Pathogenesis of alcoholic neuropathy
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.)
Pathogenesis of alcoholic neuropathy
Kucera P, Balaz M, Varsik P, Kurca E
Bratisl Lek Listy 2002; 103 (1): 26-29
1st Department of Neurology, University Hospital, Faculty of Medicine,
Comenius University, Bratislava, and Department of Neurology, Uni-
versity Hospital, Martin
Address for correspondence: P. Kucera, MD, 1st Dept of Neurology,
University Hospital, LFUK, Mickiewiczova 13, 813 69 Bratislava, Slo-
1st Department of Neurology, University Hospital, Faculty of Medicine, Comenius University, Bratislava, Slovakia.email@example.com
Chronic alcoholism is a medical, economical and social problem. Motility and mental function disor-
ders 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 alco-
holic 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 sys-
tems 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.)
Key words: alcoholic neuropathy, peripheral nervous system, chronic alcoholism.
The most obvious influence of regular alcohol intake is seen
in the disturbance of cortical and motility function of human
body. Certain changes of psychical functions attributable to al-
coholic dementia and psychosis are well-described which are
often connected to alcohol paralysis based on degenerative chang-
es of the cerebellum, basal ganglia and brainstem with clinical
picture of Wernickes' encephalopathy and central pontine my-
elinolysis. Alcohol-induced central nervous system disorders
have since the ancient times been in the spotlight of medical
sciences because of disturbances of psychic and motor functions.
However the peripheral nerve system disorder with apparent pe-
ripheral neuropathy accompanied by disorders of the autonomic
system and posterolateral columns of spinal cord is very common.
Because alcoholic neuropathy (AN) pathogenesis still lacks
a clear explanation it does not have a clear place in the classifi-
cation of peripheral nervous system (PNS) disorders. Certain
authors classify alcoholic neuropathy as a nutritional PNS disor-
der (Rowland, 1995), a toxic disorder (Adams andVictor, 1993;
Victor and Ropper, 2001) or a metabolic and exotoxic neuropa-
thy (Varsik et al, 1999).
History and present
The first surprising evidence on influence of alcohol on ner-
vous system is from Lettsom (1780), and alcoholic paralysis was
described by Jackson (1822), Hun (1855) and later by Dreschfeld
(1886). Morphology and clinical symptomatology of AN was
characterised in detail by Dejerine (1887). Greenfield and Car-
michael (1935) described the AN connected with so called sub-
acute degenerative changes of the spinal cord while electrophys-
iological aspects of this type of AN were described by Behse
and Buchthal (1977). Vinken and Bruyn (1970) claimed, that the
classification of PNS disorders was flowed because the etiolog-
ic and morphologic aspects of various disorders were mixed up.
In the pure morphological classification of PNS disorders by
Sluga (1977), the neuronal, myelin sheath, interstitial tissue and
mixed disorders of peripheral nerves were considered separately
for the first time.
The Executive Committee of the Research Group prepared
the etiological classification of the PNS disorders with AN clas-
sified in the group of acquired exotoxic PNS disorders. It still
remains unclear if the PNS disorder attributed to lack of essen-
Kucera P et al: Pathogenesis of alcoholic neuropathy
tial nutrients (especially thiamine) in alcoholics is present also
in well nourished persons with regular intake of alcohol.
McLeod (1982) alleges doubts about the reversibility of even
partial damage to PNS structures compared to the tendency of
central nerve system (CNS) damage (notably mental and motor)
to reverse. This experience suggests the different pathogenesis
of PNS and CNS damage. From various evidence in contempo-
rary literature it seems that CNS disorders could be attributed to
the exotoxic influence of alcohol, while the damage to PNS could
be caused by metabolic and nutritional deficiency factors.
The epidemiological data indicate that the chronic abuse of
alcohol reaches 10 % (the percent of known alcoholics summed
up with "anonymous" alcoholics) in certain regions (Adams and
Victor, 1993) and that the frequency of AN (combined with par-
enchymatous organs diseases) may range 12--30 % (Erbsloh,
1967; Scheid, 1980).
