose/therapeutic use , Liver Cirrhosis/complications , Liver Cirrhosis/drug therapy , Phenylbutyrates , Rifaximin/therapeutic useABSTRACT
BACKGROUND AND AIMS: Wilson's disease (WD) is a genetic disease with systemic accumulation of copper that leads to symptoms from the liver and brain. However, the underlying defects in copper transport kinetics are only partly understood. We sought to quantify hepatic copper turnover in patients with WD compared with heterozygote and control subjects using PET with copper-64 (64 Cu) as a tracer. Furthermore, we assessed the diagnostic potential of the method. APPROACH AND RESULTS: Nine patients with WD, 5 healthy heterozygote subjects, and 8 healthy controls were injected with an i.v. bolus of 64 Cu followed by a 90-min dynamic PET scan of the liver and static whole-body PET/CT scans after 1.5, 6, and 20 h. Blood 64 Cu concentrations were measured in parallel. Hepatic copper retention and redistribution were evaluated by standardized uptake values (SUVs). At 90 min, hepatic SUVs were similar in the three groups. In contrast, at 20 h postinjection, the SUV in WD patients (mean ± SEM, 31 ± 4) was higher than in heterozygotes (24 ± 3) and controls (21 ± 4; p < 0.001). An SUV-ratio of hepatic 64 Cu concentration at 20 and 1.5 h completely discriminated between WD patients and control groups (p < 0.0001; ANOVA). By Patlak analysis of the initial 90 min of the PET scan, the steady-state hepatic clearance of 64 Cu was estimated to be slightly lower in patients with WD than in controls (p = 0.04). CONCLUSIONS: 64 Cu PET imaging enables visualization and quantification of the hepatic copper retention characteristic for WD patients. This method represents a valuable tool for future studies of WD pathophysiology, and may assist the development of therapies, and accurate diagnosis.
Subject(s)
Hepatolenticular Degeneration , Hepatolenticular Degeneration/diagnostic imaging , Hepatolenticular Degeneration/genetics , Heterozygote , Humans , Positron Emission Tomography Computed Tomography , Positron-Emission TomographyABSTRACT
BACKGROUND AND AIM: Physical activity confers health benefits in many diseases but remains almost unstudied for cirrhosis. We investigated whether a period of resistance training affects the subsequent long-term risk of hospitalization or mortality among patients with cirrhosis. METHODS: The study includes 39 participants with cirrhosis Child-Pugh class A/B who participated in a prior clinical trial randomized to either resistance training three times per week for 12 weeks or a control group. We gathered data through medical records from trial entry and the following 3 years. The outcomes were time to first hospitalization and all-cause mortality. We used regression models to examine the associations between trial groups and outcomes, adjusting for Child-Pugh class, age, gender, and comorbidity. RESULTS: Nine patients who trained and 15 controls were hospitalized, resulting in a lower risk of first hospitalization in the training group (adjusted subdistribution hazard ratio of 0.40, 95% confidence interval [CI] [0.17, 0.92]; P = 0.03). One patient who trained and six controls died, resulting in a lower all-cause mortality in the training group (adjusted hazard ratio of 0.06, 95% CI [0.01, 0.66]; P = 0.02). CONCLUSION: Twelve weeks of resistance training was associated with a reduced risk of first hospitalization and mortality among patients with cirrhosis Child-Pugh class A/B 3 years after trial entry. The mechanisms of this effect are not identified, and larger studies are warranted.
Subject(s)
Resistance Training , Humans , Follow-Up Studies , Liver Cirrhosis/complications , Fibrosis , Hospitalization , HospitalsABSTRACT
Patients with cirrhosis are prone to electrolyte disorders, including hypokalaemia. The available evidence suggests that hypokalaemia facilitates hyperammonaemia and thus increases the risk for hepatic encephalopathy (HE). In case studies, plasma potassium decrements were followed by plasma ammonia increments and HE progression, which was reversed by potassium supplementation. The explanation to the hyperammonaemia may be that hypokalaemia both stimulates renal ammonia production and reduces hepatic ammonia elimination by urea synthesis. Further, hypokalaemia eases the entrance of the increased ammonia into the central nervous system because the lower potassium ion concentration favours the competition of NH4+ ions for potassium transporters across the blood brain barrier, and because hypokalaemia-induced metabolic alkalosis increases the amount of gaseous ammonia, which freely passes the barrier. Potassium depletion thus seems to be a mechanistic contributor to HE, supporting the clinical notion of routinely correcting low potassium in patients with cirrhosis.
