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Metabolic Acidosis and Thiamine Deficiency

  • Susan A. Romanski
    Correspondence
    Address reprint requests and correspondence to Dr. S·. A. Romanski, Division of Endocrinology, Metabolism, and Nutrition, Mayo Clinic Rochester, 200 First Street SW, Rochester, MN 55905
    Affiliations
    Division of Endocrinology, Metabolism, Nutrition and Internal Medicine, Mayo Clinic Rochester, Rochester, Minnesota
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  • M. Molly McMahon
    Affiliations
    Division of Endocrinology, Metabolism, Nutrition and Internal Medicine, Mayo Clinic Rochester, Rochester, Minnesota
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      We describe a 19-year-old patient who was receiving home parenteral nutrition in whom lactic acidosis developed. A review of her home parenteral nutrition formula revealed the absence of multivitamins, most significantly thiamine. After thiamine administration, the acidosis resolved, and the patient experienced pronounced clinical improvement. Clinicians must be aware that thiamine is essential for normal glucose metabolism and that thiamine deficiency can lead to lactic acidosis. Thiamine deficiency should be included in the differential diagnosis of lactic acidosis. The recent shortage of intravenous multivitamin preparations has led to documented cases of lactic acidosis as a result of thiamine deficiency, and a previous shortage led to several deaths due to lactic acidosis as a consequence of thiamine deficiency. All patients receiving parenteral nutrition must also receive adequate vitamin supplementation.
      CDC (Centers for Disease Control and Prevention), CoA (coenzyme A), ETKA (erythrocyte transketolase activity), PDH (pyruvate dehydrogenase)
      Thiamine, vitamin B1, is essential for normal glucose metabolism. Thiamine deficiency can cause substantial morbidity and even mortality. It should be included in the differential diagnosis of lactic acidosis. Herein we describe a 19-year-old woman who was receiving parenteral nutrition in whom lactic acidosis developed. The patient's condition improved considerably after administration of thiamine.

      REPORT OF CASE

      A 19-year-old woman sought medical advice from her local physician because of a 3-year history of episodic nausea, vomiting, diarrhea, and abdominal pain. Initially, the symptoms had occurred only with her menses and lasted 3 to 5 days. Subsequently, however, the frequency and severity of her symptoms increased to the point that they were almost continuous, and multiple hospitalizations were necessary. Cholecystectomy was performed after a hepatic iminodiacetic acid scan revealed delayed gallbladder emptying, and laparoscopic surgery was performed for mild endometriosis. These operations provided only temporary relief. After a brief time, the patient was unable to tolerate any oral intake and lost 18 kg, 31% of her original body weight.
      Six weeks before the patient's admission to our medical center for evaluation of persistent, unexplained nausea, vomiting, diarrhea, and abdominal pain, a Groshong catheter was placed for parenteral nutrition. Parenteral nutrition was her only source of nutrition, and her weight stabilized after it was initiated.
      Physical examination of the patient revealed a height of 173 cm and a weight of 39.4 kg. Her blood pressure was 130/80 mm Hg while she was supine and 105/65 mm Hg while she was standing. The resting heart rate was 120 beats/min, and the rhythm was regular. Her respiratory rate was 24/min. Her mucous membranes were dry. No mucocutaneous signs of vitamin deficiency were evident. Findings on her thyroid examination were normal. Her abdomen was diffusely tender. Fat and muscle stores were decreased. Skin turgor was good, and no peripheral edema was noted.
      Laboratory tests yielded the following results (normal ranges shown parenthetically): normal complete blood cell count; sodium, 128 mEq/L (135 to 145); potassium, 3.1 mEq/L (3.6 to 4.8); calcium, 10 mg/dL (8.9 to 10.1); magnesium, 2.0 mg/dL (1.7 to 2.1); phosphorus, 3.4 mg/dL (2.5 to 4.5); chloride, 100 mEq/L (100 to 108); bicarbonate, 13 mEq/L (22 to 29); anion gap (measured twice for confirmation), 15 and 20 (7 to 15); creatinine, 0.6 mg/dL (0.6 to 0.9); and albumin, 4.2 g/dL (3.5 to 5). Results of liver tests were normal. The plasma glucose was 299 mg/dL (70 to 100). Arterial blood gas studies while the patient was breathing room air revealed the following results: oxygen tension of 125 torr (70 to 100), carbon dioxide tension of 33 torr (35 to 45), pH of 7.21 (7.35 to 7.45), bicarbonate of 13 mEq/L (21 to 25), and oxygen saturation of 98% (92 to 97). These initial results were diagnostic of an anion gap metabolic acidosis. Further testing was done to determine the cause. The lactate concentration was substantially increased at 9.6 mmol/L (0.93 to 1.65). β-Hydroxybutyrate was normal at 0.1 mmol/L (less than 0.4). Testing for ingestion of substances that can cause an anion gap metabolic acidosis, such as ethylene glycol, methanol, and salicylates, was not performed because of a low index of suspicion.
      Because thiamine deficiency can cause lactic acidosis, we contacted the patient's local parenteral nutrition provider to obtain information about her home parenteral nutrition program. We discovered that, for the preceding 19 days, she had received no multivitamins, trace elements, calcium, or phosphorus. This information, in conjunction with the lactic acidosis, heightened our concern about thiamine deficiency. An erythrocyte transketolase activity (ETKA) level was ordered; however, the test was not completed. The patient received intravenously administered thiamine, 100 mg daily for 2 days, followed by daily administration of 50 mg orally for the next 14 weeks. Ten hours after the first dose of thiamine, the serum bicarbonate level was 24 mEq/L (it had been 13), and the anion gap was 6 (it had been 15). Sixteen hours after the first thiamine dose, the serum lactate level was 2.5 mmol/L (it had been 9.6). Clinically, the patient improved dramatically; her nausea and vomiting resolved, she had less fatigue, and her respiratory rate decreased to 14/min.
      Initially, parenteral nutrition was continued. By the time of dismissal, the patient was able to consume adequate calories and fluids orally, and parenteral nutrition was discontinued.
      Multiple investigations were performed before and during the patient's hospitalization. No definite cause of her initial symptoms was established. Despite our recommendations, she refused to undergo any further investigation.