In the era of the light microscopy the morphologic changes
attributable to AN were thought to be caused by demyelinisation
based on the findings of Gombault at the end of 19th century
and the work of Greenfield and Carmichael (1935) and Denny-
The electronic microscopy proved clearly the presence of
primary axonal lesion in AN (Bichhoff, 1971; Behse and Buch-
thal, 1977). The primary axonal damage and secondary demye-
linisation of motor and sensitive fibers (especially small diame-
ter fibers) (Ludin and Tackmann, 1984) are considered to consti-
tute the morphologic basis of alcoholic damage to nerve tissue
at present. The demyelinisation is explained as the result of a
slowing-down (deceleration) of axoplasmic flow and a degrada-
tion of the quality of biological properties of axonal enzymes
and proteins. This type of degeneration so called "dying-back"
resembles the Wallerian degeneration. Without any doubt etha-
nol and its toxic degradation metabolites affect neuronal metab-
olism including the metabolic pathways of nucleus, lysosomes,
peroxisomes, endoplasmatic reticule and cytoplasm. Alcohol
enters the blood as early as 5 minutes after ingestion and its re-
sorbtion peaks after 30--90 minutes. The resorbtion is increased
in the subjects with gastric disorders and in women. The alcohol
gradually enters the cerebrospinal fluid, alveoli, urine and stool.
The study of Fennely et al (1967) contributed important find-
ings of decreased levels of B1, B2, B6 a B12 vitamins, nicotinic
acid, folic acid, lipoic acid, biotine and pantothenic acid to less
than 50 % of usual values compared with healthy subjects. The
decreased levels were later described to be present not only in
subjects with AN, but also in alcoholics with no apparent AN
(Stibler and Borg, 1986). Tomasulo et al (1986) described the 20
% increase of thiamine excretion in stool of alcoholic subjects.
Stibler and Kjellin (1976) proved that the elevation of carbohy-
drate-deficient transferine (CDT) levels in alcoholics with a sub-
sequent decrease to normal levels only after 2 to 4 weeks of
alcohol withdrawal. The microchromatographic electro-focus-
ing method proved that the CDT consists of two isoforms of
serum transferine (with the absence of terminal sacharids: sialic
acid, galactosis and N-acetylglucosamine).
These findings suggest the difficulty of clear differentiation
of the immediate toxic influence of ethanol on nerve tissue from
its metabolic effects connected with nutritional and vitamin dep-
rivation often seen in alcoholics. This is one of the reasons which
contributes to the classification of AN to the group of metabol-
ic-toxic (exotoxic and endotoxic) neuropathies.
The key role in the degradation of ethanol is played by eth-
anol dehydrogenase and acetaldehyde dehydrogenase -- both two-
step enzymatic systems by which the ethanol is converted to
acetate which is further metabolised in human organism. Both
systems require the availability of NAD
(nicotine amide ade-
nine dinucleotide), which is reduced by both systems to NADH
(reduced form of NAD
). The acetaldehyde dehydrogenase is a
mitochondrial enzyme that underwent a single aminoacid sub-
stitution (mutation) in about 50 % of the Asian population in a
way similar to the genetic changes in sickle cell anaemia (1996).
In individuals with such a mutated dehydrogenase who consume
the alcoholic beverages, the acetaldehyde levels in organism reach
values about 20 times higher than in individuals without the
A certain amount of acetaldehyde is not metabolised in usu-
al pathways (Fig. 1) and binds irreversibly to proteins which
results in the creation of cytotoxic proteins which adversely af-
fect the function of nervous system cells. These abnormal pro-
teins influence other cell populations especially the hepatocytes
where the damage to hepatic mitochondria results in hepatic cir-
rhosis with reduction of energetic substrates in the liver. The
action of these abnormal proteins is explained by the competi-
Fig. 1. Degradation of alcohol and intermediary metabolic pathways.
Bratisl Lek Listy 2002; 103 (1): 26-29
tion with normal proteins causing the damage to function and
metabolism of the cell (Achord, 1995).
