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Biomedical subjects

C Madl

Publications and source records attributed to C Madl.

At least 19 recordsLinked to original sources
PubMed2004

Brain energy metabolism during hypoglycaemia in healthy and type 1 diabetic subjects.

AIMS/HYPOTHESIS: This study aimed to examine brain energy metabolism during moderate insulin-induced hypoglycaemia in Type 1 diabetic patients and healthy volunteers. METHODS: Type 1 diabetic patients (mean diabetes duration 13 +/- 2.5 years; HbA1c 6.8 +/- 0.3%) and matched controls were studied before, during (0-120 min) and after (120-240 min) hypoglycaemic (approximately 3.0 mmol/l) hyperinsulinaemic (1.5 mU x kg(-1) min(-1)) clamp tests. Brain energy metabolism was assessed by in vivo 31P nuclear magnetic resonance spectroscopy of the occipital lobe (3 Tesla, 10-cm surface coil). RESULTS: During hypoglycaemia, the diabetic patients showed blunted endocrine counter-regulation. Throughout the study, the phosphocreatine:gamma-ATP ratios were lower in the diabetic patients (baseline: controls 3.08 +/- 0.29 vs diabetic patients 2.65 +/- 0.43, p<0.01; hypoglycaemia: 2.97 +/- 0.38 vs 2.60 +/- 0.35, p<0.05; recovery: 3.01 +/- 0.28 vs 2.60 +/- 0.35, p<0.01). Intracellular pH increased in both groups, being higher in diabetic patients (7.096 +/- 0.010 vs. 7.107 +/- 0.015, p<0.04), whereas intracellular magnesium concentrations decreased in both groups (controls: 377 +/- 33 vs 321 +/- 39; diabetic patients: 388 +/- 47 vs 336 +/- 68 micromol/l; p<0.05). CONCLUSIONS/INTERPRETATION: Despite a lower cerebral phosphocreatine:gamma-ATP ratio in Type 1 diabetic patients at baseline, this ratio does not change in control or diabetic patients during modest hypoglycaemia. However, both groups exhibit subtle changes in intracellular pH and intracellular magnesium concentrations.

Adenosine Triphosphate↗
PubMed2004

Changes of serum chloride and metabolic acid-base state in critical illness.

Alterations of electrolytes and albumin cause metabolic acid-base disorders. It is unclear, however, to what degree these plasma components affect the overall metabolic acid-base state in the course of critical illness. We performed serial analyses of the metabolic acid-base state in 30 critically ill patients over the course of 1 week. We applied a physical-chemical acid-base model and used a linear regression model to determine the influence of sodium, chloride, unmeasured anions and albumin on the net metabolic acid-base state. Progressive hypochloraemia was identified as the main cause of developing metabolic alkalosis. Changes in serum chloride and unmeasured anions were responsible for changes of 41% and 22% in the metabolic acid-base state, respectively. Sodium and albumin played a minor role. In conclusion, chloride is the major determinant of metabolic acid-base state in critical illness.

Acid-Base Imbalance↗
PubMed2003

Exocrine pancreatic dysfunction in sepsis.

BACKGROUND: Sepsis in critical illness is associated with the progressive failure of multiple organs. This study aims to establish a correlation between the severity of sepsis and exocrine pancreatic dysfunction. MATERIALS AND METHODS: In a prospective cohort study pancreatic exocrine function was tested by means of a secretin-cholecystokinin test in 21 critically ill, mechanically ventilated patients with sepsis according to criteria of the American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference Committee (ACCP/SCCM): 11 patients with shock and 10 patients without shock. Data were compared with seven healthy controls. RESULTS: The volume of duodenal fluid was not statistically different in the three groups. Sepsis patients without shock had significantly reduced content of amylase and chymotrypsin in duodenal juice compared with healthy controls (P < 0.01). Secretion of amylase, chymotrypsin, trypsin (P < 0.01 each) and bicarbonate in duodenal fluid (P < 0.05) was impaired in the septic shock patients when compared with the healthy controls. The content of trypsin was different between sepsis patients and septic shock patients (P < 0.05). Spearman correlation analysis was significant between the amylase secretion and the APACHE III and SOFA scores (P < 0.01). The SOFA score was also related to secretion of trypsin (P < 0.05). In patients on pressor therapy, use of norepinephrine was associated with a significant decrease in bicarbonate secretion (P < 0.05). CONCLUSIONS: Sepsis is associated with secretory pancreatic dysfunction that is worse in septic shock than in sepsis without shock. Impaired exocrine function was significantly correlated to the APACHE III and SOFA scores.