Subject(s)
Hepatic Encephalopathy , Hyperammonemia , Hypokalemia , Humans , Hepatic Encephalopathy/metabolism , Ammonia , Hypokalemia/complications , Hyperammonemia/metabolism , Liver Cirrhosis/complications , Liver Cirrhosis/metabolism , PotassiumABSTRACT
INTRODUCTION: Autoimmune hepatitis (AIH) is a chronic inflammatory liver disease and as such may increase the risk of cancer. We examined cancer risks in a nationwide cohort of patients with AIH. METHODS: This study was based on nationwide Danish healthcare registries. We identified all persons diagnosed with AIH between 1994 and 2018. We included 1805 patients with AIH and 16,617 age- and sex-matched population controls. We estimated cumulative risks of cancers and risk ratios (RRs) between patients and controls. Within the cohort of patients with AIH, we examined the impact of immunosuppressive treatment (IST) and cirrhosis on cancer risks. RESULTS: The 10-year risk of any cancer was 13.6% (95% confidence interval [CI] 11.7-15.6) in patients with AIH with an RR of 1.5 (95% CI 1.3-1.7) compared with controls. Patients with AIH had a 10-year risk of 0.5% (95% CI 0.2-1.1) for hepatocellular carcinoma. The 10-year risk was 1.6% (95% CI 1.0-2.5) for colorectal cancer (RR: 2.1 [95% CI 1.3-3.5]) and 4.0% (95% CI 3.0-5.3) for nonmelanoma skin cancer (RR: 1.8 [95% CI 1.3-2.5]). Among patients with AIH, the risk of cancer was higher for those with cirrhosis (hazard ratio: 1.3 [95% CI 1.0-1.7]), and it also increased 1.05-fold (95% CI 1.0-1.1) for every year the patient was on IST. DISCUSSION: AIH was associated with a 1.5-fold increased 10-year risk of cancer compared with age- and sex-matched controls. Among patients with AIH, the risk of cancer was higher for those with cirrhosis, and it also increased slightly with longer duration of IST.
Subject(s)
Hepatitis, Autoimmune/complications , Neoplasms/epidemiology , Population Surveillance , Risk Assessment/methods , Adult , Aged , Denmark/epidemiology , Female , Follow-Up Studies , Hepatitis, Autoimmune/epidemiology , Humans , Incidence , Male , Middle Aged , Neoplasms/etiology , Risk Factors , Time FactorsABSTRACT
BACKGROUND AND AIMS: Cirrhosis affects hemostasis, but its effects across the spectrum of thromboses remain poorly understood. We examined risks and outcomes of venous and arterial thrombosis. APPROACH AND RESULTS: We used nation-wide Danish health care registries to identify outpatients with cirrhosis and a sex- and age-matched comparison cohort without cirrhosis from the general population. Patients with cirrhosis and comparators were followed until they had a venous thromboembolism (VTE), acute myocardial infarction (AMI), or ischemic stroke (IS) or died. We computed absolute risks and HRs of thrombosis and compared outcomes after thrombosis. We included 5,854 patients with cirrhosis (median Model for End-Stage Liver Disease score, 9; interquartile range, 7-13), and their risk of any of the thrombotic events was 0.8% after 1 year and 6.3% after 10 years. They were more likely than the 23,870 matched comparators to have a VTE (adjusted hazard ratio [aHR], 2.0; 95% CI, 1.5-2.6) or IS (aHR, 1.7; 95% CI, 1.3-2.3), but not AMI (aHR, 0.7; 95% CI, 0.5-0.9). Among patients with cirrhosis, decompensation increased the risk of AMI, but not the other thromboses. Following thrombosis, patients with cirrhosis had higher 90-day mortality than comparators (after VTE: 17% vs. 7%; after AMI: 27% vs. 5%; after IS: 10% vs. 7%) and were less likely to receive antithrombotic treatment. CONCLUSIONS: Patients with cirrhosis had an increased risk of VTE and IS, but not AMI. Among patients with cirrhosis, decompensation increased the risk of AMI, exclusively. Mortality after thrombosis was higher in patients with cirrhosis than in other patients. These findings are relevant for decisions about antithrombotic prophylaxis in patients with cirrhosis.
