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Keywords:

  • aged;
  • diuretics;
  • drug–nutrient interaction;
  • nutrition;
  • thiamine

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Subjects and methods
  5. Results
  6. Discussion
  7. Acknowledgement
  8. References

Abstract. Härdig L, Daae C, Dellborg M, Kontny F, Bøhmer T (Sahlgrenska University Hospital/Östra, Göteborg, Sweden, and Aker University Hospital, Oslo, Norway). Reduced thiamine phosphate, but not thiamine diphosphate, in erythrocytes in elderly patients with congestive heart failure treated with furosemide. J Intern Med 2000; 247: 597–600.

Objectives. To measure the concentrations of thiamine and thiamine esters by high-pressure liquid chromatography (HPLC) in elderly patients treated with furosemide for heart failure and in a control group.

Design. A cross-sectional study of blood thiamine and thiamine ester concentrations.

Subjects. Forty-one patients admitted to hospital for heart failure and 34 elderly living at home. No vitamin supplementation was allowed.

Results. Compared with the healthy controls, furosemide-treated patients had significantly reduced whole blood thiamine phosphate (TP; 4.4 ± 2.2 vs. 7.6 ± 2.0 nmol L–1) and thiamine diphosphate (TPP; 76 ± 21.5 vs. 91 ± 19.8 nmol L–1) (mean ± SD). When the thiamine concentrations were related to the haemoglobin concentrations, which were reduced in the heart failure patients, the levels of TP (nmol g–1 Hb) were 0.38 ± 0.26 vs. 0.54 ± 0.17 (P < 0.0001), and of TPP were 6.35 ± 1.76 vs. 6.37 ± 1.29 (P = 0.95). There were no differences in T and TP concentrations in plasma between the two groups.

Conclusions. The elderly patients with heart failure treated with furosemide have not reduced the storage form of thiamine, TPP, but only TP. This change is most likely not an expression of a thiamine deficiency, but rather of an altered metabolism of thiamine, which is not understood at present.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Subjects and methods
  5. Results
  6. Discussion
  7. Acknowledgement
  8. References

Thiamine (vitamin Bl) is present in the human body as thiamine (T), thiamine monophosphate (TP), thiamine diphosphate (TPP) and thiamine triphosphate (TPPP). The most important ester, TPP, serves as coenzyme for the oxidative decarboxylation in the mitochondria [1 ]. The biochemical function of the other T compounds is not known, but T and TP are the ones actively transported into the nervous system [2]. TPPP is assumed to a be a storage form for TPP in the nervous tissue and possibly other tissues [3], but it is present in plasma for short periods after a thiamine load [4].

Thiamine is phosphorylated directly to TPP by thiamine diphosphokinase, and TPP is dephosphorylated to TP by thiamine diphosphatase [1]. The only enzyme of this pathway which has been found in serum is thiamine diphosphatase, which explains why no TPP is found in serum [5].

Thiamine deficiency is clinically recognized as dry or wet beriberi, the latter being associated with sodium and water retention, peripheral vasodilation and biventricular cardiac failure [6]. Deficiency of T is endemic in areas where food intake consists mainly of polished rice, but it also occurs in Western countries, where it is seen in individuals who abuse alcohol and amongst both the hospitalized elderly and the elderly living at home [7–10].

Furosemide induces a thiamine deficiency in animals [11]. Humans with congestive heart failure (CHF) treated with high doses of furosemide developed such a deficiency and improved by T substitution [1213]. It is still unclear, however, whether T supplementation generally has a role in the management of heart failure [14]. In elderly patients, in whom malnutrition is prevalent even in affluent societies [1516], the T status in aged heart failure patients has been measured only by indirect methods [17].

Thiamine and its esters can now be measured directly by high-performance liquid chromatography [18], the most sensitive and specific method for determining the nutritional status of thiamin [19]. We have therefore measured the thiamine status utilising the HPLC method, in patients with CHF treated with furosemide and in a reference group of healthy elderly.

Subjects and methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Subjects and methods
  5. Results
  6. Discussion
  7. Acknowledgement
  8. References

Patients

Forty-one elderly patients (21 males and 20 females) treated with a regimen for CHF, including at least 60 mg day–1 furosemide for at least 4 weeks, were included in the study. Their age was (mean ± SD) 78 ± 7 years, and the furosemide dose was 98 ± 30 mg day–1. Nineteen patients were treated with digitoxin (the most widely used digitalis glycoside in Norway), 12 with ACE inhibitors, eight with potassium-saving diuretics, and five with potassium supplementation. The aetiology of the CHF was ischaemic heart disease in 23 patients, hypertension in nine, valvular heart disease in five, and dilated cardiomyopathy in three. In five patients, no definite aetiology was found. Some patients had more than one cause for the heart failure. The patients were classified according to the New York Heart Association (NYHA) classification [20] as follows: I, one patient; II, 12 patients; III, 25 patients; and IV, 3 patients. Patients with alcohol abuse, hepatic failure, diabetes mellitus, terminal diseases or who had used vitamin supplementation within the last 3 months were excluded.