      DISCUSSION

      Lactic acidosis is one of the most common causes of an anion gap metabolic acidosis in critically ill patients. It is defined as an acid-base disorder, resulting from the accumulation of lactic acid in body fluids. The diagnosis is made by measurement of the serum or plasma lactate concentration in a patient with an increased anion gap. A plasma lactate concentration of 5 mmol/L or greater is diagnostic. The lactate concentration directly correlates with the severity of illness and the patient's prognosis. This increase in the lactate concentration is often, but not necessarily, accompanied by hypobicarbonatemia and acidemia.
      • Madias NE
      Lactic acidosis.
      For lactate measurement, a correct technique is important during sample collection. The essential aspects are to avoid exercise of the arm used for venipuncture and to avoid use of a tourniquet for sample collection, both of which can falsely increase the lactate concentration. Thus, the patient should be at rest before collection of the sample. In addition, a delay in sample analysis, especially a whole blood sample, can cause a falsely increased lactate concentration.
      The differential diagnoses of lactic acidosis are historically classified in two groups: type A, which includes acidosis due to hypoxia, and type B, acidosis not due to hypoxia.
      • Stacpoole PW
      Lactic acidosis.
      Patients with lactic acidosis often have several contributing factors or causes from groups A and B. Causes of type A lactic acidosis include tissue hypoperfusion (such as that due to cardiac failure or decreased systemic vascular resistance) and reduced arterial oxygen content due to pulmonary disease, severe anemia, or carbon monoxide poisoning.
      • Stacpoole PW
      Lactic acidosis.
      Causes of type B acidosis include liver failure, renal failure, cancer, strenuous exercise, seizure, ingestion of large amounts of alcohol by undernourished patients, toxicity due to biguanide therapy, and thiamine deficiency.
      • Stacpoole PW
      Lactic acidosis.
      If thiamine deficiency is suspected, ETKA and thiamine pyrophosphate effect (the percentage of increase in ETKA after addition of thiamine pyrophosphate in vitro) can be measured for an objective documentation of the deficiency.
      • Tanphaichitr V
      Thiamin. In:.
      • Wilson JD
      Vitamin deficiency and excess. In:.
      Although the cause of our patient's lactic acidosis may have been multifactorial, thiamine deficiency was the major cause based on her dramatic clinical and biochemical response to thiamine administration. Another possible factor contributing to her lactic acidosis was tissue hypoperfusion as a result of hypovolemia. This was not a major factor, however, because she did not have hypotension.
      Thiamine, vitamin B1, is a water-soluble vitamin that is essential for normal aerobic metabolism. Its chemical structure is that of a pyrimidine group and a thiazole group joined by a methylene bridge.
      • Tanphaichitr V
      Thiamin. In:.
      (Fig. 1). Dietary sources of thiamine include fortified cereals and grains, legumes and nuts, organ meats, beef, and pork. The recommended daily allowance for thiamine is 0.5 mg/1,000 kcal. It is absorbed by active transport and passive diffusion in the jejunum and ileum.
      • Tanphaichitr V
      Thiamin. In:.
      Figure thumbnail gr1
      Fig. 1Structure of thiamine and its metabolism to thiamine pyrophosphate. ATP = adenosine triphosphate.
      Thiamine is essential for normal glucose metabolism. After absorption, thiamine is phosphorylated in the small bowel to thiamine pyrophosphate. Thiamine pyrophosphate is the cofactor for three important enzymes: pyruvate dehydrogenase (PDH), α-ketoglutarate dehydrogenase, and transketolase.
      • Stryer L
      PDH is a multienzyme complex in the inner mitochondrial membrane that, under aerobic conditions, catalyzes the oxidative decarboxylation of pyruvate to acetyl coenzyme A (CoA). Acetyl CoA can then enter the citric acid cycle.
      • Stryer L
      • Behal RH
      • Buxton DB
      • Robertson JG
      • Olson MS
      Regulation of the pyruvate dehydrogenase muitienzyme complex.
      In thiamine deficiency, pyruvate cannot undergo this conversion, and its concentration increases.
