A 2-month-old boy is brought to the emergency department due to irritability and vomiting. The patient is exclusively breastfed but has not been tolerating feeds since yesterday. Urine output has decreased. The mother has a history of obesity and had gastric bypass surgery several years prior to pregnancy. Temperature is 37 C (98.6 F), pulse is 190/min, and respirations are 60/min. The patient is in moderate respiratory distress and has an enlarged liver. Physical examination is otherwise normal. Chest radiography reveals cardiomegaly. Further work-up shows impaired carbohydrate metabolism with increased serum levels of lactate and decreased erythrocyte transketolase activity. Which of the following additional enzymes is most likely to have impaired activity in this patient?
Thiamine deficiency | |
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*Thiamine is a cofactor for transketolase, pyruvate dehydrogenase, & α-ketoglutarate dehydrogenase. | |
This patient has decreased activity of erythrocyte transketolase (ETKA), a thiamine-dependent enzyme in the pentose phosphate pathway. This finding is essentially diagnostic for thiamine (vitamin B1) deficiency. The primary risk factor for thiamine deficiency is malnutrition; in this case, gastric bypass surgery without appropriate micronutrient supplementation likely led to maternal thiamine deficiency and, in turn, to deficiency in this exclusively breastfed infant.
In addition to involvement in transketolase activity, thiamine is a cofactor for other enzymes involved in glucose metabolism (eg, 2-carbon transfer, decarboxylation), including alpha-ketoglutarate dehydrogenase and pyruvate dehydrogenase (converts pyruvate to acetyl-CoA). Impaired pyruvate dehydrogenase activity diverts pyruvate to the anaerobic glycolysis pathway, which produces lactate. Lactic acidosis leads to decreased peripheral vascular resistance, which contributes to the classic finding of high-output heart failure. However, over time, direct impairment of myocyte energy production leads to reduced cardiac contractility and a low-output state.
Myocardial dysfunction due to thiamine deficiency is referred to as wet beriberi. Infantile beriberi is rare but often fulminant, with symptoms related to pulmonary/systemic fluid overload, including feeding intolerance and respiratory distress, as well as cardiomegaly and hepatomegaly, as seen in this patient. Wet beriberi can be fatal without prompt thiamine supplementation.
(Choice A) Alpha-1,4-glucosidase deficiency (Pompe disease) causes cardiomegaly due to glycogen accumulation in myocytes; heart failure can lead to hepatomegaly. Infants typically have profound weakness and hypotonia, findings not present in this patient. Moreover, ETKA and lactate would be normal.
(Choice B) Alpha-L-iduronidase deficiency (Hurler syndrome) results in the accumulation of glycosaminoglycans and often presents with hepatomegaly; heart failure can also occur. In contrast to this patient, characteristic coarse facial features and recurrent respiratory infections are expected; serum lactate and ETKA would be normal.
(Choice C) Galactose-1-phosphate uridyltransferase deficiency (galactosemia) results in impaired galactose metabolism. Hepatomegaly and vomiting are common but typically develop in the first week of life and are associated with jaundice and hypotonia. ETKA would be normal.
(Choice D) Glucose-6-phosphatase deficiency (von Gierke disease) results in accumulation of glycogen in the liver, causing hepatomegaly; lactic acidosis is common. However, cardiomegaly would not be seen, and ETKA would be normal.
Educational objective:
Decreased erythrocyte transketolase activity is seen with deficiency of thiamine (vitamin B1), which is a cofactor for several enzymes (eg, pyruvate dehydrogenase) involved in glucose metabolism. Severe deficiency can lead to heart failure (wet beriberi), which in infants may manifest as respiratory distress and feeding intolerance with cardiomegaly and hepatomegaly.