Subject(s)
End Stage Liver Disease/complications , Liver Cirrhosis/complications , Venous Thromboembolism/epidemiology , Denmark/epidemiology , End Stage Liver Disease/blood , End Stage Liver Disease/diagnosis , End Stage Liver Disease/mortality , Female , Follow-Up Studies , Humans , Kaplan-Meier Estimate , Liver Cirrhosis/blood , Liver Cirrhosis/diagnosis , Liver Cirrhosis/mortality , Male , Middle Aged , Registries/statistics & numerical data , Risk Factors , Severity of Illness Index , Venous Thromboembolism/etiologyABSTRACT
Hepatic encephalopathy (HE) is a frequent and devastating but generally reversible neuropsychiatric complication secondary to chronic and acute liver failure. During HE, brain energy metabolism is markedly reduced and it remains unclear whether this is due to external or internal energy supply limitations, or secondary to depressed neuronal cellular functions - and if so, which mechanisms that are in play. The extent of deteriorated cerebral function correlates to blood ammonia levels but the metabolic link to ammonia is not clear. Early studies suggested that high levels of ammonia inhibited key tricarboxylic acid (TCA) cycle enzymes thus limiting mitochondrial energy production and oxygen consumption; however, later studies by us and others showed that this is not the case in vivo. Here, based on a series of translational studies from our group, we advocate the view that the low cerebral energy metabolism of HE is likely to be caused by neuronal metabolic depression due to an elevated GABAergic tone rather than by restricted energy availability. The increased GABAergic tone seems to be secondary to synthesis of large amounts of glutamine in astrocytes for detoxification of ammonia with the glutamine acting as a precursor for elevated neuronal synthesis of vesicular GABA.
Subject(s)
Hepatic Encephalopathy , Hyperammonemia , Ammonia/metabolism , Brain/metabolism , Energy Metabolism , Glutamine/metabolism , Hepatic Encephalopathy/etiology , Hepatic Encephalopathy/metabolism , Humans , Hyperammonemia/metabolism , Neurons/metabolismABSTRACT
Non-alcoholic fatty liver disease (NAFLD) currently affects 25% of the global adult population. Cognitive impairment is a recently recognised comorbidity impeding memory, attention, and concentration, affecting the patients' activities of daily living and reducing their quality of life. This systematic review provides an overview of the evidence for, and potential pathophysiological mechanisms behind brain dysfunction at a neurobiological level, in preclinical NAFLD. We performed a systematic literature search for animal models of NAFLD studying intracerebral conditions using PubMed, Embase and Scopus. We included studies that reported data on neurobiology in rodent and pig models with evidence of steatosis or steatohepatitis assessed by liver histology. 534 unique studies were identified, and 30 studies met the selection criteria, and were included. Findings of neurobiological changes were divided into five key areas: (1) neuroinflammation, (2) neurodegeneration, (3) neurotransmitter alterations, (4) oxidative stress, and (5) changes in proteins and synaptic density. Despite significant heterogeneity in the study designs, all but one study of preclinical NAFLD reported changes in one or more of the above key areas when compared to control animals. In conclusion, this systematic review supports an association between all stages of NAFLD (from simple steatosis to non-alcoholic steatohepatitis (NASH)) and neurobiological changes in preclinical models.
ABSTRACT
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.