Adult↗
PubMed2003

Electrophysiological assessment of the afferent sensory pathway in cardiac arrest survivors.

BACKGROUND: Hypoxic-ischaemic brain damage in cardiac arrest survivors is global, but postmortem histology could identify parts of the brain that are selectively vulnerable to ischaemia, comprising the thalamus and cortex. We hypothesized that hypoxic-ischaemic brain damage increases along the afferent sensory pathway with a stepwise decrease of detectable somatosensory evoked potential peaks. METHODS: Somatosensory evoked potentials were recorded within 72 h after cardiac arrest in 305 comatose patients after cardiopulmonary resuscitation. We measured the short latency SEP peaks N9, P15, N20, P25 (reflecting the peripheral-thalamo-cortical pathway) and the long latency SEP peaks N35 and N70 (reflecting complex cortico-cortical interactions). Patients with a Cerebral Performance Category score > 2 at 1 year were defined as patients with hypoxic-ischaemic brain damage. RESULTS: Patients with hypoxic-ischaemic brain damage (n = 232) showed a statistically significant decrease of detectable peaks (P < 0.05) along the thalamo-cortical afferent pathway: N13, P15, N20, P25 and N70 peaks were detectable in 99%, 63%, 59%, 55% and 44% patients, respectively. In patients without hypoxic-ischaemic brain damage (n = 73) the N13, P15, N20, P25 peaks were detectable in all, and the N35 and N70 peaks in 98%. Furthermore, in patients with hypoxic-ischaemic brain damage and detectable SEP peaks, P15, N20, P25, N35 and N70, peak latencies were prolonged (P < 0.05) and N20 and N70 amplitudes were decreased (P < 0.05) compared with patients without hypoxic-ischaemic brain damage. CONCLUSION: Extent of hypoxic-ischaemic brain damage in cardiac arrest survivors increases along the afferent sensory pathway, with pronounced vulnerability of thalamic and cortical brain regions.

Adolescent↗
PubMed2002

Hepatopulmonary syndrome: prevalence and predictive value of various cut offs for arterial oxygenation and their clinical consequences.

BACKGROUND: The hepatopulmonary syndrome (HPS) is defined as the triad of liver disease, arterial deoxygenation, and pulmonary vascular dilatation. The reported prevalence of HPS in cirrhotic patients varies between 4% and 19%, and various threshold values defining arterial deoxygenation have been used and recommended previously. However, it is not known how the prevalence of HPS differs using different cut off values for arterial deoxygenation. METHODS: We studied 127 patients for the presence of HPS using transthoracic contrast echocardiography for detection of pulmonary vasodilation, pulmonary function tests, and blood gas analysis. RESULTS: Ninety eight patients were included in the study, of whom 33 (34%) had a positive contrast echocardiography. Using an increased alveolar-arterial difference for the partial pressure of oxygen (AaDO(2)) as an indication of hypoxaemia, the prevalence of HPS was considerably higher (>15 mm Hg, 32%; >20 mm Hg, 31%; and >age related threshold, 28%) than using reduced partial pressure of arterial oxygen (PaO(2)) as a threshold (<80 mm Hg, 19%; <70 mm Hg, 15%; and <age related threshold, 15%). For AaDO(2) as the cut off, the positive predictive value for a diagnosis of HPS was low (34%, 37%, and 53%, respectively). In contrast, PaO(2) as a cut off had considerably higher positive predictive values (44%, 93%, and 94%, respectively). Introducing PaO(2) <65 mm Hg as the cut off, the positive predictive value increased to 100%. Dyspnoea was more often present in patients with "clinically significant" HPS (57%) compared with "subclinical HPS" (8%), and patients without HPS (6%). The Child-Pugh score correlated significantly with the severity of HPS. Two of five liver transplanted patients with "subclinical HPS" had embolic brain infarcts, possibly induced by venous emboli passing through dilated intrapulmonary vessels. CONCLUSIONS: Defining arterial hypoxaemia in HPS by different, previously used, cut off values for arterial oxygenation leads to a wide variation in the prevalence of HPS in the same sample of cirrhotic patients.

