All alcohols may cause inebriation, depending on the dose. Based on limited animal data, it appears that higher molecular weight alcohols are more intoxicating than lower molecular weight alcohols (therefore, isopropanol ≈ ethylene glycol > ethanol > methanol).169 However, the absence of apparent inebriation does not exclude toxic alcohol ingestion, particularly if the patient chronically drinks ethanol and is thereby tolerant to its central nervous system (CNS) effects.160 This is intuitively obvious; serum methanol concentrations of 25 to 50 mg/dL may potentially be associated with toxicity, whereas in most states one may legally drive a car with a blood alcohol concentration of 80 mg/dL.
The CNS manifestations of toxic alcohol poisoning are incompletely understood. It is assumed by analogy that inebriation is similar to that of ethanol, where effects are mediated through increased GABAergic tone both directly and through inhibition of presynaptic GABA, GABAA receptors as well as inhibition of the N-methyl-D-aspartic acid (NMDA) glutamate receptors.6,31,60,72,121 Although the CNS effects of other alcohols are clinically similar, there is no direct evidence that they are mechanistically the same.
Metabolic acidosis with an elevated anion gap is a hallmark of toxic alcohol poisoning. This is a consequence of the metabolism of these alcohols to toxic organic acids. The acids have no rapid natural metabolic pathway of elimination unlike acetic acid from ethanol metabolism, which can enter the Krebs cycle, and therefore they accumulate. In methanol poisoning, formic acid and lactic acid in the most seriously ill are responsible for the acidosis, whereas in ethylene glycol poisoning, glycolic acid is the primary acid responsible for the acidosis, with other metabolites making a minor contribution. An exception to the formation of an acid metabolite is isopropanol, which is metabolized to acetone. Acetone is a ketone, not an aldehyde, and therefore cannot be further metabolized by aldehyde dehydrogenase (ALDH) (Fig. 107–3). Thus it has no organic acid metabolite and does not cause metabolic acidosis. In fact, ketosis without acidosis is diagnostic of isopropanol poisoning. Occasionally, a non-anion gap metabolic acidosis may result from ethylene glycol poisoning (almost 18% in one series), often concurrently with anion gap acidosis.155 The mechanism for this is unclear, but a similar pattern has been observed in the setting of diabetic ketoacidosis, lactic acidosis, alcoholic ketoacidosis, and toluene poisoning.
Additional end-organ effects depend on which alcohol is involved. Methanol causes visual impairment ranging from blurry or hazy vision or defects in color vision, to "snowfield vision" or total blindness in severe poisoning. On physical examination, central scotoma may be present on visual field testing, and both hyperemia and pallor of the optic disc, papilledema, and an afferent papillary defect are described as characteristic findings.18,131,176 Electroretinography may demonstrate a diminished b-wave,163 a marker of bipolar cell dysfunction, and optical coherence tomography (similar in principal to ultrasound, but using reflected light waves to image translucent tissues) may demonstrate peripapillary nerve fiber swelling and intraretinal fluid accumulation.54 The formate metabolite of methanol is a mitochondrial toxin, inhibiting cytochrome oxidase and thereby interferes with oxidative phosphorylation.46,127,128 Although it is unclear why this results in ocular toxicity while other tissues are relatively spared, retinal pigmented epithelial cells and optic nerve cells appear to be uniquely susceptible.44,116,162,163
Interestingly, neurons in the basal ganglia appear to be similarly susceptible to this toxicity; bilateral basal ganglia lesions, the putamen, and less commonly, caudate nucleus are characteristically abnormal visualized on cerebral computerized tomography or magnetic resonance imaging after methanol poisoning.3,8,19,20,40,42,49,55,67,68,136,147,151 While lesions of this type are nonspecific, and may occur in other disease states, such as hypoxia, hypotension, and carbon monoxide exposure, they may occur in the absence of hypotension and hypoxia in methanol poisoning,117 suggesting a direct toxic mechanism. In one series, typical radiological lesions were present in six of nine cases.151 Other CNS lesions reported include necrosis of the corpus callosum93 and intracranial hemorrhage.9,150 Rarely, injury to other tissues may also occur; both renal failure and pancreatitis are reported after methanol poisoning.70,96 For unclear reasons, one case series showed a much higher incidence of pancreatitis (50%)70 and in another, 11 of 15 patients had pancreatitis166 but this is not typical. Some of the renal failure that results from methanol poisoning may be due to myoglobinuria.61 In one series of methanol-poisoned patients with renal failure, about half had associated myoglobinuria. Patients with renal failure were also more likely than a control group of patients to have severe poisoning, as manifested by low initial serum pH, high initial osmolality, and high peak formate concentration.166
The most prominent end organ effect of ethylene glycol is nephrotoxicity. The oxalic acid metabolite forms a complex with calcium to precipitate as calcium oxalate monohydrate crystals in the renal tubules, leading to acute renal failure.50,62,64,118,141,159,161 The diagnosis of ethylene glycol poisoning has been made at autopsy by demonstrating this abnormality, including one homicide case;7,104 in another case, the diagnosis was made by renal biopsy.92 Although the intermediate products of ethylene glycol metabolism and possibly ethylene glycol itself were shown to be directly toxic to the renal tubules in some studies,34,50,140,143 this appears not to occur at clinically relevant concentrations.62 Currently no explanation exists for the presence of necrotic lesions to the glomerular basement membrane on some pathology specimens50 as oxalic acid generally does not cause glomerular injury.88
Ethylene glycol can occasionally affect other organ systems. In severe poisoning, the oxalic acid metabolite may be present in sufficient amounts to cause systemic hypocalcemia by precipitation with calcium. This can result in prolongation of the QT interval on the electrocardiogram and ventricular dysrhythmias.149 Cerebral edema was present on CT scan in two patients that died of ethylene glycol poisoning.53,161 Precipitation of calcium oxalate crystals in the brain has also been found on autopsy after severe ethylene glycol poisoning5,50,53 and may account for the multiple cranial nerve abnormalities that occasionally develop,39,157 although there is as yet no direct evidence of causation. Peripheral polyradiculoneuropathy has been diagnosed by EMG in a case of ethylene glycol poisoning,4 and intracranial hemorrhage involving the globus pallidus has also occurred.30 A leukemoid reaction may also occur in the setting of severe ethylene glycol poisoning, but the mechanism remains unclear.112,124 One pediatric case of hemophagocytic syndrome and liver failure in the setting of ethylene glycol poisoning resulted in fatality.100 Finally, two patients developed parkinsonism after concomitant poisoning by methanol and ethylene glycol.144
Hemorrhagic gastritis has been reported in association with isopropyl alcohol intoxication. Although this has previously been assumed to be caused by a local irritant effect, one reported case of hemorrhagic gastritis after percutaneous isopropanol exposure suggests that this is not the only mechanism, and may in fact be a specific end-organ effect.43 Hemorrhagic tracheobronchitis has occurred in fatal cases of isopropanol aspiration.2