Case Report Metabolic Acidosis and Thiamine Deficiency SUSAN A. ROMANSKI, M.D., AND M. MOLLY McMAHON, M.D. 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 T hiamine, vitamin B 1 , is essential for normal glucose metaboli sm. Thiamine deficiency can cause sub- stantial morbidity and even mortality . It should be in- cluded in the differential diagnosis of lactic acidosis. Herein we describe a 19-year-old woman who was receiv- ing parenteral nutrition in whom lactic acidosis developed. The patient's condition improved considerably after ad- ministration 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 gallblad- der emptying , and laparoscopic surgery was performed for mild endometriosis. These operations provided only tem- porary 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 cath- From the Division of Endocrinology, Metabolism, Nutrition and Inter- nal Medicine, Mayo Clinic Rochester, Rochester, Minnesota. Address reprint requests and correspondence to Dr. 5·. A. Romanski, Division of Endocrinology, Metabolism, and Nutrition, Mayo Clinic Rochester, 200 First Street SW, Rochester, MN 55905. Mayo CUn Proc 1999;74:259-263 259 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. Mayo Clin Proc 1999;74:259-263 CDC = Centers for Disease Control and Prevention; CoA = coenzyme A; ETKA = erythrocyte transketolase activity; PDH =pyruvate dehydrogenase eter was placed for parenteral nutrition. Parenteral nutri- tion was her only source of nutrition , and her weight stabi- lized after it was initiated. Physical examination of the patient revealed a height of 173 ern 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 muco- cutaneous signs of vitamin deficiency were evident. Find- ings on her thyroid examination were normal. Her abdo- men 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 mEqlL (135 to 145); potassium, 3.1 mEqlL (3.6 to 4.8); calcium, IO mg/dL (8.9 to 10.1); mag- nesium , 2.0 mg/dL (1.7 to 2.1); phosphorus , 3.4 mg/dL (2.5 to 4.5); chloride , 100 mEqlL (100 to 108); bicarbonate , 13 mEqlL (22 to 29); anion gap (measured twice for confirma- tion), 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 of33 torr (35 to 45), pH of 7.21 (7.35 to 7.45), bicarbonate of 13 mEqJL (2 1 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). was normal at © 1999 Mayo Founda tion/ or Medical Education and Research For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.
Metabolic Acidosis and Thiamine Deficiency
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Metabolic Acidosis and Thiamine DeficiencySUSAN A. ROMANSKI, M.D., AND M. MOLLY McMAHON, M.D.
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
T hiamine, vitamin B 1 , is essential for normal glucose
metaboli sm. Thiamine deficiency can cause sub stantial morbidity and even mortality . It should be in cluded in the differential diagnosis of lactic acidosis. Herein we describe a 19-year-old woman who was receiv ing parenteral nutrition in whom lactic acidosis developed. The patient's condition improved considerably after ad ministration 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 gallblad der emptying , and laparoscopic surgery was performed for mild endometriosis. These operations provided only tem porary 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 cath-
Fromthe Division of Endocrinology, Metabolism, Nutrition and Inter nal Medicine, Mayo Clinic Rochester, Rochester, Minnesota.
Address reprint requests and correspondence to Dr. 5·. A. Romanski, Division of Endocrinology, Metabolism, and Nutrition, Mayo Clinic Rochester, 200 First Street SW, Rochester, MN 55905.
Mayo CUn Proc 1999;74:259-263 259
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.
Mayo Clin Proc 1999;74:259-263
CDC = Centers for Disease Control and Prevention; CoA = coenzyme A; ETKA = erythrocyte transketolase activity ; PDH =pyruvate dehydrogenase
eter was placed for parenteral nutrition. Parenteral nutri tion was her only source of nutrition , and her weight stabi lized after it was initiated.