Aged↗
PubMed2002

Influence of hydroxy ethyl starch infusion on serum bilirubin levels in cirrhotic patients treated with artificial liver support.

Serum bilirubin levels are commonly used to assess extracorporeal detoxification by liver support systems. We tested the hypothesis that intravenous colloids administered before liver support treatment could confound bilirubin values. Eight cirrhotic patients received an infusion of a 6% hydroxy ethyl starch solution (10 ml/kg, 30 minutes) before detoxification using a liver support system (FPSA). Bilirubin was measured before and 1 hour after infusion, and after FPSA treatment (7 hours). Infusion of hydroxy ethyl starch was associated with a drop in bilirubin values (mean, 18%, range, 1-44%, p=0.03 versus baseline values). Bilirubin levels were further reduced during FPSA treatment (mean, 27%, range, 22-34%; p=0.02 versus pretreatment values). In conclusion, hydroxy ethyl starch solution may decrease bilirubin levels in hyperbilirubinemic cirrhotic patients receiving extracorporeal detoxification. The role of potentially confounding factors in liver support studies is discussed further.

Bilirubin↗
PubMed2002

Effects of sorbent suspension dialysis on plasma amino acid levels in cirrhotic patients with refractory hepatic encephalopathy.

In cirrhotic patients, plasma amino acid levels are severely deranged. A decreased ratio of branched-chain to aromatic amino acids (Fischer ratio) has been implicated in the pathogenesis of hepatic encephalopathy. In this prospective study, we investigated the effects of extracorporeal detoxification on amino acid levels using a sorbent suspension dialysis system. Twenty patients with documented cirrhosis and hepatic encephalopathy grade II-III not responding to standard treatment were randomized to receive either six hours of sorbent dialysis and standardized conventional medical treatment or ongoing medical treatment alone. In contrast to previous uncontrolled studies, no significant effect on amino acid levels, Fischer ratio or clinical grade of hepatic encephalopathy was detected in either treatment group. In conclusion, a 6-hour treatment with sorbent dialysis did not significantly influence plasma levels of amino acids and did not ameliorate the clinical grade of hepatic encephalopathy.

Adult↗
PubMed2001

Emergency angioplasty and stent deployment for acute occlusion of an anomalous single coronary artery (all three coronary arteries from one ostium in the right sinus of Valsalva).

A single coronary ostium is traditionally considered to be of little clinical significance. We report a case of a single ostium in the right sinus of Valsalva, giving rise to the right coronary artery, from which the left main coronary artery originated. Sudden death occurred seven days after acute gastrointestinal bleeding and subsequent interruption of aspirin therapy. Acute coronary angiography following successful resuscitation revealed an ascending thrombus in the right coronary artery. The patient underwent a complex percutaneous coronary angioplasty with stent deployment. We conclude that coronary artery disease may lead to severe ischemia with a large area at risk and major complications in patients with coronary anomalies. Patients with acute stent implantation might benefit from platelet aggregation even in cases of recent intestinal bleeding.

Aged↗
PubMed2001

Time-dependency of sensory evoked potentials in comatose cardiac arrest survivors.

