Pathogenesis of alcoholic neuropathy.

1st Dept of Neurology, University Hospital, LFUK, Mickiewiczova 13, 813 69 Bratislava, Slovakia.
Bratislavske lekarske listy (Impact Factor: 0.45). 02/2002; 103(1):26-9.
Source: PubMed

ABSTRACT Chronic alcoholism is a medical, economical and social problem. Motility and mental function disorders are among the complications of chronic alcoholism and have been known for more than two centuries as "alcoholic paralysis", and are caused by alcoholic neuropathy. The pathogenesis of alcoholic neuropathy does not appear to be identical with central nervous system disorders which are caused by chronic alcoholism and it seems that it results from a failure of the protection barrier systems in the peripheral nervous system. To the pathogenesis of alcoholic neuropathy includes: 1. direct toxic effects of alcohol on the cellular population of the central nervous system and other tissues, especially of parenchymatous organs (in particular of the liver), 2. indirect metabolic and exotoxic changes mediated by malabsorption, maldigestion and secondary caloric and energy deprivation, 3. effects of genetic factors. (Fig. 2, Ref. 23.)


Available from: Marek Balaz, May 28, 2015
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    ABSTRACT: Chronic alcohol consumption produces painful peripheral neuropathy for which there is no reliable successful therapy, mainly due to lack of understanding of its pathobiology. Alcoholic neuropathy involves coasting caused by damage to nerves that results from long term excessive drinking of alcohol and is characterized by spontaneous burning pain, hyperalgesia and allodynia. The mechanism behind alcoholic neuropathy is not well understood, but several explanations have been proposed. These include activation of spinal cord microglia after chronic alcohol consumption, oxidative stress leading to free radical damage to nerves, activation of mGlu5 receptors in the spinal cord and activation of the sympathoadrenal and hypothalamo-pituitary-adrenal (HPA) axis. Nutritional deficiency (especially thiamine deficiency) and/or the direct toxic effect of alcohol or both have also been implicated in alcohol-induced neuropathic pain. Treatment is directed towards halting further damage to the peripheral nerves and restoring their normal functioning. This can be achieved by alcohol abstinence and a nutritionally balanced diet supplemented by all B vitamins. However, in the setting of ongoing alcohol use, vitamin supplementation alone has not been convincingly shown to be sufficient for improvement in most patients. The present review is focused around the multiple pathways involved in the development of peripheral neuropathy associated with chronic alcohol intake and the different therapeutic agents which may find a place in the therapeutic armamentarium for both prevention and management of alcoholic neuropathy.
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    ABSTRACT: Acute intermittent porphyria (AIP, MIM #176000) is an inherited metabolic disease due to a partial deficiency of the third enzyme, hydroxymethylbilane synthase (HMBS, EC:, in the haem biosynthesis. Neurological symptoms during an acute attack, which is the major manifestation of AIP, are variable and relatively rare, but may endanger a patient's life. In the present study, 12 Russian and two Finnish AIP patients with severe neurological manifestations during an acute attack were studied prospectively from 1995 to 2006. Autonomic neuropathy manifested as abdominal pain (88%), tachycardia (94%), hypertension (75%) and constipation (88%). The most common neurological sign was acute motor peripheral neuropathy (PNP, 81%) often associated with neuropathic sensory loss (54%) and CNS involvement (85%). Despite heterogeneity of the neurological manifestations in our patients with acute porphyria, the major pattern of PNP associated with abdominal pain, dysautonomia, CNS involvement and mild hepatopathy could be demonstrated. If more strict inclusion criteria for biochemical abnormalities (>10-fold increase in excretion of urinary PBG) are applied, neurological manifestations in an acute attack are probably more homogeneous than described previously, which suggests that some of the neurological patients described previously may not have acute porphyria but rather secondary porphyrinuria. Screening for acute porphyria using urinary PBG is useful in a selected group of neurological patients with acute PNP or encephalopathy and seizures associated with pain and dysautonomia. Clinical manifestations and the outcome of