Physical examination of the patient revealed a height of 173 ern 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 muco cutaneous signs of vitamin deficiency were evident. Find ings on her thyroid examination were normal. Her abdo men 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 mEqlL (135 to 145); potassium, 3.1 mEqlL (3.6 to 4.8); calcium, IO mg/dL (8.9 to 10.1); mag nesium, 2.0 mg/dL (1.7 to 2.1); phosphorus , 3.4 mg/dL (2.5 to 4.5); chloride , 100 mEqlL (100 to 108); bicarbonate , 13 mEqlL (22 to 29); anion gap (measured twice for confirma tion), 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 of33 torr (35 to 45), pH of 7.21 (7.35 to 7.45), bicarbonate of 13 mEqJL (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). ~-Hydroxybutyrate was normal at
© 1999 Mayo Founda tion/ or Medical Education and Research
For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.
260 Thiamine Deficiency
0.1 mmol/L (less than 0.4). Testing for ingestion of sub stances 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 pro vider to obtain information about her home parenteral nu trition 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 thia mine deficiency. An erythrocyte transketolase activity (ETKA) level was ordered; however , the test was not com pleted. The patient received intravenously administered thiamine, 100 mg daily for 2 days, followed by daily ad ministration 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 dramaticall y; 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 dis continued.
Multiple investigations were performed before and dur ing the patient's hospitalization. No definite cause of her initial symptoms was established. Despite our recommen dations, 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 accu mulation of lactic acid in body fluids. The diagnosi s is made by measurement of the serum or plasma lactate con centration in a patient with an increased anion gap. A plasma lactate concentration of 5 mmol/L or greater is diagnostic. The lactate concentration directly correlate s 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. I
For lactate measurement, a correct technique is im portant during sample collection. The essential aspects are to avoid exercise of the ann 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
Mayo Clin Proc , March 1999, Vol 74
a whole blood sample, can cause a falsely increased lactate concentration.
The differential diagnoses of lactic acidosis are histori cally classified in two groups : type A, which includes acidosis due to hypoxia , and type B, acidosis not due to hypoxia.' Patients with lactic acidosis often have several contributing factors or causes from groups A and B. Causes of type A lactic acidosis include tissue hypoperfu sion (such as that due to cardiac failure or decreased sys temic vascular resistance) and reduced arterial oxygen con tent due to pulmonary disease , severe anemia, or carbon monoxide poisoning. ' Causes of type B acidosis include liver failure, renal failure, cancer , strenuous exercise, sei zure , ingestion of large amounts of alcohol by undernour ished patients, toxicity due to biguanide therapy, and thia mine deficienc y.' If thiamine deficiency is suspected , ETKA and thiamine pyrophosphate effect (the percentage of increase in ETKA after addition of thiamine pyrophos phate in vitro) can be measured for an objective documen tation of the deficiency.v'
Although the cause of our patient's lactic acido sis may have been multifactorial, thiamine deficiency was the major cause based on her dramatic clinical and bio chemical 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 B I , 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! (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/I ,OOO kcal. It is absorbed by active transport and passive diffusion in the jejunum and ileum.'
Thiamine is essential for normal glucose metaboli sm. After absorption , thiamine is phosphorylated in the small bowel to thiamine pyrophosphate. Thiamine pyrophos phate is the cofactor for three important enzymes: pyruvate dehydrogenase (PDH), a-ketoglutarate dehydrogenase, and transketolase. " PDH is a multienzyme complex in the inner mitochondrial membrane that, under aerobic condi tions, catalyzes the oxidati ve decarboxylation of pyruvate to acetyl coenzyme A (CoA). Acetyl CoA can then enter the citric acid cycle.l" In thiamine deficiency, pyruvate cannot undergo this conversion, and its concentration in creases. " This excess pyruvate is then converted to lactate by the action of lactate dehydrogenase- (Fig. 2). This conversion also results in the release of protons in equal number to the molecules of lactate produced through hy-
For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.
Mayo CIin Proc, March 1999, Vol 74
Thiamine tATP
Thiamine Deficiency 261
Fig. 1. Structure of thiamine and its metabolism to thiamine pyrophosphate. ATP = adenosine triphosphate.
drolysis of adenosine triphosphate during anaerobic glycol ysis. This production of hydrogen ions leads to the acido sis associated with thiamine deficiency. 1 o-Ketoglutarate dehydrogenase is an enzyme complex that is structur ally homologous to PDH. It catalyzes the oxidative de carboxylation of n-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-? (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."?