OBJECTIVE: To assess the validity of early sensory evoked potential (SEP) recording for reliable outcome prediction in comatose cardiac arrest survivors within 48 h after restoration of spontaneous circulation (ROSC). DESIGN AND SETTING: Prospective cohort study in a medical intensive care unit of a university hospital. PATIENTS: Twenty-five comatose, mechanically ventilated patients following cardiopulmonary resuscitation MEASUREMENTS AND RESULTS: Median nerve short- and long-latency SEP were recorded 4, 12, 24, and 48 h after ROSC. Cortical N20 peak latency and cervicomedullary conduction time decreased (improved) significantly between 4, 12, and 24 h after resuscitation in 22 of the enrolled patients. There was no further change in short-latency SEP at 48 h. The cortical N70 peak was initially detectable in seven patients. The number of patients with increased N70 peak increased to 11 at 12 h and 14 at 24 h; there was no further change at 48 h. Specificity of the N70 peak latency (critical cutoff 130 ms) increased from 0.43 at 4 h to 1.0 at 24 h after ROSC. Sensitivity decreased from 1.0 at 4 h to 0.83 at 24 h after ROSC. CONCLUSION: Within 24 h after ROSC there was a significant improvement in SEP. Therefore we recommend allowing a period of at least 24 h after cardiopulmonary resuscitation for obtaining a reliable prognosis based on SEP.

Adult↗
PubMed2001

Aerosolized iloprost therapy could not replace long-term IV epoprostenol (prostacyclin) administration in severe pulmonary hypertension.

OBJECTIVES: To switch patients with severe pulmonary hypertension and previous life-threatening catheter-related complications from long-term IV epoprostenol therapy to aerosolized iloprost therapy. DESIGN: Open, uncontrolled trial. SETTING: Medical ICU of a university hospital. PATIENTS: Two patients with primary pulmonary hypertension and one patient with pulmonary hypertension after surgical closure of atrial septal defect (mean pulmonary artery pressure > or =50 mm Hg). All were classified as New York Heart Association class II under treatment with continuous IV epoprostenol for 4 years. INTERVENTIONS: Stepwise reduction of IV epoprostenol (1 ng/kg/min steps every 3 to 10 h) during repeated inhalations of aerosolized iloprost (150 to 300 microg/d with 6 to 18 inhalations/d). Continuous pulmonary and systemic arterial monitoring were performed. RESULTS: Aerosolized iloprost reduced pulmonary artery pressure by 49%, 49%, and 45%, respectively, and increased cardiac output by 70%, 75%, and 41% in the three patients. The effect lasted for 20 min and was similar at different doses of IV epoprostenol. Persistent treatment change to inhaled iloprost could not be achieved because all patients developed signs of right heart failure. After termination of iloprost inhalations, return to standard epoprostenol therapy led to clinical and hemodynamic restoration. CONCLUSIONS: Although aerosolized iloprost demonstrated short-term hemodynamic effects, it could not be utilized as alternative chronic vasodilator in patients with severe pulmonary hypertension.

Administration, Inhalation↗
PubMed2001

A controlled study of sorbent suspension dialysis in chronic liver disease and hepatic encephalopathy.

To investigate the role of extracorporeal detoxification in cirrhotic patients with advanced hepatic encephalopathy not responding to medical treatment, 20 patients were randomized to receive six hours of additional sorbent dialysis or ongoing standardized medical treatment. Following treatment, the clinical stage of encephalopathy remained unchanged in both groups. Abnormal sensory evoked potentials improved following sorbent dialysis (N70 latency, 128 ms before versus 110 ms after treatment, P<0,05; cervico-cranial transmission, 7.7 ms versus 6.8 ms, P<0.01) indicating improvement in important aspects of cerebral function. In contrast, brain function remained unchanged following medical treatment (N70 latency, 114 ms versus 113 ms; cervico-cranial transmission, 7.7 ms versus 7.2 ms, P=NS, respectively). Serum benzodiazepine levels decreased significantly after sorbent dialysis but not after medical treatment. Biocompatibility of sorbent dialysis was limited and clinical complications occurred in a proportion of patients. In conclusion, a six-hour treatment with sorbent suspension dialysis did not ameliorate the clinical stage of HE but improved neurophysiologic function in cirrhotic patients who had not responded to conventional medical treatment.