Thirty-four healthy elderly subjects living at home (18 men, 16 women), aged 79 ± 5 years, served as controls. No vitamin supplementation was allowed during the last 3 months.

All patients and healthy controls had an adequate nutritional status, estimated from a structured interview, with at least six hot meals per week and three meals per day. Body mass index (BMI) was recorded as part of the clinical examination.

Patients and controls gave informed consent and the regional committee of ethics approved the study.

Laboratory measurements

Blood samples were collected in overnight-fasted individuals for routine tests. Thiamine and thiamine phosphate esters were measured by HPLC [18]. The detection limit with this method is 3–16 fmol L–1. The intra-assay coefficient of variation is, measured in our laboratory, 5.4, 4.8 and 6.4% for T, TP and TPP, respectively [18]. As haematocrit was not measured, the concentrations of erythrocyte TP and TPP were also related to Hb g–1. Conventional clinical analyses were carried out using a Hitachi 717 multianalyser (Boehringer, Mannheim, Mannheim, Germany).

Statistical analysis

All variables are expressed as means ± SD. Group comparisons were performed with an unpaired t-test, and for skewed distributions a Mann–Whitney rank sum test was used. A two sided P-value of < 0.05 was considered significant.

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Subjects and methods
  5. Results
  6. Discussion
  7. Acknowledgement
  8. References

The patients had significantly lower concentrations of haemoglobin and s-albumin, and higher creatinine concentrations, than the controls ( Table l). The erythrocyte levels of TP and TPP presented as nmol L–1 were significantly reduced in the CHF patients compared with the controls. This difference disappeared for TPP (but not TP) levels, when thiamine ester concentrations were related to haemoglobin and expressed as nmol g–1 Hb. There were no differences in serum T, TP and TPP concentrations between the groups ( Table 2 ).

Table 2.  Thiamine and thiamine phosphate esters in furosemide-treated congestive heart failure patients and healthy elderly controls
Congestive heart failureHealthy elderly
 nmol L–1nmol g–1 Hbnmol L–1nmol g–1 Hb
  • Values are expressed as means ± SD.

  • T, thiamine; TP, thiamin monophosphate; TPP, thiamine diphosphate.

  • *

    P, significant < 0.01.

Blood
 T16 ± 15.51.34 ± 1.5314 ± 6.00.99 ± 0.41
 TP4.4 ± 2.8 *0.38 ± 0.25 *7.6 ± 2.00.54 ± 0.26
 TPP76 ± 21.5 *6.35 ± 1.7691 ± 19.86.37 ± 1.29
Serum
 T7.9 ± 3.48.4 ± 3.1
 TP3.2 ± 1.73.2 ± 1.5
 TPP<1<1

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Subjects and methods
  5. Results
  6. Discussion
  7. Acknowledgement
  8. References

Our patients differed significantly in Hb and creatinine compared with the healthy elderly. This is not unusual in patients with advanced CHF where a number belong to NYHA groups III and IV. Our patients had comparable body weights with the controls and had not developed cardiac cachexia. We think therefore that our patients are fairly representative of the elderly with CHF.

By our HPLC method, we measured the different T compounds where the serum and blood T and TP have a much shorter half-life than the erythrocyte TPP [4]. TPP accounts for more than 80% of total erythrocyte T, and alone is taken as the best expression of the T nutritional status [192122].

Thiamine deficiency has been reported in younger patients with cardiac failure treated with furosemide [1112] but not in others [22], and when studied in the elderly with the transketolase method, only 13% of the CHF patients revealed a T deficiency, compared with 29% of the controls [17]. A study of Swedish Caucasian patients with a mean age of 60 years revealed no T deficiency [22]. Malnutrition is prevalent in elderly hospitalized patients [1415] and T deficiency was therefore expected to be present when these patients were treated with high doses of furosemide. This study shows that even elderly CHF patients generally do not develop a T deficiency during furosemide treatment. Two patients also had a reduced TPP (defined as being below mean – 2 SD of that of controls) when their haemoglobin was taken into account, indicating a T deficiency. These patients will most likely benefit from T substitution as reported [1213].

The levels of TP in erythrocytes were reduced in the CHF patients. This TP is formed in cells and released into the plasma where it can be further degraded. It is difficult to ascribe a separate role for this compound. This reduction should therefore not be taken as a sign of T deficiency as long as TPP levels are normal.

The prevalence of T nutrition will probably vary from one study to another, depending on the dosage of furosemide used and whether the flour is enriched or not. Loop diuretics are still a cornerstone of the treatment of cardiac failure [23], but thanks to new drugs, furosemide will most likely be used in lower dosages than before, with a reduced tendency to induce T deficiency. As long as furosemide is used, T deficiency might appear and should be looked for in these patients.

