Peripheral systems: neuropathy.

Long-term, excessive consumption of alcoholic beverages produces a peripheral neuropathy with symptoms of decreased superficial sensation, hyperalgesia, and weakness. Alcoholic neuropathy is characterized by axonal degeneration with reduced density of both small and large fibers and axonal sprouting. Electrophysiologic studies reveal a marked reduction in the amplitude of sensory potentials and moderate slowing of nerve conduction, mainly in the lower extremities. Dietary deficiency of vitamins, which are often associated with chronic alcoholism, can contribute to the pathogenesis. Recent studies using animal models have identified several mechanisms by which ethanol impacts peripheral nerve function. Ethanol can exert direct neurotoxic effects on peripheral nerves via its metabolite acetaldehyde and by enhancing oxidative stress. Ethanol activation of protein kinase Cε signaling in primary afferent nociceptors plays an important role in lowering nociceptive threshold. Further, ethanol causes cytoskeletal dysfunction and inhibits both anterograde and retrograde axonal transport. Alcoholic neuropathy is potentially reversible and treatments include abstinence from alcoholic beverages and consumption of a nutritionally balanced diet supplemented with B vitamins. However, response to these treatment strategies can be variable, which underscores the need for novel therapeutic strategies. In this review, we provide an overview of the clinical findings and insights on molecular mechanisms from animal models.

Small-fiber degeneration in alcohol-related peripheral neuropathy.

BACKGROUND: Alcohol-related peripheral neuropathy (ALN) is generally characterized as an axonal large-fiber polyneuropathy caused by thiamine deficiency. We hypothesized, based on clinical observations, that ALN is associated with a small-fiber polyneuropathy that can be diagnosed with skin biopsy in heavy alcohol drinking subjects with normal thiamine status. METHODS: Eighteen individuals (9 heavy alcohol drinking subjects and 9 healthy control subjects) were assessed for the potential utility of skin biopsies in detecting ALN-associated small nerve fiber degeneration. Heavy drinking was defined as greater than 4 drinks/d and 5 drinks/d in women and men, respectively, as determined by the Timeline Follow-Back and lifetime drinking history. All subjects underwent neurological examination, nerve conduction studies, and skin biopsies to quantify end nerve fiber densities (ENFD). Other causes of neuropathy were excluded and thiamine status was assessed. RESULTS: Average ENFD were significantly decreased at the calf in the alcohol group as compared with control group (p < 0.0001). Histological sections demonstrated striking attrition and architectural simplification of intraepidermal nerve fibers in the heavy alcohol drinking subjects. There were no significant intergroup differences with respect to clinical assessments of neuropathy or thiamine status. CONCLUSIONS: ALN is associated with a small-fiber neuropathy that can be detected with skin biopsy in heavy alcohol drinking individuals with normal thiamine status. Skin biopsy is a useful, minimally invasive biomarker that could extend studies to understand the effect of alcohol on the peripheral nerves and to evaluate potential therapeutic agents in larger clinical trials.

Erythrocyte transketolase activity in patients with diabetic and alcoholic neuropathies.

INTRODUCTION: The activity of erythrocyte transketolase induced by thiamine pyrophosphate and normalized to age of the patient is a marker of thiamine metabolism disturbances with pathological consequences in the central and peripheral nervous system. The measurement of erythrocyte transketolase activity enables evaluation of the thiamine status and therapeutic decisions in the disorders of the nervous system related to its deficiency. The aim of the study was to compare different modes of expression of transketolase activity in the most frequent acquired neuropathies. MATERIAL AND METHODS: The study included 29 patients with type 2 diabetes mellitus (21 males, 8 females) aged 48.3 years (range: 20-70 years) and 31 subjects with a history of alcohol dependence (23 males, 8 females) aged 54.5 years (range: 28-60 years). All participants of the study showed signs and symptoms of neuropathy. The cases in both groups presented the involvement of either axon, myelin, or both, what was evidenced by electrophysiological tests (electromyography and estimation of nerve conduction velocity). The control group consisted of 20 healthy persons aged 49.1 years (range: 23-70 years). Transketolase activity in erythrocytes (TK) was assessed by means of the spectrophotometric method. Basic TK activity was expressed as units per gram of haemoglobin (g Hb), moreover the normalized transketolase activity ratio (NTKZ) and percentage of activation of thiamine pyrophosphate (TPP) were calculated. RESULTS: The basal TK activity was decreased in cases with diabetic neuropathy (0.64 ± 0.342 U/g Hb, p = 0.0131), whereas in patients with alcoholic neuropathy only a trend (p = 0.058) of the decrease was noticed (0.85 ± 0.484 U/g Hb), in relation to the control group (1.005 ± 0.390 U/g Hb). Normalized transketolase activity ratio in erythrocytes has not shown any statistically significant differences. The median TPP did not indicate any thiamine deficiency, both in the group of diabetic and alcoholic neuropathy. CONCLUSIONS: The decrease in transketolase activity in diabetic neuropathy may be independent of thiamine deficiency. Abnormalities in transketolase activity, when expressed in three modalities: basal activity, normalized transketolase activity ratio and the activity after the stimulation with thiamine pyrophosphate may be differentiated as thiamine-dependent or resulting from posttranslational modification.