We can assume that three major systems are included the
degradation of alcohol:
1) two-step dehydrogenase system as mentioned above (al-
cohol dehydrogenase and acetaldehyde dehydrogenase with
coenzyme). This system is located in the cytoplasm (alco-
hol dehydrogenase) or mitochondrial structures (aldehyde dehy-
drogenase) respectively with close connections to cytochrome
2) peroxisomal catalase,
3) MEOS microsomal ethanol oxidating system, located
in microsomal membrane fraction, connected with the oxidation
of NADPH (reduced form of nicotine amide adenine dinucle-
otide phosphate) to NADP
(nicotine amide adenine dinucleotide
The toxic influence on cellular metabolism is very likely
present not only in nervous cell population but also in other or-
gans, namely the hepatocytes. The liver damage is present in
about 25 % of alcoholics. It becomes congested with fat, the
venules are enlarged and the tissue becomes infiltrated with lym-
phocytes. On the cellular level the mitochondria size is increased.
Gradually the liver becomes fibrotic and very often the cirrhosis
One of the other important issues in alcoholic individuals is
the source of their caloric intake. These individuals draw the
majority of calories from the caloric rich alcoholic beverages
with low nutritive value (the lack of important nutrients and vi-
tamins). Chronic abuse of alcohol depletes the pool of liver pro-
teins which are consumed for energy production and the insuffi-
cient intake of proteins only worsens this imbalance. Resulting
disturbances in protein and lipid metabolism leads to undernour-
ishment which adversely influences other metabolic pathways,
including those influencing the function of the nervous system.
The experimental animal studies suggest that the application
of toxic substance may influence the protein metabolism of
nerves. After certain toxic compounds (organophosphorus com-
pounds, acrylamide) peripheral neuropathy develops with con-
firmed protein metabolism disorder. One of the important pro-
teins affected is the neuronal target esterase (NTE), which plays
an important role in the development and function of neurons
probably by influencing the signal pathways between neuronal
and glial cells (Glynn, 2000; Moretto, 2000). The damage to this
important enzyme may lead to disturbance of neuronal function
and deceleration of axoplasmic flow. Such changes together with
the demyelinisation result in a picture similar to Wallerian de-
generation -- so called chemical nerve transsection (Glynn, 2000).
The toxic influence of alcohol on cells of the nervous sys-
tem and of other tissues plays an important part in the develop-
ment of chronic metabolic disorders. These changes are slow
and gradual and only in later stages result in malabsorption and
maldigestion. These states further progress to development of
undernourishment with associated disturbances of hemopoesis,
skin and muscle function, nervous system function and other
metabolic disorders (Fig. 2).
Consequently the problem of different influences of alcohol
on different part of the nervous system comes into question. While
the CNS has its own barrier systems (blood-brain barrier), which
may defy the metabolic and toxic influences and their effect on
brain functions for a significant period of time, the PNS lacks
this protective barrier which can contribute to the fact that PNS
disorders are present in 12--30 % of alcohol abusers (Erbsloh,
1967; Scheid, 1980).
Finally genetic factors have to be taken into account. Obvi-
ously the genetic conditioned enzymatic defects may cause the
dysfunction of nervous system. The decreased tolerance of alco-
hol ingestion in Asian population is well known. Many works stud-
ied the incidence of alcohol abuse in siblings of alcoholics. An
increased incidence of alcohol abuse in monozygotic twins com-
pared to dizygotic twins or to adopted children raised in families
of alcoholics was observed (Noble, 1996). The genetic associa-
tion of D2 (dopamine) receptor encoding is mentioned as well.
Should we therefore acclaim the Plutarch and Aristotle who
suggested that the alcoholics give birth to children alcoholics
Achord JL. Alcohol and the liver. Sci Amer Sci Med 1995; March/
Adams RD, Victor M. Principles of Neurology. Fifth edition. McGraw-
Hill Inc., 1993, 1386.
Behse FF, Buchthal F. Alcoholic neuropathy: Clinical, electrophysio-
logical and biopsy findings. Ann Neurol 1977; 2: 95.
Fig. 2. Signs of malabsorption.
Kucera P et al: Pathogenesis of alcoholic neuropathy
Bischhoff A. Die alkoholishe Polyneuropathie. Klinische, ultrastruktu-
relle und pathogenetische Aspekte. Dtsch Med Wschr 1971; 96: 317.
