Lactic acidosis, thiamin deficiency

The authors suggested that in any patient receiving parenteral nutrition without added vitamins who develops lactic acidosis, thiamine deficiency should be suspected. 

The answer is B. While all of the listed conditions are consistent with lethargy and developmental defects, the lactic acidosis rules out pyruvate kinase deficiency. Thiamine and niacin deficiencies are unlikely due to the lack of effect of vitamin supplementation. Excess pyruvate is the source of the elevated alanine in the serum. The clinical findings are thus consistent with pyruvate carboxylase deficiency, which is associated with severe hypoglycemia due to fasting due to impaired gluconeogenesis. 

Thiamin-Responsive Pyruvate Dehydrogenase Deficiency Genetic deficiency of pyruvate dehydrogenase Ela (which is on the X chromosome) leads to potentially fatal lactic acidosis, with psychomotor retardation, central nervous system damage, atrophy of muscle fibers and ataxia, and developmental delay. At least some cases respond to the administration of high doses (20 to 3,000 mg per day) of thiamin. In those cases where the enzyme has been studied, there is a considerable increase in the of the enzyme for thiamin diphosphate. Female carriers of this X-linked disease are affected to a variable extent, depending on the X-chromosome inactivation pattern in different tissues (Robinson et al., 1996). 

In the second case, the authors were unsure if the associated graft failure was due to the acute metabolic acidosis or thiamine deficiency, since the absence of thiamine in the diet leads to poor glucose oxidation, resulting in accumulation of lactic acid and metabolic acidosis, which is refractory to any treatment except thiamine supplementation. 

Lactic acidosis can occur through thiamine deficiency during parenteral nutrition (73). 

A thorough nutrition-focused history and physical examination is the most valuable means of screening patients for vitamin deficiency or toxicity (Table 135-9). It is uncommon to see a single vitamin deficiency usually multiple vitamin deficiencies occur with general malnutrition. Single vitamin deficiencies do occur, however. Thiamine deficiency may result in lactic acidosis and encephalopathy, whereas pernicious anemia due to vitamin B12 deficiency has been reported with increasing frequency, especially in the elderly. Recently, the incidence of vitamin D deficiency has increased in children. Laboratory assessment may be useful to confirm the clinical suspicion of a deficiency state. The first indication of a deficiency is usually a fall in circulating serum concentrations of the vitamin or its coenzyme. 

Centers for Disease Control and Prevention. Lactic acidosis traced to thiamin deficiency related to nationwide shortage of multivitamins fortotal parenteral nutrition—United States, 1997. JAMA 1997 278 109-111. 

One of serious complications of thiamine deficiency caused by the impairment of pyruvate utilization by PDHC is metabolic lactic acidosis. This is recognized as the sole condition responsible for lethal outcome of some misdiagnosed or lately treated thiamine-deficient patients (Klein et al. 2004) (Figure 33.1). 

However, there are no clear cut-off values for basic laboratory parameters, which could be useful for preselecting patients at risk of potential detrimental conditions. Some parameters that are easy to detect, such as lactic/pyruvic metabolic acidosis, are not specific for thiamine deficiency (Table 33.2). On the other hand, blood TDP and transketolase assays have low sensitivity due to significant overlapping results between healthy and thiamine-deficient individuals. This makes laboratory assessment of borderline thiamine deficiency conditions difficult. Thus, anamnesis and awareness of the socio-demographic conditions of the patient are as important as laboratory tests in the early diagnosis of thiamine deficiency. 

The role of thiamin diphosphate in pyruvate dehydrogenase means that in deficiency there is impaired conversion of pyruvate to acetyl CoA, and hence impaired entry of pyruvate into the citric acid cycle (section 5.4.3.1). Especially in subjects on a relatively high-carbohydrate diet, this results in increased plasma concentrations of lactate and pyruvate, which may lead to life-threatening lactic acidosis (see also Problem 5.2). 

While peripheral neuritis and acute cardiac beriberi with lactic acidosis occur in thiamin deficiency associated with alcohol abuse, the more usual presentation is as the Wernicke—Korsakoff syndrome, due to central nervous system lesions. Initially there is a confused state, Korsakoff s psychosis, which is characterized by confabulation and loss of recent memory, although memory for past events may be unimpaired. Later, clear neurological signs develop — Wernicke s encephalopathy. This is characterized by nystagmus and extraocular palsy. Post-mortem examination shows characteristic brain lesions. 

Beriberi is caused by a deficiency of thiamin (also called thiamine, aneurin(e), and vitamin Bj). Classic overt thiamin deficiency causes cardiovascular, cerebral, and peripheral neurological impairment and lactic acidosis. The disease emerged in epidemic proportions at the end of the nineteenth century in Asian and Southeast Asian countries. Its appearance coincided with the introduction of the roller mills that enabled white rice to be produced at a price that poor people could afford. Unfortunately, milled rice is particularly poor in thiamin thus, for people for whom food was almost entirely rice, there was a high risk of deficiency and mortality from beriberi. Outbreaks of acute cardiac beriberi still occur, but usually among people who live under restricted conditions. The major concern today is subclinical deficiencies in patients with trauma or among the elderly. There is also a particular form of clinical beriberi that occurs in patients who abuse alcohol, known as the Wer-nicke-Korsakoff syndrome. Subclinical deficiency may be revealed by reduced blood and urinary thiamin levels, elevated blood pyruvate/lactate concentrations and a-ketoglutarate activity, and decreased erythrocyte transketolase (ETKL) activity. Currently, the in vitro stimulation of ETKL activity by thiamin diphosphate (TDP) is the most useful functional test of thiamin status where an acute deficiency state may have occurred. The stimulation is measured as the TDP effect. 

Brunette, M.G., Delvin, E., Hazel, B. and Scriver, C.R. (1972), Thiamin responsive lactic acidosis in a patient with deficient low Km pyruvate carboxylase activity in liver. Pediatrics, 50,702. 

Maesaka, H., Kamiya, K., Misugi, K. and Tada, K. (1976), Hyperalaninemia, hyper-pyruvicemia, and lactic acidosis due to pyruvate carboxylase deficiency of liver. Treatment with thiamine and lipoic acid. Eur. J. Pediatr., 122,159. 

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