Adult↗
PubMed2000

Methylene blue improves the hepatopulmonary syndrome.

BACKGROUND: The hypoxemia of the hepatopulmonary syndrome, seen in patients with severe chronic liver dysfunction, results from widespread pulmonary vasodilation. No established drug therapy is available for this condition. OBJECTIVE: To study the effect of methylene blue, a potent inhibitor of guanylate cyclase, in patients with severe hepatopulmonary syndrome. DESIGN: Open, uncontrolled trial. SETTING: Medical intensive care unit at the university hospital in Vienna, Austria. PATIENTS: 7 patients with advanced cirrhosis and severe hepatopulmonary syndrome with PaO(2) of 60 mm Hg or less. INTERVENTION: Insertion of a pulmonary artery catheter and an arterial indwelling catheter; intravenous administration of methylene blue, 3 mg/kg of body weight, over a 15-minute period. MEASUREMENTS: Serial measurements of gas exchange and hemodynamic variables. RESULTS: After methylene blue administration, PaO(2) increased in all patients (from a baseline mean +/- SD of 58 +/- 2.5 mm Hg to 74 +/- 11.5 mm Hg 5 hours after infusion; P = 0.006) and the alveolar-arterial difference for partial pressure of oxygen (PAO(2) - PaO(2) ) decreased in all patients, with a maximum effect achieved after 5 hours (from 49 +/- 3.3 mm Hg to 30 +/- 10.4 mm Hg; P = 0.003); even after 10 hours, PAO(2) - PaO(2) was still significantly reduced compared with baseline (P = 0.041). Oxygenation improved because of reduction in shunt fraction (from 41% +/- 3.1% to 25% +/- 4.5%; P < 0.001). Mean pulmonary artery pressure increased (from 20 +/- 5.2 mm Hg to 23 +/- 3.6 mm Hg; P = 0. 028), as did pulmonary vascular resistance (from 58 +/- 23 dyne/sec. cm(-5) to 115 +/- 56 dyne/sec. cm(-5); P = 0.012). Arterial blood pressure did not change significantly. Cardiac output decreased (from 10.6 +/- 2.2 L/min to 8.6 +/- 2.7 L/min; P = 0.008) and systemic vascular resistance increased (from 527 +/- 144 dyne/sec. cm(-5) to 729 +/- 222 dyne/sec. cm(-5); P = 0.037). Heart rate, central venous pressure, and pulmonary capillary wedge pressure remained unchanged. CONCLUSION: Intravenous methylene blue improved hypoxemia and hyperdynamic circulation in patients with liver cirrhosis and severe hepatopulmonary syndrome.

Adult↗
PubMed2000

Partial pressure of ammonia versus ammonia in hepatic encephalopathy.

Ammonia is considered the major pathogenetic factor of cerebral dysfunction in hepatic failure. The correlation between total plasma ammonia and the severity of hepatic encephalopathy (HE), however, is variable. Because ammonia that is present in gaseous form readily enters the brain, the correlation with the grade of HE of the pH-dependent partial pressure of gaseous ammonia (pNH(3)) could be better than that of total arterial ammonia levels. To test this hypothesis, 56 cirrhotic patients with acute episodes of clinical HE (median age, 54 years; range, 21-75) were studied by clinical examination and by long-latency median-nerve sensory-evoked potentials (SEPs) N70 peak, an objective and sensitive electrophysiological measure of HE. pNH(3) was calculated from arterial blood according to published methods. The clinical grade of HE correlated (P <.001) with both pNH(3) and total ammonia, but correlation was stronger with pNH(3) (r =.79 vs.69, P =.01). A similar correlation was found for N70 peak latency (r =.71 with pNH(3) vs.64 with total ammonia, respectively, P =.08). In summary, arterial pNH(3) correlates more closely than total ammonia with the degree of clinical and electrophysiological abnormalities in HE. These findings support the ammonia hypothesis of HE and suggest that pNH(3) might be superior to total ammonia in the pathophysiological evaluation of HE.