Because thiamine is water soluble, its stores are more limited than those offat-soluble vitamins. Thus, in patients whose intake is suboptimal, thiamine deficiency occurs more readily than many other deficiencies. In such pa tients, 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 Preven tion (CDC) reported three deaths due to refractory lactic acidosis secondary to thiamine deficiency. These patients were receiving parenteral nutrition without thiamine be cause 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 bod ies, hypothalamic neovascularization, and petechial hem orrhage with gliosis and engorgement of parenchymal
periaqueductal blood vessels near the third and fourth ven tricles; all lesions were diagnostic of acute thiamine defi ciency.' In June 1997, the CDC published three additional cases of thiamine deficiency in patients receiving par enteral nutrition without thiamine because of another mul tivitamin shortage. The stated time range for the develop ment of severe lactic acidosis in those three cases and in several cases reported by other investigators was 7 to 34 days." In a study of eight healthy male subjects receiving thiamine-deficient diets, urinary excretion of thiamine me tabolites was absent after 18 days." 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 meta bolic demand for thiamine. Thiamine loss may be in creased 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 defi ciency.v' In summary, thiamine deficiency may occur after a relatively brief duration of suboptimal intake, espe cially 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 long term heavy alcohol ingestion, patients who are malnour ished, patients receiving dialysis, and those who require parenteral nutrition. Patients who require parenteral nutri tion are at an even greater risk during intravenous multivi tamin shortages when vitamin supplementation may be overlooked. 3
For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.
LOH .. lactate dehydrogenase
POH - pyruvate dehydrogenase
TPP .. thiamine pyrophosphate
262 Thiamine Deficiency
t acid ~ \ cycle a-ketoglutarate
Mayo Clin Proc, March 1999, Vol 74
Fuel is completely
oxidized and coupled
to phosphorylation in
reducing substances
Fig. 2. Role of thiamine, as cofactor thiamine pyrophosphate, in aerobic metabolism. ATP = adenosine tri phosphate.
If untreated, thiamine deficiency can lead to serious morbidity and even mortality." 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 re ferred to as Shoshin beriberi. 14 Another consideration is the indirect morbidity caused by exploratory laparotomies per formed to identify and treat presumed intra-abdominal sepsis in some patients with lactic acidosis that is due to undiagnosed thiamine deficiency.v" Finally, thiamine de ficiency may contribute to hyperglycemia by means of impaired insulin secretion. 16
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.' In pa tients with suspected thiamine deficiency, thiamine should be administered before or concurrently with dex trose-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 ther apy." Thiamine in its usual replacement doses has no associated toxicity. If thiamine is consumed or adminis tered in excess of tissue needs, the surplus is excreted by the kidneys.'
SUMMARY Thiamine deficiency can cause significant morbidity and even mortality. Administration of thiamine has an ex tremely low risk of adverse effects. Health-care pro viders 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) assess ment of a patient receiving home parenteral nutrition should include an analysis of the content of the home formula.
For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.
Mayo Clin Proc, March 1999, Vol 74
REFERENCES 1. Madias NE. Lactic acidosis. Kidney Int 1986;29:752-774 2. Stacpoole PW. Lactic acidosis. Endocrinol Metab Clin North Am