Subject(s)
Hepatolenticular Degeneration , Galactose/metabolism , Hepatolenticular Degeneration/diagnosis , Humans , Liver Cirrhosis , Liver Function TestsABSTRACT
BACKGROUND: Increasing incidence of non-alcoholic fatty liver disease (NAFLD) calls for improved understanding of how the disease affects metabolic liver function. AIMS: To investigate in vivo effects of different NAFLD stages on metabolic liver function, quantified as regional and total capacity for galactose metabolism in a NAFLD model. METHODS: Male Sprague Dawley rats were fed a high-fat, high-cholesterol diet for 1 or 12 weeks, modelling early or late NAFLD, respectively. Each NAFLD group (n = 8 each) had a control group on standard chow (n = 8 each). Metabolic liver function was assessed by 2-[18F]fluoro-2-deoxy-D-galactose positron emission tomography; regional galactose metabolism was assessed as standardised uptake value (SUV). Liver tissue was harvested for histology and fat quantification. RESULTS: Early NAFLD had median 18% fat by liver volume. Late NAFLD had median 32% fat and varying features of non-alcoholic steatohepatitis (NASH). Median SUV reflecting regional galactose metabolism was reduced in early NAFLD (9.8) and more so in late NAFLD (7.4; p = 0.02), both significantly lower than in controls (12.5). In early NAFLD, lower SUV was quantitatively explained by fat infiltration. In late NAFLD, the SUV decrease was beyond that attributable to fat; probably related to structural NASH features. Total capacity for galactose elimination was intact in both groups, which in late NAFLD was attained by increased fat-free liver mass to 21 g, versus 15 g in early NAFLD and controls (both p ≤ 0.002). CONCLUSION: Regional metabolic liver function was compromised in NAFLD by fat infiltration and structural changes. Still, whole liver metabolic function was preserved in late NAFLD by a marked increase in the fat-free liver mass.
Subject(s)
Non-alcoholic Fatty Liver Disease , Animals , Rats , Male , Non-alcoholic Fatty Liver Disease/pathology , Galactose/metabolism , Rats, Sprague-Dawley , Liver/pathology , Diet, High-Fat/adverse effectsABSTRACT
BACKGROUND: The risk factors for hepatic hydrothorax are unknown. METHODS: We used data from three randomized trials of satavaptan treatment in patients with cirrhosis and ascites followed for up to 1 year. We excluded patients with previous hepatic hydrothorax or other causes for pleural effusion. The candidate risk factors were age, sex, heart rate, mean arterial pressure, diuretic-resistant ascites, a recurrent need for paracentesis, diabetes, hepatic encephalopathy, International Normalized Ratio, creatinine, bilirubin, albumin, sodium, platelet count, use of non-selective beta-blockers (NSBBs), spironolactone, furosemide, proton pump inhibitors, and insulin. We identified risk factors using a Fine and Gray regression model and backward selection. We reported subdistribution hazard ratios (sHR) for hepatic hydrothorax. Death without hepatic hydrothorax was a competing risk. RESULTS: Our study included 942 patients, of whom 41 developed hepatic hydrothorax and 65 died without having developed it. A recurrent need for paracentesis (sHR: 2.55, 95% CI: 1.28-5.08), bilirubin (sHR: 1.18 per 10 µmol/l increase, 95% CI: 1.09-1.28), diabetes (sHR: 2.49, 95% CI: 1.30-4.77) and non-use of non-selective beta-blockers (sHR: 2.27, 95% CI: 1.13-4.53) were risk factors for hepatic hydrothorax. Development of hepatic hydrothorax was associated with a high mortality-hazard ratio of 4.35 (95% CI: 2.76-6.97). CONCLUSIONS: In patients with cirrhosis and ascites, risk factors for hepatic hydrothorax were a recurrent need for paracentesis, a high bilirubin, diabetes and non-use of NSBBs. Among these patients with cirrhosis and ascites, development of hepatic hydrothorax increased mortality fourfold.