      • Centers for Disease Control and Prevention
      Deaths associated with thiamine-defieient total parenteral nutrition.
      • Velez RJ
      • Myers B
      • Guber MS
      Severe acute metabolic acidosis [acute beriberi): an avoidable complication of total parenteral nutrition.
      This excess pyruvate is then converted to lactate by the action of lactate dehydrogenase
      • Stacpoole PW
      Lactic acidosis.
      (Fig. 2). This conversion also results in the release of protons in equal number to the molecules of lactate produced through hy-drolysis of adenosine triphosphate during anaerobic glycolysis. This production of hydrogen ions leads to the acidosis associated with thiamine deficiency.
      • Madias NE
      Lactic acidosis.
      α-Ketoglutarate dehydrogenase is an enzyme complex that is structurally homologous to PDH. It catalyzes the oxidative decarboxylation of α-ketoglutarate to succinyl CoA. In the thiamine-deficient state, this reaction does not occur efficiently, and a metabolic block in the citric acid cycle develops
      • Stryer L
      • Centers for Disease Control and Prevention
      Deaths associated with thiamine-defieient total parenteral nutrition.
      (Fig. 2). Transketolase catalyzes the reactions of the pentose phosphate pathway. These cytoplasmic reactions produce pentoses for nucleic acid synthesis and the reduced form of nicotinamide-adenine dinucleotide phosphate for other synthetic reactions, including fatty acid synthesis.
      • Rindi G
      Thiamin. In:.
      • Stryer L
      Figure thumbnail gr2
      Fig. 2Role of thiamine, as cofactor thiamine pyrophosphate, in aerobic metabolism. ATP = adenosine triphosphate.
      Because thiamine is water soluble, its stores are more limited than those of fat-soluble vitamins. Thus, in patients whose intake is suboptimal, thiamine deficiency occurs more readily than many other deficiencies. In such patients, the time frame for the development of thiamine deficiency has been estimated to be less than 4 weeks. In January 1989, the Centers for Disease Control and Prevention (CDC) reported three deaths due to refractory lactic acidosis secondary to thiamine deficiency. These patients were receiving parenteral nutrition without thiamine because of a nationwide intravenous multivitamin shortage. Each patient died within 5 weeks after initiation of parenteral nutrition. Autopsies were performed on two of the patients, and examination of the brain tissue revealed necrosis and petechial hemorrhages in the mamillary bodies, hypothalamic neovascularization, and petechial hemorrhage with gliosis and engorgement of parenchymal periaqueductal blood vessels near the third and fourth ventricles; all lesions were diagnostic of acute thiamine deficiency,
      • Centers for Disease Control and Prevention
      Deaths associated with thiamine-defieient total parenteral nutrition.
      In June 1997, the CDC published three additional cases of thiamine deficiency in patients receiving parenteral nutrition without thiamine because of another multivitamin shortage. The stated time range for the development of severe lactic acidosis in those three cases and in several cases reported by other investigators was 7 to 34 days.
      • Centers for Disease Control and Prevention
      Lactic acidosis traced to thiamine deficiency related to nationwide shortage of multivitamins for total parenteral nutrition—United States, 1997.
      In a study of eight healthy male subjects receiving thiamine-deficient diets, urinary excretion of thiamine metabolites was absent after 18 days.
      • Ziporin ZZ
      • Nunes WT
      • Powell RC
      • Waring PP
      • Sauberilch HE
      Thiamine requirement in the adult human as measured by urinary excretion of thiamine metabolites.
      The rate of depletion depends on the clinical setting. Thiamine requirements increase when a person has a fever, experiences physical stress, or is pregnant. A high glucose load, such as that provided with parenteral nutrition, also increases the metabolic demand for thiamine. Thiamine loss may be increased by hemodialysis and peritoneal dialysis, diuretic therapy, and diarrhea. In addition, thiamine absorption is decreased in patients consuming substantial amounts of alcohol and in those with malabsorption or folate deficiency.
      • Tanphaichitr V
