Mice develop signs of encephalopathy 10 days after being rendered thiamine deficient. Immunohistochemistry in these animals demonstrates destruction of the blood–brain barrier with resultant extravasation of albumin.43 Similarly, rats develop symptoms after 10 days of thiamine deficiency and subsequently demonstrate deterioration of the blood–brain barrier with hemorrhage into the mammillary bodies and other areas of the brain.17 This pattern is similar to findings described in humans with Wernicke encephalopathy.84 Although there are no controlled trials of thiamine deprivation in humans, several unfortunate events support this time course. One report describes three patients who were given total parenteral nutrition without multivitamins; signs and symptoms developed in 7, 10, and 14 days, respectively.124 Similar reports confirm this time course with some variability based on the nutritional status of the patients.4,61,74,80 Infants given a soy-based formula that lacked thiamine also developed findings consistent with Wernicke encephalopathy.32
The proximate cause of Wernicke encephalopathy is unclear. In human autopsy studies, brain samples from alcoholic patients with Wernicke-Korsakoff syndrome demonstrate decreased function of pyruvate dehydrogenase, α-ketoglutarate dehydrogenase, and transketolase when compared with controls.15 However, a similar decrease in enzyme activity of neuronal tissue was demonstrated in alcoholics who died from hepatic coma without ever manifesting signs of Wernicke encephalopathy.65 This finding is understandable given that high concentrations of ammonia inhibit α-ketoglutarate dehydrogenase.12 Likewise, the activity of thiamine-requiring Krebs cycle enzymes is reduced in thiamine-replete patients with neurodegenerative diseases.11 Thus, while thiamine deficiency produces deficits in critical enzymes in humans, many have argued that it is unclear whether these deficits are either necessary or sufficient to produce clinical disease.
Animal models offer insight into the mechanisms involved in developing thiamine-deficient neurologic injury. While the exact chain of events leading to these structural abnormalities is unclear, several models demonstrate key portions of the pathway. Thiamine deficiency in rats produces 200% to 640% increases in concentrations of glutamate,64 which presumably results from blockade of α-ketoglutarate dehydrogenase. Excess α-ketoglutarate is shunted away from the Krebs cycle to form glutamate. Rats subsequently develop increases in lactate in vulnerable regions of the brain marked by the induction of the protooncogene c-fos. Both the histochemical lesions and the gene induction can be blocked by the administration of the calcium channel blocker nicardipine.73 This suggests a strong role for excitatory amino acid–induced alterations in calcium transport in the genesis of thiamine-deficient encephalopathy.52 In other animal models of thiamine deficiency, neuronal tissues are also directly injured by oxidative stress and lipid peroxidation.18,45,46,52 Additional investigations demonstrate roles for triggered mast cell degranulation,33 histamine,64 and nitric oxide58 in the generation of neuronal injury. The final common pathway is localized cerebral edema, which may result from altered expression of aquaporin.23
In what may be the most important finding since Wernicke’s original description, is that Kono and colleagues recently described two healthy nonalcoholic brothers who developed signs, symptoms, and neuroimaging findings consistent with Wernicke encephalopathy despite normal serum thiamine concentrations.57 Both brothers were confirmed to have compound mutations of the SLC19A3 gene (K44E and E320Q) encoding for low-affinity thiamine transport (THTR2). High-dose thiamine (up to 600 mg) was clinically effective. The more severe E320Q homozygous THTR2 mutation manifests as impaired thiamine uptake, progressive brain atrophy, bilateral thalami and basal ganglia lesions, and epileptic spasms beginning early in infancy.134 Several other mutations (including G23V and T422A and those inducing premature termination codons) produce loss of thiamine THTR2 transport function and a spectrum of generalized dystonia; epilepsy; and bilateral striatal, caudate, putamen, and cortical lesions.27,99,109 Patients may respond to high-dose thiamine and/or biotin.99 As demonstrated by magnetic resonance imaging, vasogenic edema is a characteristic finding during the acute crises.112 When added to the cases where thiamine was excluded from total parenteral nutrition or infant formula, these findings definitively relate intracellular thiamine concentrations to clinical and anatomical manifestations of Wernicke encephalopathy and thiamine deficiency.