Subject(s)
Diabetes Mellitus , Hydrothorax , Adrenergic beta-Antagonists , Ascites/etiology , Ascites/therapy , Bilirubin , Cohort Studies , Humans , Hydrothorax/etiology , Hydrothorax/therapy , Liver Cirrhosis/complications , Liver Cirrhosis/therapy , Risk FactorsABSTRACT
INTRODUCTION AND OBJECTIVES: Spontaneous bacterial peritonitis (SBP) is a frequent complication to cirrhosis with an unclear long-term prognosis. We aimed to examine its effect on mortality in two independent patient cohorts. PATIENTS AND METHODS: We used Danish healthcare data on cirrhosis patients with a first-time paracentesis in 2000-2014 and data from three randomized controlled trials on satavaptan treatment of ascites conducted in 2006-2008. We used the Kaplan-Meier method to estimate cumulative mortality, and Cox regression to compare the confounder-adjusted mortality hazard for patients with vs. without SBP. RESULTS: In the Danish Healthcare Cohort, we included 1.282 patients of whom 133 (10.4%) had SBP. The SBP patients' cumulative 4-month mortality was 51.2% (95% CI: 43.0-59.9%) vs. 34.7% (95% CI: 32.0-37.6) in those without SBP. The SBP patients' confounder-adjusted mortality hazard was 1.54-fold higher (95% CI: 1.18-2.00) in the four months after paracentesis, but was not increased thereafter (confounder-adjusted mortality hazard 1.02, 95% 0.72-1.46). In the satavaptan trial data of 1,198 cirrhosis patients with ascites, the 93 patients with SBP had a cumulative 4-month mortality of 38.6% (95% CI: 29.3-49.7) compared with 11.4% (95% CI: 8.5-15.2) in those without. The SBP patients' confounder-adjusted mortality hazard ratio was 3.86 (95% CI: 2.44-6.12) during the first four months, and was 1.23 (95% CI: 0.54-2.83) thereafter. CONCLUSIONS: In both cohorts of patients with cirrhosis, an SBP episode had a high short-term mortality compared to patients without SBP, and had no lasting effect on the long-term mortality.
Subject(s)
Bacterial Infections , Peritonitis , Ascites/etiology , Bacterial Infections/diagnosis , Bacterial Infections/drug therapy , Humans , Liver Cirrhosis/complications , Liver Cirrhosis/diagnosis , Peritonitis/diagnosis , Peritonitis/drug therapy , Prognosis , Randomized Controlled Trials as Topic , Risk FactorsABSTRACT
Hepatic encephalopathy (HE) is cerebral dysfunction caused by liver failure and inflicts 30-40% of patients with liver cirrhosis during their disease course. Clinically manifest HE is often preceded by minimal HE (MHE) - a clinically undetectable cognitive disturbance closely associated with loss of quality of life. Accordingly, detecting and treating MHE improve the patients' daily functioning and prevent HE-related hospital admissions. The scope of this review article is to create an overview of the validation level and usage of psychometric tests used to detect MHE: Portosystemic hepatic encephalopathy test, continuous reaction time test, Stroop EncephalApp, animal naming test, critical flicker frequency test, and inhibitory control test. Our work is aimed at the clinician or scientist who is about to decide on which psychometric test would fit best in their clinic, cohort, or study. First, we outline psychometric test validation obstacles and requirements. Then, we systematically approach the literature on each test and select well-conducted studies to answer the following questions:⢠Which percentage of patients with cirrhosis does the test deem as having MHE?⢠Is the test able to predict clinically manifest HE?⢠Is there a well-known test-retest variation and inter-observer variation?⢠Is the test able to detect a treatment response?⢠Is the test result affected by age, educational level, gender, or comorbidities?
Subject(s)
Cognitive Dysfunction , Hepatic Encephalopathy , Cognitive Dysfunction/complications , Humans , Liver Cirrhosis/complications , Liver Cirrhosis/diagnosis , Psychometrics/methods , Quality of LifeABSTRACT
BACKGROUND & AIMS: Golexanolone is a novel small molecule GABA-A receptor-modulating steroid antagonist under development for the treatment of cognitive and vigilance disorders caused by allosteric over-activation of GABA-A receptors by neurosteroids. It restored spatial learning and motor coordination in animal models of hepatic encephalopathy (HE) and mitigated the effects of intravenous allopregnanolone in healthy adults in a dose-dependent fashion. Herein, we report data on the safety, pharmacokinetics (PK) and efficacy of golexanolone in adult patients with cirrhosis. METHODS: Following single/multiple ascending dose studies, adults with Child-Pugh A/B cirrhosis and abnormal continuous reaction time (CRT) on screening were randomized to 3 weeks' dosing with golexanolone (10, 40 or 80 mg BID) or placebo. CRT, psychometric hepatic encephalopathy score (PHES), animal naming test (ANT), Epworth sleepiness scale (ESS) and electroencephalogram (mean dominant