      Thiamin. In:.
      • Wilson JD
      Vitamin deficiency and excess. In:.
      In summary, thiamine deficiency may occur after a relatively brief duration of suboptimal intake, especially in critically ill patients who may have one or more of the previously mentioned risk factors. Populations at high risk of thiamine deficiency are those with longterm heavy alcohol ingestion, patients who are malnourished, patients receiving dialysis, and those who require parenteral nutrition. Patients who require parenteral nutrition are at an even greater risk during intravenous multivitamin shortages when vitamin supplementation may be overlooked.
      • Tanphaichitr V
      Thiamin. In:.
      If untreated, thiamine deficiency can lead to serious morbidity and even mortality.
      • Harper CG
      Sudden, unexpected death and Wernicke's encephalopathy: a complication of prolonged intravenous feeding.
      Potential complications include lactic acidosis, Wernicke-Korsakoff syndrome, wet beriberi (cardiac failure and edema), and dry beriberi (peripheral neuropathy and muscle wasting). Fulminant cases of wet beriberi, characterized by tachycardia, dyspnea, cardiomegaly, and circulatory collapse, are referred to as Shoshin beriberi.
      • Meulders Q
      • Laterre PF
      • Sergant M
      • Corbeel L
      Shoshin beriberi: a fulminant beriberi heart disease.
      Another consideration is the indirect morbidity caused by exploratory laparotomies performed to identify and treat presumed intra-abdominal sepsis in some patients with lactic acidosis that is due to undiagnosed thiamine deficiency.
      • Velez RJ
      • Myers B
      • Guber MS
      Severe acute metabolic acidosis [acute beriberi): an avoidable complication of total parenteral nutrition.
      • Kitamura K
      • Takahashi T
      • Tanaka H
      • Shimotsuma M
      • Haglwara A
      • Yamaguchi T
      • et al.
      Two cases of thiamine deficiency-induced lactic acidosis during total parenteral nutrition.
      Finally, thiamine deficiency may contribute to hyperglycemia by means of impaired insulin secretion.
      • Rathanaswaml P
      • Sundaresan R
      Effects of insulin secretagogues on the secretion of insulin during thiamine deficiency.
      Thiamine deficiency may have contributed to our patient's hyperglycemia because her glucose concentration normalized within 24 hours after thiamine administration. In addition, excess caloric administration before admission contributed to her hyperglycemia. Her home parenteral nutrition was providing 217% of her basal caloric needs, as calculated by the Harris-Benedict equation.
      If thiamine deficiency is suspected, thiamine should be administered promptly. A common replacement dose of thiamine is 50 to 100 mg administered intravenously or intramuscularly daily for 7 to 14 days, followed by oral supplementation until recovery is complete.
      • Tanphaichitr V
      Thiamin. In:.
      In patients with suspected thiamine deficiency, thiamine should be administered before or concurrently with dextrose-containing fluids. A glucose load will increase meta bolic demand for thiamine and may precipitate adverse outcomes if it is given before initiation of thiamine therapy.
      • Marcus R
      • Coulston AM
      Water-soluble vitamins: the vitamin B complex and ascorbic acid.
      Thiamine in its usual replacement doses has no associated toxicity. If thiamine is consumed or administered in excess of tissue needs, the surplus is excreted by the kidneys.
      • Tanphaichitr V
      Thiamin. In:.

      SUMMARY

      Thiamine deficiency can cause significant morbidity and even mortality. Administration of thiamine has an extremely low risk of adverse effects. Health-care providers must have a high index of suspicion and err on the side of thiamine supplementation in order to prevent the complications of deficiency. This case report illustrates three important points: (1) thiamine deficiency should be included in the differential diagnosis of lactic acidosis, (2) patients receiving parenteral nutrition must also receive adequate multivitamin supplementation, and (3) assessment of a patient receiving home parenteral nutrition should include an analysis of the content of the home formula.

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