Dejerine J. Contribution l'étude de la névrite alcoolique (forme paraly-
tique, forme ataxique, tachycardie par névrite du pneumogastrique). Arch
Physiol Norm Pathol (Paris) 1887; 3,S,X: 248.
Denny-Brown DE. Neurological aspects of thiamin deficiency. Fed Proc
1958; 17 (Suppl 2): 35.
Dreschfeld J. Further observations on alcoholic paralysis. Brain 1886;
Erbslöh F. Peripheres Nervensystem. Polytope Erkrankunge (Polyneu-
ritid, In: Almanach für Neurologie und Psychiatrie, 1967, Lehmann,
Fennelly J, Frank O, Baker H, Leevy CM. Peripheral neuropathy of
the alcoholic-aethiologic role of aneurin and other B-complex vitamins.
Brit Med J 1964; II: 1290.
Glynn P: Neural development and neurodegeneration: two faces of ne-
uropathy target esterase. Prof Neurobiol 2000, May, 61 (1): 6174.
Greenfield JG, Carmichael EA. The peripheral nerves in cases of suba-
cute combined degeneration of the cord. Brain 1935; 58: 483.
Hun H. Alcoholic paralysis. Amer J Med Sci 1885; 89: 372.
Jackson J: On a peculiar disease resulting from the use of ardent spirits.
New Engl J Med 1822; 2: 351.
Lettsom JC. Some remarks on the effects of Lignum Quassiae. Mem
Med Soc Lond 1780; 1: 128.
Ludin HP, Tackman W. Polyneuropathien. Stuttgart--New York, Georg
Thieme Verlag 1984, 250255.
McLeod JG. Alcohol, nutrition and the nervous system. Med J Austral
1992; September 18: 273274.
Moretto A. Promoters and promotion of axonopathies. Toxicol Lett 2000;
March 15: 1721, 112133.
Noble EP. The gene that remarks alcoholism. Amer Sci Med 1996,
Scheid W. Lehrbuch der Neurologie. Vierte Auflage. Stuttgart, Georg
Thieme Verlag 1980.
Sluga E. Polyneuropathien, Typen und Diffensierung. Ergebnisse biop-
tische Untersuchungen. In: Bauer HJ, Gänshirt H, Vogel P (Hrsg): Shrif-
tenreite Neurologie. Berlin, Springer 1974.
Stibler H, Borg S. Carbohydrate composition of transferin in alcoholic
patients. Alcoholism: Clin Exp Res 1986; 10: 6164.
Stibler H, Kjellin KG. Isoelectric focusing and electrophoresis of CSF
proteins in ... of different origins. J Neurol 1976; 30: 269285.
Tomasulo PA, Kater MRH, Iber FL. Impairment of thiamine resorption
in alcoholism. Amer J Clin Nutr 1968; 21: 1340.
Varsik P (Ed). Neurológia II. Patogenéza aklinika nervových chorôb.
Bratislava Lufema 1999.
Victor M, Adams RD. The effect of alcohol on the nervous system. Res
Publ Assoc Res Nerv Merit Dis 1953; 32: 526.
Victor M, Adams RD, Collins GH. The Wernicke-Korsakoff Syndro-
me. AClinical and Pathological Study of 245 Patients, 82 with Postmor-
tem Examinations. Philadelphia, FA Davis 1971.
Victor M. Polyneuropathy due to nutritional deficiency and alcoholism.
In: Dyck PJ, Thomas PK, Lambert EH, Bunge R (Eds): Peripheral Neu-
ropathy. Second ed. 1899, Philadelphia, W.B. Saunders, 1984.
Victor M, Ropper AH. The Adams and Victors Principles of Neurolo-
gy. Seventh Ed. McGraw-Hill Inc., 2001, 1692.
Vinken PJ, Bruyn GW. Handbook of Clinical Neurology. Disease of
nerves. Vol. 7, part 1. North Holland Publ. Company, 1970, 679.
Received January 18, 2001.
Accepted December 7, 2001.