frequency [MDF]; delta+theta/alpha+beta ratio [DT/AB]) were obtained at baseline, 10, and 21 days. RESULTS: Golexanolone exhibited satisfactory safety and PK. Baseline characteristics were similar between the 12 and 33 patients randomized to placebo or golexanolone, respectively. By prespecified analyses, golexanolone was associated with directionally favourable changes vs. placebo in ESS (p = 0.047), MDF (p = 0.142) and DT/AB (p = 0.021). All patients also showed directionally favourable changes in CRT, PHES and ANT, but with no statistical difference between golexanolone and placebo. Post hoc analyses taking into account the variability and improvement in CRT, PHES and ANT observed between screening and baseline suggested an efficacy signal by cognitive measures as well. CONCLUSION: Golexanolone was well tolerated and associated with improvement in cognitive performance. These results implicate GABA-A receptor-modulating neurosteroids in the pathogenesis of HE and support the therapeutic potential of golexanolone. LAY SUMMARY: Many patients with cirrhosis experience subtle but disabling cognitive problems, including sleepiness and poor attention span, that impair their ability to be gainfully employed or carry out activities of daily living. This pilot study tested the hypothesis that these problems with cognition, for which there is no approved treatment, might be improved by an experimental drug, golexanolone, designed to normalize the function of receptors which inhibit brain function. The results of this study suggest that golexanolone is well tolerated and may improve cognition, as reflected by measures of sleepiness, attention span and brain wave activity, paving the way for future larger studies of this promising experimental drug. CLINICAL TRIAL REGISTRATION NUMBER: EudraCT 2016-003651-30.
Subject(s)
Cognition/drug effects , GABA-A Receptor Antagonists , Hepatic Encephalopathy , Phenanthrenes , Activities of Daily Living , Arousal/drug effects , Attention/drug effects , Double-Blind Method , Drugs, Investigational , Electroencephalography/methods , Female , GABA-A Receptor Antagonists/administration & dosage , GABA-A Receptor Antagonists/adverse effects , GABA-A Receptor Antagonists/pharmacokinetics , Hepatic Encephalopathy/diagnosis , Hepatic Encephalopathy/drug therapy , Hepatic Encephalopathy/etiology , Hepatic Encephalopathy/metabolism , Humans , Liver Cirrhosis/complications , Male , Middle Aged , Neuropsychological Tests , Neurosteroids/administration & dosage , Neurosteroids/adverse effects , Neurosteroids/pharmacokinetics , Phenanthrenes/administration & dosage , Phenanthrenes/adverse effects , Phenanthrenes/pharmacokinetics , Pilot Projects , Sleepiness/drug effects , Treatment OutcomeABSTRACT
Our study provides novel findings of experimental hypokalemia reducing urea cycle functionality and thereby severely increasing plasma ammonia. This is pathophysiologically interesting because plasma ammonia increases during hypokalemia by a hitherto unknown mechanism, which may be particular important in relation to the unexplained link between hypokalemia and hepatic encephalopathy. Potassium deficiency decreases gene expression, protein synthesis, and growth. The urea cycle maintains body nitrogen homeostasis including removal of toxic ammonia. Hyperammonemia is an obligatory trait of liver failure, increasing the risk for hepatic encephalopathy, and hypokalemia is reported to increase ammonia. We aimed to clarify the effects of experimental hypokalemia on the in vivo capacity of the urea cycle, on the genes of the enzymes involved, and on ammonia concentrations. Female Wistar rats were fed a potassium-free diet for 13 days. Half of the rats were then potassium repleted. Both groups were compared with pair- and free-fed controls. The following were measured: in vivo capacity of urea-nitrogen synthesis (CUNS); gene expression (mRNA) of urea cycle enzymes; plasma potassium, sodium, and ammonia; intracellular potassium, sodium, and magnesium in liver, kidney, and muscle tissues; and liver sodium/potassium pumps. Liver histology was assessed. The diet induced hypokalemia of 1.9 ± 0.4 mmol/L. Compared with pair-fed controls, the in vivo CUNS was reduced by 34% (P < 0.01), gene expression of argininosuccinate synthetase 1 (ASS1) was decreased by 33% (P < 0.05), and plasma ammonia concentrations were eightfold elevated (P < 0.001). Kidney and muscle tissue potassium contents were markedly decreased but unchanged in liver tissue. Protein expressions of liver sodium/potassium pumps were unchanged. Repletion of potassium reverted all the changes. Hypokalemia decreased the capacity for urea synthesis via gene effects. The intervention led to marked hyperammonemia, quantitatively explainable by the compromised urea cycle. Our findings motivate clinical studies of patients with liver disease.