acute attacks were used as a basis for developing a 30-score scale of the severity of an acute attack. This scale can easily be used in clinical practice and to standardise the outcome of an attack. Degree of muscle weakness scored by MRC, prolonged mechanical ventilation, bulbar paralysis, impairment of consciousness and hyponatraemia were important signs of a poor prognosis. Arrhythmia was less important and autonomic dysfunction, severity of pain and mental symptoms did not affect the outcome. The delay in the diagnosis and repeated administrations of precipitating factors were the main cause of proceeding of an acute attack into pareses and severe CNS involvement and a fatal outcome in two patients. Nerve conduction studies and needle EMG were performed in eleven AIP patients during an acute attack and/or in remission. Nine patients had severe PNP and two patients had an acute encephalopathy but no clinically evident PNP. In addition to axonopathy, features suggestive of demyelination could be demonstrated in patients with severe PNP during an acute attack. PNP with a moderate muscle weakness was mainly pure axonal. Sensory involvement was common in acute PNP and could be subclinical. Decreased conduction velocities with normal amplitudes of evoked potentials during acute attacks with no clinically evident PNP indicated subclinical polyneuropathy. Reversible symmetrical lesions comparable with posterior reversible encephalopathy syndrome (PRES) were revealed in two patients' brain CT or MRI during an acute attack. In other five patients brain MRI during or soon after the symptoms was normal. The frequency of reversible brain oedema in AIP is probably under-estimated since it may be short-lasting and often indistinguishable on CT or MRI. In the present study, nine different mutations were identified in the HMBS gene in 11 unrelated Russian AIP patients from North Western Russia and their 32 relatives. AIP was diagnosed in nine symptom-free relatives. The majority of the mutations were family-specific and confirmed allelic heterogeneity also among Russian AIP patients. Three mutations, c.825+5G>C, c.825+3_825+6del and c.770T>C, were novel. Six mutations, c.77G>A (p.R26H), c.517C>T (p.R173W), c.583C>T (p.R195C), c.673C>T (p.R225X), c.739T>C (p.C247R) and c.748G>C (p.E250A), have previously been identified in AIP patients from Western and other Eastern European populations. The effects of novel mutations were studied by amplification and sequencing of the reverse-transcribed total RNA obtained from the patients' lymphoblastoid or fibroblast cell lines. The mutations c.825+5G>C and c.770T>C resulted in varyable amounts of abnormal transcripts, r.822_825del (p.C275fsX2) and [r.770u>c, r.652_771del, r.613_771del (p.L257P, p.G218_L257del, p.I205_L257del)]. All mutations demonstrated low residual activities (0.1-1.3 %) when expressed in COS-1 cells confirming the causality of the mutations and the enzymatic defect of the disease. The clinical outcome, prognosis and correlation between the HMBS genotype and phenotype were studied in 143 Finnish and Russian AIP patients with ten mutations (c.33G>T, c.97delA, InsAlu333, p.R149X, p.R167W, p.R173W, p.R173Q, p.R225G, p.R225X, c.1073delA) and more than six patients in each group. The patients were selected from the pool of 287 Finnish AIP patients presented in a Finnish Porphyria Register (1966-2003) and 23 Russian AIP patients (diagnosed 1995-2003). Patients with the p.R167W and p.R225G mutations showed lower penetrance (19% and 11%) and the recurrence rate (33% and 0%) in comparison to the patients with other mutations (range 36 to 67% and 0 to 66%, respectively), as well as milder biochemical abnormalities [urinary porphobilinogen 47±10 vs. 163±21 mol/L, p<0.001; uroporphyrin 130±40 vs. 942±183 nmol/L, p<0.001] suggesting a milder form of AIP in these patients. Erythrocyte HMBS activity did not correlate with the porphobilinogen excretion in remission or the clinical of the disease. In all AIP severity patients, normal PBG excretion predicted freedom from acute attacks. Urinary PBG excretion together with gender, age at the time of diagnosis and mutation type could predict the likelihood of acute attacks in AIP patients. Neurologiset löydökset ja molekyyligenetiikka äkillisessä jaksottaisessa porfyriassa Lounais-Venäjän alueella. Äkillinen jaksottainen porfyria kuuluu hemin biosynteesihäiriöihin, jotka ovat perinnöllisiä aineenvaihdunsairauksia. Lääkkeet, paasto tai hormonaaliset muutokset elimistössä lisäävät hemin muodostumista maksassa ja entsyymin puutteesta kärsivät potilaat keräävät