Adult↗
PubMed2000

Normothermic cardiopulmonary bypass is beneficial for cognitive brain function after coronary artery bypass grafting--a prospective randomized trial.

BACKGROUND: Hypothermic and normothermic cardiopulmonary bypass (CPB) have resulted in apparently contradictionary cardiac and neurologic outcome. Cerebrovascular risk and cognitive dysfunction associated with normothermic CPB still remain uncertain. MATERIALS AND METHODS: In a prospective randomized study, we measured the effects of mildly hypothermic (32 degrees C, n=72) vs. normothermic (37 degrees C, n=72) CPB on cognitive brain function. All patients received elective coronary artery bypass grafting (mean age 62.1+/-6.3 years, mean ejection fraction 60.4+/-13%). Cognitive brain function was objectively measured by cognitive P300 auditory-evoked potentials before surgery, 1 week and 4 months after surgery, respectively. Additionally, standard psychometric tests ('trailmaking test A', 'mini-mental state') were performed and clinical outcome was monitored. RESULTS: Patients, operated with mild hypothermia, showed a marked impairment of cognitive brain function. As compared with before surgery (370+/-45 ms), P300 evoked potentials were prolonged at 1 week (385+/-37 ms; P<0.001) and even at 4 months (378+/-34 ms, P<0.001) after surgery, respectively. In contrast, patients operated with normothermic CPB, did not show an impairment of P300 peak latencies (before surgery 369+/-36 ms, 1 week after surgery 376+/-38 ms, n.s.; 4 months after surgery 371+/-32 ms, n.s.). Group comparison revealed a trend towards prolonged P300 peak latencies in the patient group undergoing mildly hypothermic CPB (P=0.0634) 1 week after surgery. Four months postoperatively, no difference between the two groups could be shown (P=n.s.) Trailmaking test A and mini mental state test failed to discriminate any difference. Five patients died (mild hypothermia n=3, normothermia n=2) postoperatively (cardiac related n=3, sepsis n=2). None of the patients experienced major adverse cerebrovascular events. CONCLUSIONS: Objective cognitive P300 auditory evoked potential measurements indicate, that subclinical impairment of cognitive brain function is more pronounced in patients undergoing mildly hypothermic CPB as compared with normothermic CPB for CABG.

Brain↗
PubMed2000

Biocompatibility of a cuprophane charcoal-based detoxification device in cirrhotic patients with hepatic encephalopathy.

Extracorporeal detoxification has been proposed to treat patients with hepatic encephalopathy (HE) not responding to standard therapy. To investigate the biocompatibility of a cuprophane charcoal-based detoxification device, a prospective, randomized, controlled study was performed. Of 41 consecutive patients with cirrhosis and HE grade II or III who did not improve with conventional treatment, 20 patients (median age, 56 years; range, 33 to 71 years; 13 men) were randomly assigned to either ongoing conventional treatment or one additional 6-hour treatment with a sorbent suspension dialysis system. Main outcome parameters were physiological function and blood parameters of biocompatibility. In the 10 patients undergoing combined conventional and sorbent suspension dialysis treatment, blood pressure remained unchanged and body temperature and heart rate increased (P: < 0.01). Platelet count decreased (medians, from 75 to 26 g/L; P: < 0.001) and international normalized ratio increased after combined treatment (2.0 to 2.2; P: < 0.001). Three patients developed bleeding complications during treatment or shortly after. Treated patients showed increases in levels of plasma elastase (104 to 586 microg/L; P: = 0.001), tumor necrosis factor-alpha (5.4 to 7.5 pg/mL; P: = 0.04), and interleukin-6 (118 to 139 pg/mL; P: = 0.04), but not interferon-gamma and E-selectin. No changes were observed in the 10 patients treated conventionally. In conclusion, despite technical refinements compared with charcoal hemoperfusion, biocompatibility of sorbent suspension dialysis is still very limited. Clinical complications were apparently caused by blood-membrane interactions and disseminated intravascular coagulation. We suggest further developments in design and appropriate strategies of anticoagulation to improve the biocompatibility of artificial liver support.