Acknowledgement

  1. Top of page
  2. Abstract
  3. Introduction
  4. Subjects and methods
  5. Results
  6. Discussion
  7. Acknowledgement
  8. References

LH and CD have contributed equally to this work. We thank Berit Falch for technical assistance in the thiamine analysis, and Gerd Kållstråm for her contribution in blood sampling.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Subjects and methods
  5. Results
  6. Discussion
  7. Acknowledgement
  8. References
  • 1
    Haas RH. Thiamin and the brain. Annu Rev Nutr 1988; 8: 483 515.
  • 2
    Tallaksen CME, Bøhmer T, Bell H. Concentrations of water-solubile vitamins thiamin, ascorbic acid, and folic acid in serum and cerebrospinal fluid of healthy individuals Am J Clin Nutr 1992; 56: 559 64.
  • 3
    Cooper JR & Pincus JH. The role of thiamine in nervous tissue. Neurochem Res 1979; 4: 223 39.
  • 4
    Tallaksen CME, Sande A, Bøhmer T, Bell H, Karlsen J . Kinetics of thiamin and thiamin phosphate esters in human blood, plasma and urine after 50 mg intravenously or orally. Eur J Clin Pharmacol 1993; 44: 73 78.
  • 5
    Thom JY, Davis RE, Icke GC. Dephosporylation of thiamin pyrophosphate by fresh human plasma. Int J Vit Nutr Res 1985; 55: 269 73.
  • 6
    Editorial. Cardiovascular beriberi. Lancet 1982; I: 287.
  • 7
    Griffiths LL, Brocklehurst JC, Scott DL, Marks J, Blackley J. Thiamine and ascorbic acid levels in the elderly. Geront Clin 1967; 9: 1 10.
  • 8
    O’Rourke NP, Bunker VW, Thomas AJ, Finglas PM, Bailey AL, Clayton BE. Thiamine status of healthy and institutionalized elderly subjects: analysis of dietary intake and biochemical indices. Age Ageing 1990; 19: 325 29.
  • 9
    Chen MF, Chen LT, Gold M, Worth Boyce H. Plasma and erythrocyte thiamin concentrations in geriatric outpatients. J Am Coll Nutr 1996; 15: 231 36.
  • 10
    Nichols H & Basu T. Thiamin status of the elderly: dietary intake and thiamin pyrophosphate response. J Am Coll Nutr 1994; 13: 57 61.
  • 11
    Yui Y, Ltokawa Y, Kawai C. Furosemide-induced thiamine deficiency. Cardiovasc Res 1980; 14: 537 40.
  • 12
    Seligmann H, Halkin H, Rauchfleisch S et al. Thiamine deficiency in patients with congestive heart failure receiving long-term furosemide therapy: a pilot study. Am J Med 1991; 91: 151 55.
  • 13
    Shimon I, Almog S, Vered Z et al. Improved left ventricular function after thiamine supplementation in patients with congestive heart failure receiving long-term furosemide therapy. Am J Med 1995; 98: 485 90.
  • 14
    Leslie D & Gheorghiade M. Is there a role for thiamine supplementation in the management for heart failure. Am Heart J 1996; 131: 1248 50.
  • 15
    Mowe M & Bøhmer T. The prevalence of undiagnosed protein-calorie undernutrition in a population of hospitalized elderly patients. J Am Geriatr Soc 1991; 39: 1089 92.
  • 16
    Mowe M, Bøhmer T, Kindt E. Reduced nutritional status in an elderly population (> 70 y) is probable before disease and possibly contributes to the development of disease. Am J Clin Nutr 1994; 59: 317 24.
  • 17
    Kwok T, Falconer-Smith F, Potter F, Ives Dr. Thiamine status of elderly patients with cardiac failure. Age Ageing 1992; 21: 67 71.
  • 18
    Tallaksen CME, Bøhmer T, Bell H. Concomitant determination of thiamin and its phosphate esters in human blood and serum by high performance liquid chromatography. J Chromatogr 1991; 564: 127 36.
  • 19
    Herve C, Beyne P, Lettéron Ph, Delacoux E. Comparison of erythrocyte transketolase activity with thiamine and thiamine phosphate ester levels in chronic alcoholic patients. Clin Chim Acta 1995 ; 234: 91 100.
  • 20
    The Criteria Committe of the New York Heart Association. Diseases of the Heart and Blood Vessels; Nomenclature and Criteria for Diagnosis, 6th edn. Boston: Little, Brown, 1984.
  • 21
    Tallaksen C, Bell H, Bøhmer T. Thiamin and thiamin phosphate ester deficiency assessed by high performance liquid chromatography in four clinical cases of Wernicke encephalopathy. Alcohol Clin Exp Res 1993; 17: 712 16.
  • 22
    Yue Q-Y, Beermann B, Lindstrøm B, Nyquist O. No difference in blood thiamine diphosphate levels between Swedish Caucasian patients with congestive heart failure treated with furosemide and patients without heart failure. J Intern Med 1997; 242: 491 95.
  • 23
    Task Force on the Working Group on Heart Failure of the European Society of Cardiology. Guidelines for the diagnosis of heart failure. Eur Heart J 1997; 18: 736 53.

Received 27 August 1999; revision received 3 November 1999; accepted 4 November 1999.