porfyriinien esiasteita kehoonsa. Nämä esiasteet ovat myrkyllisiä hermokudokselle. Tauti ilmenee siten äkillisenä kohtauksena, joka alkaa usein lievillä psyykkisillä oireilla kuten unettomuudella ja levottomuudella ja etenee autonomisen hermoston häiriöihin, jossa tyypillisimpänä oireena on voimakas vatsakipu. Jos kohtaus etenee, potilaalle voi kehittyä lihasheikkoutta, kouristuksia ja tajunnantason laskua, ja siten se voi olla henkeä uhkaava tilanne. Nykyisin varhaisen diagnostiikan ja hoidon seurauksena neurologiset ilmentymät ovat harvinaisia, mutta osa äkillistä porfyriaa sairastavista potilaista on selvästi alttiimpia halvauksille. Akuutti porfyria varmistetaan virtsanäytteestä, josta mitataan porfyriinien esiasteet. Kohtauksen aikana ne ovat selkeästi koholla ja diagnoosi varmistetaan myöhemmin geenitestillä. Tämän tutkimuksen tarkoituksena oli selvittää äkillistä porfyriaa sairastavien esiintyvyys Pietarin alueella. 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Mutaatiot olivat kolmessa perheessä paikallisia ja aikaisemmin tuntemattomia, mutta kahdeksassa suvussa oli jo muualla Euroopassa ja Suomessa tunnistettuja mutaatioita. Länsi- eurooppalaisten mutaatioiden kulkeutuminen Pietariin selittynee sillä, että se on ollut kansainvälinen kaupunki jo 300 vuotta. Kun yhdistimme suomalaisten ja lounais-venäläisten potilaiden kliiniset tiedot, biokemialliset tulokset ja geenivirheiden analyysit, saatoimme luokitella potilaat mutaatioiden perusteella myös kliinisiin ryhmiin. Jotkut mutaatiot aiheuttivat selvästi vähemmän oireita kuin toiset. Lisäksi virtsan porfyriinien esiasteiden määrää oireettomassa vaiheessa ja mutaation laatua voidaan käyttää ennustettaessa taudin luonnollista kulkua yksittäisen potilaan kohdalla.
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    ABSTRACT: Background: The blood glucose concentration might determine the degree of academic performance. Decrease in the glucose concentration leads to a lowering of cognitive functions. Objectives: To produce a model of students’ alcohol use based on glucose homeostasis control and cognitive functions. Methods: The study involved 13 male volunteers (8 moderate alcohol users and 5 non-alcohol users) – medical students and took 6.5 hours on fasting. Selection criteria were based on a screening survey conducted among students in Minsk, Belarus. Out of 1499 students, 185 were abstainers, 1052 – moderate drinkers, 262 – problem drinkers. The experiment was divided into three phases: first phase – the students were administered AUDIT, MAST, CAGE, STAI, Academic Performance questionnaires; second phase - the students worked with text № 1 (physiology of bone tissue and subsequently answered on the questions that followed it); third phase – with text № 2 (physiology of autonomic nervous system and also answered subsequently on the questions that followed it). Blood glucose level was measured at 2 hours intervals, including the initial level. Tests on short-term, long-term memory and attention were used in every phase of the experiment. The probability value for significance was set at p<0.05. Results: The moderate drinkers had significantly lower glucose concentration after 4-6 hours, compared to their initial concentration, as well as to the values of the abstainers. Disturbances in cognitive functions, precisely a decrease in the effectiveness of active attention and a faster development of fatigue after 4-6 hours of mental work in alcohol users, compared to abstainers was statistically proven. The Intellectual Capacity on various tests/tasks positively correlated with the blood glucose level and in the 2-3 phases of the experiment and according to the results of the academic performances (ρ = +0.75; p<0.01). Alcohol users had 12.5–40.0 times higher number of errors on various tests/tasks than the non-alcohol users (p<0.001). The errors made on various tests/tasks increased with decrease in the blood glucose concentration (ρ = – 0.83; p<0.01). Significant increase in the Visual Productivity Coefficient among abstainers was also observed (p<0.05). Conclusion: This is the first study to show that alcohol use, even in episodic moderate doses (28ml/person with 1-2 times frequency per month) is accompanied by long-term glucose homeostasis disorders, leading to cognitive function disturbances and a decrease in the effectiveness of mental activities. These disorders in glucose homeostasis, cognitive functions were retained after 7-10 days of moderate alcohol use and might be the reason for the low academic performances among students who use alcoholic beverages.