Adult↗
PubMed2000

Resting energy expenditure in short-term starvation is increased as a result of an increase in serum norepinephrine.

BACKGROUND: The effects of food restriction on energy metabolism have been under investigation for more than a century. Data obtained are conflicting and research has failed to provide conclusive results. OBJECTIVE: The objective of this study was to test the hypothesis that in lean subjects under normal living conditions, short-term starvation leads to an increase in serum concentrations of catecholamines and thus to an increase in resting energy expenditure. DESIGN: Resting energy expenditure, measured by indirect calorimetry, and hormone and substrate concentrations were measured in 11 healthy, lean subjects on days 1, 2, 3, and 4 of an 84-h starvation period. RESULTS: Resting energy expenditure increased significantly from 3.97 +/- 0.9 kJ/min on day 1 to 4.53 +/- 0.9 kJ/min on day 3 (P < 0.05). The increase in resting energy expenditure was associated with an increase in the norepinephrine concentration from 1716. +/- 574 pmol/L on day 1 to 3728 +/- 1636 pmol/L on day 4 (P < 0.05). Serum glucose decreased from 4.9 +/- 0.5 to 3.5 +/- 0.5 mmol/L (P < 0.05), whereas insulin did not change significantly. CONCLUSIONS: Resting energy expenditure increases in early starvation, accompanied by an increase in plasma norepinephrine. This increase in norepinephrine seems to be due to a decline in serum glucose and may be the initial signal for metabolic changes in early starvation.

3-Hydroxybutyric Acid↗
PubMed2000

The impact of apolipoprotein E genotypes on age at onset of symptoms and phenotypic expression in Wilson's disease.

Wilson's disease is a disorder of biliary copper excretion that may result in severe neurological symptoms and advanced liver disease. The wide variation of phenotypic disease expression cannot be fully explained by the different mutations of the Wilson disease gene. In neurological disorders, such as Alzheimer's disease, temporal lobe epilepsy and cerebral trauma, the presence of the apolipoprotein E (ApoE) allele epsilon4 is associated with an increased vulnerability of the brain to the effects of the disease, whereas the presence of the ApoE genotype epsilon3/3 appears to provide moderate neuroprotection. We examined whether this hypothesis holds true for the development of neurological symptoms in patients with Wilson's disease. The ApoE genotype and the H1069Q mutation (the most common in Wilson's disease) status were determined by polymerase chain reaction-based mutation assays in 121 well-characterized, symptomatic index patients with Wilson's disease. An investigation profile was established in which the patients were grouped according to the clinical symptoms at presentation, the ApoE genotypes and the status of the H1069Q mutation. Fifty-nine per cent of the 121 patients had the allele combination ApoE epsilon3/3 (21% ApoE epsilon3/4, 19% ApoE epsilon3/2, 1% ApoE epsilon4/2). The distribution of ApoE genotypes did not deviate from known distributions in healthy European subjects. Within the group of 40 H1069Q-homozygous patients, the onset of symptoms was significantly delayed in patients with the ApoE epsilon3/3 genotype (25 +/- 6 years at presentation) compared with patients with the ApoE epsilon3/4 genotype (20 +/- 3 years at presentation). In this study, the ApoE genotype was established as an important factor delaying the onset of neurological and hepatic symptoms, but not modifying phenotypic disease expression in a homogeneous group of patients with Wilson's disease (all H1069Q-homozygotes, similar genetic background). The presence of ApoE epsilon3/3 attenuates clinical manifestations in Wilson's disease by mechanisms which might involve the antioxidant and membrane-stabilizing properties of the ApoE 3 protein.

Adolescent↗