1993 Jun;22:221-245 3. Tanphalchltr V. Thiamin. In: Shils ME, Olson JA, Shike M, editors.
Modern Nutrition in Health and Disease. Vol 1. 8th ed. Philadelphia: Lea & Febiger; 1994. pp 359-365
4. Wilson JD. Vitamin deficiency and excess. In: Isselbacher KJ, Braunwald E, Wilson JD, Martin JB, Fauci AS, Kasper DL, editors. Harrison's Principles of Internal Medicine. 13th ed. New York: McGraw-Hili; 1994. pp 472-480
5. Stryer L. Biochemistry. 2nd ed. San Francisco: WH Freeman; 1981. pp 281-304
6. Behal RH, Buxton DB, Robertson JG, Olson MS. Regulation of the pyruvate dehydrogenase muitienzyme complex. Annu Rev Nutr 1993;13:497-520
7. Centers for Disease Control and Prevention. Deaths associated with thiamine-deficient total parenteral nutrition. MMWR Morb Mortal Wkly Rep 1989;38:43-46
8. Velez RJ,Myers B, Guber MS. Severe acute metabolic acidosis (acute beriberi): an avoidable complication of total parenteral nutrition. JPEN J Parenter Enteral Nutr 1985;9:216-219
9. Rlndl G. Thiamin. In: Ziegler EE, Filer U Jr, editors. Present Knowledge in Nutrition. 7th ed. Washington (DC): ILSI Press; 1996. pp 160-166
10. Stryer L. Biochemistry. 2nd ed. San Francisco: WH Freeman; 1981. pp 331-355
Thiamine Deficiency 263
11. 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. MMWR Morb Mortal WklyRep 1997;46:523-528
12. Ziporln ZZ, Nunes WT, Powell RC, Waring PP, Sauberllch HE. Thia mine requirement in the adult human as measured by urinary excretion of thiamine metabolites. J Nutr 1965;85:297-304
13. Harper CG. Sudden, unexpected death and Wernicke's en cephalopathy: a complication of prolonged intravenous feeding. Aust N Z J Med 1980;10:230-235
14. Meulders Q, Laterre PF, Sergant M, Corbeel L. Shoshin beriberi: a fulminant beriberi heart disease. Acta Clin Belg 1988;43:115 119
15. Kitamura K, Takahashi T, Tanaka H, Shlmotsuma M, Haglwara A, Yamaguchi T, et al. Two cases of thiamine deficiency-induced lactic acidosis during total parenteral nutrition. Tohoku J Exp Med 1993; 171:129-133
16. Rathanaswaml P, Sundaresan R. Effects of insulin secretagogues on the secretion of insulin during thiamine deficiency. Biochem Int 1988;17:523-528
17. Marcus R, Coulston AM. Water-soluble vitamins: the vitamin B complex and ascorbic acid. In: Hardman JG, Limbird LE, Molinoff PB, Ruddon RW.Gilman AG,editors. Goodman and Gilman's ThePharma cological Basis of Therapeutics. 9th ed. New York: McGraw-Hili; 1996. pp 1555-1557
For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.
Metabolic Acidosis and Thiamine Deficiency
REPORT OF CASE
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
T hiamine, vitamin B 1 , is essential for normal glucose
metaboli sm. Thiamine deficiency can cause sub stantial morbidity and even mortality . It should be in cluded in the differential diagnosis of lactic acidosis. Herein we describe a 19-year-old woman who was receiv ing parenteral nutrition in whom lactic acidosis developed. The patient's condition improved considerably after ad ministration 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 gallblad der emptying , and laparoscopic surgery was performed for mild endometriosis. These operations provided only tem porary 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 cath-
Fromthe Division of Endocrinology, Metabolism, Nutrition and Inter nal Medicine, Mayo Clinic Rochester, Rochester, Minnesota.
Address reprint requests and correspondence to Dr. 5·. A. Romanski, Division of Endocrinology, Metabolism, and Nutrition, Mayo Clinic Rochester, 200 First Street SW, Rochester, MN 55905.
Mayo CUn Proc 1999;74:259-263 259
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.
Mayo Clin Proc 1999;74:259-263
CDC = Centers for Disease Control and Prevention; CoA = coenzyme A; ETKA = erythrocyte transketolase activity ; PDH =pyruvate dehydrogenase
eter was placed for parenteral nutrition. Parenteral nutri tion was her only source of nutrition , and her weight stabi lized after it was initiated.
Physical examination of the patient revealed a height of 173 ern 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 muco cutaneous signs of vitamin deficiency were evident. Find ings on her thyroid examination were normal. Her abdo men 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 mEqlL (135 to 145); potassium, 3.1 mEqlL (3.6 to 4.8); calcium, IO mg/dL (8.9 to 10.1); mag nesium, 2.0 mg/dL (1.7 to 2.1); phosphorus , 3.4 mg/dL (2.5 to 4.5); chloride , 100 mEqlL (100 to 108); bicarbonate , 13 mEqlL (22 to 29); anion gap (measured twice for confirma tion), 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 of33 torr (35 to 45), pH of 7.21 (7.35 to 7.45), bicarbonate of 13 mEqJL (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). ~-Hydroxybutyrate was normal at
© 1999 Mayo Founda tion/ or Medical Education and Research
For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.
