Thiamine deficiency and supplementation in heart failure

Thiamine is a water-soluble vitamin that is an important coenzyme for various metabolic processes in the body.  These include the regulation of glucose metabolism, the Krebs cycle (generates ATP), the pentose shunt (generates NADPH), and maintenance of sodium/potassium gradients in the brain (necessary for conducting nerve impulses).  Thiamine is mostly obtained from dietary intake with absorption occurring in the jejunum and ileum. After traveling to the liver, thiamine spends a relatively short amount of time in the blood before distributing to tissues throughout

the body.  Only 0.8% of total body thiamine resides in the blood, making serum thiamine measurements unreliable indicators of total body stores (they are more a reflection of recent thiamine intake).¹

 

Thiamine deficiency manifestations

Thiamine deficiency primarily presents itself in one of two forms, dry or wet (i.e., cardiac) beriberi.  Dry beriberi’s manifestations are primarily neurologic in nature (affecting both the central and peripheral nervous systems).  These findings include ataxia, confusion, delirium, psychosis, peripheral neuropathy, seizures, movements disorder, oculomotor abnormalities, and the Wernike/Korsakoff syndrome.  Wet beriberi presents with vasodilation, fluid retention, heart failure (usually high output at first), and lactic acidosis.  Unfortunately, this "wet" constellation overlaps identically with heart failure symptoms from other causes and there is no pathognomonic distinction between the two states.  This overlap means the relatively high prevalence of heart failure makes the relatively low prevalence of thiamine deficiency-induced wet beriberi very easy to overlook. ¹

 

Mechanism of heart failure in thiamine deficiency

The mechanism of wet beriberi is briefly as follows.  Among other effects, lack of thiamine causes dysfunction in the Krebs cycle, reducing the conversion of pyruvate to acetyl-CoA and therefore ATP formation.  Cells still need energy to function so glycolysis is upregulated, as is the use of fat stores.  This causes a further increase in pyruvate (from glycolysis) and a release of ketones (from fat).  The increased pyruvate still cannot be converted to acetyl-CoA (as long as there’s still thiamine deficiency) so it becomes converted to lactate which causes lactic acidosis.  The entire cardiovascular system is disrupted from acidosis plus the lack of energy production resulting in decreased systemic vascular resistance (so vasodilation), increased oxygen consumption, increased venous congestion, and increased cardiac output (until myocardial weakness eventually occurs which then becomes a low cardiac output state). ^1,2

 

Prevalence in heart failure patients

Unfortunately, prevalence rates for thiamine deficiency in heart failure vary tremendously, ranging anywhere from single digits up to 98% in patients with heart failure.  It is difficult to come up with one estimate about prevalence for a few reasons.  One, there is no convenient and reliable test for measuring total body thiamine stores.  As mentioned, serum concentrations reflect recent ingestion of thiamine, more so than total body stores.  Urine thiamine concentrations can be measured but these are directly related to serum concentrations so suffer the same limitation.  Other tests such as erythrocyte transketolase activity (ETKA), erythrocyte thiamine pyrophosphate (TPP), and HPLC can also be done to diagnose thiamine deficiency but each has their own limitations.  One study of patients hospitalized for heart failure exacerbations found a thiamine deficiency prevalence of 33% using the highly sensitive TPP method. ^1,2

 

Why so many patients? Where is the thiamine?

Patients with heart failure seem to be at increased risk of thiamine deficiency due to several factors, a number of which have to do with using Loop diuretics, a mainstay of treatment in the heart failure population.   

Approaching this from a kinetic mindset, the cause of the deficiency has to do with either a lack of supply, an inability to utilize the thiamine, or increased elimination.  Decreased absorption can occur in heart failure patients due to splanchnic congestion or the patient’s dietary habits.  Patients may experience early satiety or cachexia associated with heart failure and/or they may voluntarily adopt a diet that may be devoid of adequate thiamine.  Certain high salt foods that the patient may intentionally be avoiding as part of their heart failure management may coincidentally have been good sources of thiamine.  A reduced ability to utilize thiamine may occur in the setting of hypokalemia or hypomagnesemia which can occur secondary to Loop diuretic use.  Finally, increased elimination occurs through enhanced urinary clearance.  Recall that thiamine is a water soluble vitamin and its elimination in the urine is proportional to urine volume. This means that as Loop diuretics cause more urine production, more thiamine will be lost from both the blood and total body stores. ^1-3    

Aside from risk factors associated with heart failure and Loop diuretic use, other risk factors for thiamine deficiency include inadequate dietary intake, advanced age, trauma, surgery, fever, institutionalization, excess alcohol use, malabsorption syndromes (including following bariatric surgery and refeeding syndrome), severe infections, eating disorders, cancer, AIDS, gastrointestinal surgery, persistent diarrhea or vomiting, and certain other medication use. ¹

 

Does supplementing thiamine improve heart failure outcomes?

A systematic review and meta-analysis describe the few small studies that have been conducted to test if supplementing thiamine improved outcomes in patient with heart failure.  Investigators used various dosing strategies and had different outcomes, making generalizability difficult.  In general, the studies administered around 200 to 300 mg of thiamine (some IV and some orally) per day for anywhere from a week to several weeks and they looked at outcomes such as left ventricular ejection fraction (LVEF), NYHA functional class, blood pressure, and urine output.  Several of the studies were prospective randomized controlled trials and found the EF increased by a statistically significant amount (absolute increases around 3-5% or from an LVEF of 28% to an LVEF of 32%).   Improving heart function (i.e., EF) is a good prognostic sign even though mortality was not yet demonstrated (the studies were not powered to see improvements in mortality though so that's not much of a criticism).  Of note, all of these studies were very small (largest arm was 30 patients).³

These results, albeit limited, give us the suggestion that thiamine supplementation may benefit patients with heart failure.  The fact that thiamine is relatively cheap and lacks toxicity make it a fairly low bar to attempt to explore its future use.

 

Take home points:

• Better studies are needed to determine the prevalence of thiamine deficiency in the modern heart failure population

• Heart failure from thiamine deficiency is clinically indistinguishable from other causes of heart failure 

• Very small studies of thiamine supplementation have shown improvements in LVEF (though not all studies show it)

• Doses used were 200 to 300 mg IV/oral per day for a week to several weeks

 

References:

1. DiNicolantonia JJ, Niazi AK, Lavie CJ, et al. Thiamine Supplementation for the Treatment of Heart Failure: A Review of the Literature Congest Heart Fail 2013;19:214-22.

2. Helali J, Park S, Ziaeian B, et al. Thiamine and Heart Failure: Challenging Cases of Modern-Day Cardiac Beriberi. Mayo Clin Proc Innov Qual Outcomes. 2019 May 27;3(2):221-5.

3. Jain A, Mehta R, Al-Ani M, et al. Determining the Role of Thiamine Deficiency in Systolic Heart Failure: A Meta-Analysis and Systematic Review. J Card Fail. 2015 Dec;21(12):1000-7.

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