Subject(s)
Ammonia/blood , Hyperammonemia/etiology , Hypokalemia/etiology , Potassium Deficiency/complications , Potassium/blood , Urea/blood , Animals , Disease Models, Animal , Female , Gene Expression Regulation, Enzymologic , Hyperammonemia/blood , Hyperammonemia/genetics , Hypokalemia/blood , Hypokalemia/genetics , Kidney/metabolism , Liver/metabolism , Muscle, Skeletal/metabolism , Potassium Deficiency/blood , Potassium, Dietary/administration & dosage , Potassium, Dietary/metabolism , Rats, WistarABSTRACT
BACKGROUND AND AIMS: In 1984, Scheinberg and Sternlieb estimated the prevalence of Wilson's disease to be 1:30,000 based on the limited available data. This suggested a large number of overlooked cases with potentially fatal consequences. The "Scheinberg-Sternlieb Estimate" is still widely used, although more recent clinical and genetic studies of higher quality are now available. In the present study, we included these data to update the prevalence estimate. APPROACH AND RESULTS: A MEDLINE Ovid, Science Citation Index Expanded, and PubMed systematic search for all relevant studies on the prevalence of Wilson's disease was conducted. In total, 59 studies (50 clinical and 9 population-based genetic) were included in the final analysis. We identified 4 recent clinical studies based on nationwide databases of high quality, providing prevalence estimates from 1:29,000 to 1:40,000. Higher frequency populations do exist because of frequent first-cousin marriages and/or a higher mutation frequency. When calculating prevalence from the incidence related to number of births, estimates were 1:40,000-1:50,000. Clinical screening studies, including examination for Kayser-Fleischer rings or ceruloplasmin, did not improve these estimates because of insufficient sample size or selection biases. Population-based genetic studies in US and UK populations were not in disagreement with the clinically based estimates. At the same time, studies from France and Sardinia suggested that the genetic prevalence may be 3-4 times higher than the clinical disease prevalence. This raises the question whether the penetrance is indeed 100% as generally assumed. CONCLUSIONS: The original prevalence estimate from 1984 of 1:30,000-1:50,000 still appears valid, at least for the United States, Europe, and Asia. In some population-based studies, the genetic prevalence was 3-4 times higher than clinically based estimates. The question of penetrance needs further evaluation.
Subject(s)
Hepatolenticular Degeneration/epidemiology , Hepatolenticular Degeneration/genetics , Humans , PrevalenceABSTRACT
OBJECTIVES: Single nucleotide polymorphisms within the interferon lambda 4 (IFNL4) gene influence liver inflammation and fibrosis in chronic liver disease. We investigated whether this is also the case during acute liver disease, alcoholic hepatitis. We, therefore, related variants within the IFNL4 gene to the clinical course of acute alcoholic hepatitis, and characterized the activation state of the IFN lambda system in these patients. METHODS: In this pilot study, 58 patients with alcoholic hepatitis were genotyped for the rs368234815IFNL4 single nucleotide polymorphism (deltaG, deltaG/TT: IFN lambda 4 positive, TT/TT: IFN lambda 4 negative). The genotypes were related to mortality, infection and inflammation and expression of the IFNL receptor 1 and IFN inducible genes were measured in liver and peripheral leukocytes. RESULTS: Amongst the alcoholic hepatitis patients who died, the IFN negative patients live longer after diagnosis, and also the IFN negative patients tended to have an overall short-term survival benefit compared to IFN lambda positive patients (p = .058). The IFN lambda 4 negative patients at diagnosis had fewer circulating monocytes and lower plasma soluble CD163. The patients with alcoholic hepatitis had reduced expression of the IFNL receptor 1in both liver and blood compared with healthy controls. In blood, the expression of IFN stimulated genes was lower than in healthy controls and most so in the patients, who died. CONCLUSIONS: The IFN lambda 4 pathway seems involved in the acute disease processes of alcoholic hepatitis and patients without IFN lambda expression seem to have a short-term survival benefit.