260 Thiamine Deficiency
0.1 mmol/L (less than 0.4). Testing for ingestion of sub stances 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 pro vider to obtain information about her home parenteral nu trition 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 thia mine deficiency. An erythrocyte transketolase activity (ETKA) level was ordered; however , the test was not com pleted. The patient received intravenously administered thiamine, 100 mg daily for 2 days, followed by daily ad ministration 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 dramaticall y; 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 dis continued.
Multiple investigations were performed before and dur ing the patient's hospitalization. No definite cause of her initial symptoms was established. Despite our recommen dations, 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 accu mulation of lactic acid in body fluids. The diagnosi s is made by measurement of the serum or plasma lactate con centration in a patient with an increased anion gap. A plasma lactate concentration of 5 mmol/L or greater is diagnostic. The lactate concentration directly correlate s 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. I
For lactate measurement, a correct technique is im portant during sample collection. The essential aspects are to avoid exercise of the ann 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
Mayo Clin Proc , March 1999, Vol 74
a whole blood sample, can cause a falsely increased lactate concentration.
The differential diagnoses of lactic acidosis are histori cally classified in two groups : type A, which includes acidosis due to hypoxia , and type B, acidosis not due to hypoxia.' Patients with lactic acidosis often have several contributing factors or causes from groups A and B. Causes of type A lactic acidosis include tissue hypoperfu sion (such as that due to cardiac failure or decreased sys temic vascular resistance) and reduced arterial oxygen con tent due to pulmonary disease , severe anemia, or carbon monoxide poisoning. ' Causes of type B acidosis include liver failure, renal failure, cancer , strenuous exercise, sei zure , ingestion of large amounts of alcohol by undernour ished patients, toxicity due to biguanide therapy, and thia mine deficienc y.' If thiamine deficiency is suspected , ETKA and thiamine pyrophosphate effect (the percentage of increase in ETKA after addition of thiamine pyrophos phate in vitro) can be measured for an objective documen tation of the deficiency.v'
Although the cause of our patient's lactic acido sis may have been multifactorial, thiamine deficiency was the major cause based on her dramatic clinical and bio chemical 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 B I , 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! (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/I ,OOO kcal. It is absorbed by active transport and passive diffusion in the jejunum and ileum.'
Thiamine is essential for normal glucose metaboli sm. After absorption , thiamine is phosphorylated in the small bowel to thiamine pyrophosphate. Thiamine pyrophos phate is the cofactor for three important enzymes: pyruvate dehydrogenase (PDH), a-ketoglutarate dehydrogenase, and transketolase. " PDH is a multienzyme complex in the inner mitochondrial membrane that, under aerobic condi tions, catalyzes the oxidati ve decarboxylation of pyruvate to acetyl coenzyme A (CoA). Acetyl CoA can then enter the citric acid cycle.l" In thiamine deficiency, pyruvate cannot undergo this conversion, and its concentration in creases. " This excess pyruvate is then converted to lactate by the action of lactate dehydrogenase- (Fig. 2). This conversion also results in the release of protons in equal number to the molecules of lactate produced through hy-
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Thiamine tATP
Thiamine Deficiency 261
Fig. 1. Structure of thiamine and its metabolism to thiamine pyrophosphate. ATP = adenosine triphosphate.
drolysis of adenosine triphosphate during anaerobic glycol ysis. This production of hydrogen ions leads to the acido sis associated with thiamine deficiency. 1 o-Ketoglutarate dehydrogenase is an enzyme complex that is structur ally homologous to PDH. It catalyzes the oxidative de carboxylation of n-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-? (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."?