When thiamine is completely removed from the human diet, tachycardia is often the first sign of deficiency. The clinical symptoms of thiamine deficiency present as two distinct patterns: “wet” beriberi or cardiovascular disease and “dry” beriberi, the neurologic disease known as Wernicke-Korsakoff syndrome. Although some patients display symptoms consistent with both disorders, usually either the cardiovascular or the neurologic manifestations predominate. A genetic variant of transketolase activity, combined with low physical activity and low-carbohydrate diet, may predispose to neurologic symptoms, whereas high-carbohydrate diets and increased physical activity lead to cardiovascular symptoms.10,131 Thus, cardiovascular disease is more common in the Asian population, and neurologic disease predominates in the northern European population.
Wet beriberi results from high output cardiac failure induced by peripheral vasodilation and the formation of arteriovenous fistulae secondary to thiamine deficiency. These patients complain of fatigue, decreased exercise tolerance, shortness of breath, and peripheral edema. Myocardial edema may be demonstrated.31 The classic triad of oculomotor abnormalities, ataxia, and global confusion defines dry beriberi or Wernicke encephalopathy. Other manifestations include hypothermia and the absence of deep-tendon reflexes.128 Vomiting and anorexia are common32,124 and may be related to increases in intracranial pressure. Additionally, patients develop a peripheral neuropathy with paresthesias, hypesthesias, and an associated myopathy, all related to axonal degeneration.102 Laboratory studies may reflect a metabolic acidosis with elevated lactate concentration brought on by excessive anaerobic glycolysis resulting from blocked entry of substrate into the Krebs cycle.22,24,55,56,63,81,90,128 Interestingly, a primary respiratory alkalosis of unclear etiology seems to be simultaneously present.29 Korsakoff psychosis, an irreversible disorder of learning and processing of new information characterized by a deficit in short-term memory and confabulation, often occurs together with Wernicke encephalopathy.125 A 10% to 20% mortality rate is associated with Wernicke encephalopathy, with survivors having an 80% risk of developing Korsakoff psychosis.86
A clinical tool for identifying patients with Wernicke encephalopathy used four signs: dietary deficiencies, oculomotor abnormalities, cerebellar dysfunction, and either an altered mental status or mild memory impairment. When two or more signs were present the tool was highly sensitive and specific.16
Epidemiology: Populations at Risk
In the United States, a healthy diet and mandatory thiamine supplementation of numerous food products protect most people from the manifestations of thiamine deficiency. Despite this, the prevalence of Wernicke encephalopathy in the general US population is estimated to be between 0.2% and 2.2%, although only 20% of these cases are estimated to be diagnosed during their lifetime.68,108 This is, unfortunately, not true in other countries. A survey of the 17 major public hospitals in the Sydney, Australia, area identified more than 1000 cases of either acute Wernicke encephalopathy or Korsakoff psychosis between 1978 and 1993.70 Similarly, a single Australian hospital identified 32 cases of Wernicke encephalopathy during a 33-month period.132 In Australia, mandatory supplementation of flour with thiamine in 1991 resulted in a dramatic reduction in hospitalized cases during 1992 and 1993,70 as well as of the percentage of cases diagnosed by postmortem studies.44 Other countries at risk include Ireland and New Zealand, where lack of a mandatory thiamine supplementation program is correlated with a high prevalence of biochemical evidence of thiamine deficiency.78
Alcoholic patients, whose consumption of ethanol is their major source of calories, are the best described and most easily recognized patients at risk for thiamine deficiency.86 In Scotland, 21% of alcoholics requiring emergency admission to the hospital were thiamine deficient, as determined by erythrocyte transketolase.50 The prevalence in US alcoholics is estimated to be 12.5%.108
Consequential thiamine deficiency is also described in incarcerated prisoners,51 patients in drug rehabilitation,35 patients receiving hemodialysis,28 patients with hyperemesis gravidarum or anorexia nervosa,115 patients receiving parenteral nutrition,4,20,21,24,61,63,80,81,111,124,126 patients with acquired immunodeficiency syndrome (AIDS),5,13,14,95 patients with malignancies,9,59,91,123 the institutionalized elderly,60,77, 78, and 79 critically ill children,53,66 patients with sepsis,29 patients with congestive heart failure on furosemide therapy,60 patients with malabsorption secondary to Clostridium difficile diarrhea,26 patients with eating disorders,127 and most recently, patients who had undergone bariatric surgery.1,3,34,37,96 Thus, despite routine dietary supplementation, many people are still at risk because of dietary limitations, alcohol abuse, or underlying medical or surgical conditions.