Subject(s)
Hepatitis, Alcoholic , Antiviral Agents , Genotype , Hepacivirus , Hepatitis, Alcoholic/genetics , Humans , Interferons , Interleukins/genetics , Pilot Projects , Polymorphism, Single NucleotideABSTRACT
In Wilson disease (WD), mutations in the gene encoding the ATP7B copper transport protein causes accumulation of copper especially in liver and brain. WD typically presents with hepatic and/or neuropsychiatric symptoms. Impaired cognition is a well-described feature in patients with neurological WD, while the reports on cognition in hepatic WD patients are fewer and less conclusive. We examined cognition in a cohort of WD patients with both phenotypes. In this cross-sectional pilot study, we investigated cognition in 28 stable Danish WD patients by the PortoSystemic Encephalopathy (PSE) and the Continuous Reaction Time (CRT) tests. Half of the patients were female, and their median age was 35.5 years (IQR 24.5). Their phenotype was hepatic in 14 (50%), neurologic in 10 (36%) and mixed in 4 (14%). The duration of treatment was > 2 year in all patients, and their condition was stable as judged by urinary copper excretion, liver enzymes, and clinical assessment. The hepatic patients did not show signs of liver failure. In total, 16 (57%) patients performed worse than normal in the PSE and/or the CRT tests. The two tests were correlated (rho = 0.60, p = 0.0007), but neither correlated with phenotype, MELD-, Child-Pugh score, 24 h-U-Cu, or treatment type. Measurable cognitive impairment was present in more than half of the stable WD patients independent of phenotype. Thus, our data questions the existence of a purely hepatic phenotype.
Subject(s)
Cognitive Dysfunction , Hepatolenticular Degeneration , Cognitive Dysfunction/etiology , Copper/metabolism , Copper-Transporting ATPases/genetics , Copper-Transporting ATPases/metabolism , Cross-Sectional Studies , Female , Hepatolenticular Degeneration/genetics , Hepatolenticular Degeneration/metabolism , Humans , Phenotype , Pilot ProjectsABSTRACT
BACKGROUND AND AIMS: Accurate estimates of hepatocellular carcinoma (HCC) risk in patients with cirrhosis are important to guide surveillance strategies. We described HCC risk among outpatients with alcohol-related cirrhosis and contrasted the risk of death from HCC with the risk of death from variceal bleeding or trauma. METHODS: This was a nationwide, registry-based historical cohort study between 2006 and 2018. We included all Danish outpatients with a hospital diagnosis of alcohol-related cirrhosis, except those with cancer, those with chronic viral hepatitis or autoimmune liver disease, and those older than 80 years. We followed them through 2018 and described the cumulative risk of HCC and the cumulative risk of death from HCC, variceal bleeding, or trauma. RESULTS: Of the 4,553 patients included, 181 developed HCC and 2,274 died. The cumulative risk of HCC was 0.9% (95% CI 0.7-1.3) after 1 year, 3.6% (95% CI 3.0-4.2) after 5 years, and 6.0% (95% CI 5.1-7.0) after 10 years, or approximately 0.7% per year. Male sex, older age, and decompensated cirrhosis predicted a higher HCC risk. After 10 years, 6.9% of deaths in the cohort could be attributed to HCC, whereas 6.5% could be attributed to variceal bleeding, and 5.0% to trauma. CONCLUSIONS: In 2006-2018, Danish outpatients with alcohol-related cirrhosis had an HCC risk of 0.7% per year, and they were nearly as likely to die from variceal bleeding or from trauma as from HCC. The implications are that many potentially harmful examinations are required for every HCC found through surveillance, so interventions targeting the prevention of other causes of death might be more cost-effective. LAY SUMMARY: We described the risk of hepatocellular carcinoma (HCC, the most common form of liver cancer originating in the liver) in Danish outpatients with cirrhosis due to harmful alcohol consumption. Accurate data on that risk are important for patient counselling and decisions about screening for HCC. The risk was about 0.7% per year, which is lower than might be expected and suggests that many potentially harmful screening examinations are required for every HCC found through surveillance.