Because thiamine is water soluble, its stores are more limited than those offat-soluble vitamins. Thus, in patients whose intake is suboptimal, thiamine deficiency occurs more readily than many other deficiencies. In such pa tients, 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 Preven tion (CDC) reported three deaths due to refractory lactic acidosis secondary to thiamine deficiency. These patients were receiving parenteral nutrition without thiamine be cause 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 bod ies, hypothalamic neovascularization, and petechial hem orrhage with gliosis and engorgement of parenchymal
periaqueductal blood vessels near the third and fourth ven tricles; all lesions were diagnostic of acute thiamine defi ciency.' In June 1997, the CDC published three additional cases of thiamine deficiency in patients receiving par enteral nutrition without thiamine because of another mul tivitamin shortage. The stated time range for the develop ment of severe lactic acidosis in those three cases and in several cases reported by other investigators was 7 to 34 days." In a study of eight healthy male subjects receiving thiamine-deficient diets, urinary excretion of thiamine me tabolites was absent after 18 days." 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 meta bolic demand for thiamine. Thiamine loss may be in creased 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 defi ciency.v' In summary, thiamine deficiency may occur after a relatively brief duration of suboptimal intake, espe cially 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 long term heavy alcohol ingestion, patients who are malnour ished, patients receiving dialysis, and those who require parenteral nutrition. Patients who require parenteral nutri tion are at an even greater risk during intravenous multivi tamin shortages when vitamin supplementation may be overlooked. 3
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LOH .. lactate dehydrogenase
POH - pyruvate dehydrogenase
TPP .. thiamine pyrophosphate
262 Thiamine Deficiency
t acid ~ \ cycle a-ketoglutarate
Mayo Clin Proc, March 1999, Vol 74
Fuel is completely
oxidized and coupled
to phosphorylation in
reducing substances
Fig. 2. Role of thiamine, as cofactor thiamine pyrophosphate, in aerobic metabolism. ATP = adenosine tri phosphate.
If untreated, thiamine deficiency can lead to serious morbidity and even mortality." 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 re ferred to as Shoshin beriberi. 14 Another consideration is the indirect morbidity caused by exploratory laparotomies per formed to identify and treat presumed intra-abdominal sepsis in some patients with lactic acidosis that is due to undiagnosed thiamine deficiency.v" Finally, thiamine de ficiency may contribute to hyperglycemia by means of impaired insulin secretion. 16
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.' In pa tients with suspected thiamine deficiency, thiamine should be administered before or concurrently with dex trose-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 ther apy." Thiamine in its usual replacement doses has no associated toxicity. If thiamine is consumed or adminis tered in excess of tissue needs, the surplus is excreted by the kidneys.'
SUMMARY Thiamine deficiency can cause significant morbidity and even mortality. Administration of thiamine has an ex tremely low risk of adverse effects. Health-care pro viders 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) assess ment of a patient receiving home parenteral nutrition should include an analysis of the content of the home formula.
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1993 Jun;22:221-245 3. Tanphalchltr V. Thiamin. In: Shils ME, Olson JA, Shike M, editors.
Modern Nutrition in Health and Disease. Vol 1. 8th ed. Philadelphia: Lea & Febiger; 1994. pp 359-365
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11. 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. MMWR Morb Mortal WklyRep 1997;46:523-528
12. Ziporln ZZ, Nunes WT, Powell RC, Waring PP, Sauberllch HE. Thia mine requirement in the adult human as measured by urinary excretion of thiamine metabolites. J Nutr 1965;85:297-304
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14. Meulders Q, Laterre PF, Sergant M, Corbeel L. Shoshin beriberi: a fulminant beriberi heart disease. Acta Clin Belg 1988;43:115 119
15. Kitamura K, Takahashi T, Tanaka H, Shlmotsuma M, Haglwara A, Yamaguchi T, et al. Two cases of thiamine deficiency-induced lactic acidosis during total parenteral nutrition. Tohoku J Exp Med 1993; 171:129-133
16. Rathanaswaml P, Sundaresan R. Effects of insulin secretagogues on the secretion of insulin during thiamine deficiency. Biochem Int 1988;17:523-528
17. Marcus R, Coulston AM. Water-soluble vitamins: the vitamin B complex and ascorbic acid. In: Hardman JG, Limbird LE, Molinoff PB, Ruddon RW.Gilman AG,editors. Goodman and Gilman's ThePharma cological Basis of Therapeutics. 9th ed. New York: McGraw-Hili; 1996. pp 1555-1557
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Metabolic Acidosis and Thiamine Deficiency
REPORT OF CASE
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