Impact of cytokines on the pathomechanism of diabetic and alcoholic neuropathies.

Diabetic and alcoholic neuropathies are heterogeneous groups with variable lesions of axons or myelin. Their pathogenesis is complex and involves multiple pathways. To elucidate the impact of immunological factors in development of these neuropathies the expression of some cytokines in serum was studied: tumour necrosis factor a (TNF-a), monocyte chemotactic protein-1 (MCP-1) and growth-regulated oncogene alpha (GRO-alpha; CXCL1). 29 patients with type 2 diabetes, 31 with chronic alcohol abuse and 20 healthy controls were included in the study. The type of neuropathy (involvement of axon or myelin) was evaluated by electrophysiological methods (EMG and nerve conduction velocity). The cytokine level was determined by ELISA method. For statistical comparison the nonparametric Mann-Whitney test was used. The evaluated material was divided according to clinical duration of neuropathy and electrophysiological pattern. Expression of TNF-alpha in both types of neuropathy does not differ from the control material. Expression of MCP-1 was higher, but insignificantly, in patients with alcoholic neuropathy. The same concerns the demyelinating form versus axonal diabetic neuropathy. Serum level of GRO-alpha; was significantly higher in patients with alcoholic neuropathy and in cases with demyelinating form of diabetic neuropathy than in control subjects. GRO-alpha; is a potent neutrophil chemoattractant playing an important role in various primary and secondary inflammatory processes. The results suggest that GRO-alpha; may contribute to the mechanism of alcoholic neuropathy and in demyelinating form of diabetic neuropathy.

[Diagnostic value of carbohydrate-deficient transferrin, gamma-glutamyltransferase and mean erythrocyte volume as laboratory markers of chronic alcohol abuse]. / Diagnostická výteznost karbohydrát deficitního transferinu, gama-glutamyltransferázy a stredního objemu erytrocytu jako laboratorních markeru chronického abúzu alkoholu.

INTRODUCTION: Our research aimed at finding out values of carbohydrate-deficient transferin (CDT), gamma-glutamyltransferase (GGT) and mean corpuscular volume (MCV) for the purposes of future etiological diagnostics of alcohol neuropathy in thin fibres. METHODS: We examined the serum of 80 control subjects (50 women and 30 men), and the serum of 33 alcoholics (20 men and 13 women) with the daily consumption of more than 60 g alcohol in the course of the last four weeks. CDT was determined with the use of microcolumn separation after iron saturation followed by turbidimetric immunoassay (ChronoAlcoI. D., Sangui Biotech, Inc.) on Cobas-Mira analyser. CDT is expressed as a percentage of the total transferin. Senzitivity, specificity, positive likelihood ration (+LR), ROC and the area under the ROC curve were determined using statistical program MedCalc. RESULTS: The senzitivity, specificity and positive likelihood ratio (+LR) for CDT-%, respectively, were 82.6, 96.7 and 24.8 for men (cut off 2.2%), and 60.0, 88.0 and 5.0 for women (cut off 2.5%). The respective values for GMT were 95.7, 90.0 and 9.6 for men (cut off 0.64 mu kat/l), and 90.0, 80.0 and 4.5 for women (cut off 0.38 mu kat/l); for MCV 82.6, 96.7 and 24.8 for men (cut off 95.0 fL), and 80.0, 100.0 and 20.0 for women (cut off 97.2 fL). The area under the ROC curve for CDT-%, GMT and MCV, respectively, were 0.940, 0.964 and 0.896 for men, and 0.829, 0.917 and 0.906 for women. CONCLUSION: In men, CDT-% and MCV showed the same values of the statistical parameters studied. GGT was more sensitive and less specific. In women, all the parameters studied presented a lesser diagnostic value, except for MCV with 100% specificity and +LR 20.0.