Carnitine deficiency in chronic critical illness

REVIEW URRENT C OPINION

Carnitine deficiency in chronic critical illness Luisa Bonafe´ a, Mette M. Berger b, Yok Ai Que b, and Jeffrey I. Mechanick c

Purpose of review New insight in mitochondrial physiology has highlighted the importance of mitochondrial dysfunction in the metabolic and neuroendocrine changes observed in patients presenting with chronic critical illness. This review highlights specifically the importance of carnitine status in this particular patient population and its impact on beta-oxidation and mitochondrial function. Recent findings The main function of carnitine is long chain fatty acid esterification and transport through the mitochondrial membrane. Carnitine depletion should be suspected in critically ill patients with risk factors such as prolonged continuous renal replacement therapy or chronic parenteral nutrition, and evidence of betaoxidation impairments such as inappropriate hypertriglyceridemia or hyperlactatemia. When fatty acid oxidation is impaired, acyl-CoAs accumulate and deplete the CoA intramitochondrial pool, hence causing a generalized mitochondrial dysfunction and multiorgan failure, with clinical consequences such as muscle weakness, rhabdomyolysis, cardiomyopathy, arrhythmia or sudden death. In such situations, carnitine plasma levels should be measured along with a complete assessment of plasma amino acid, plasma acylcarnitines and urinary organic acid analysis. Supplementation should be initiated if below normal levels (20 mmol/l) of carnitine are observed. In the absence of current guidelines, we recommend an initial supplementation of 0.5–1 g/day. Summary Metabolic modifications associated with chronic critical illness are just being explored. Carnitine deficiency in critically ill patients is one aspect of these profound and complex changes associated with prolonged stay in ICU. It is readily measurable in the plasma and can easily be substituted if needed, although guidelines are currently missing. Keywords carnitine deficiency, chronic critical illness, fatty acid metabolism, malnutrition, mitochondrial dysfunction, renal replacement therapy

INTRODUCTION Chronic critical illness (CCI) is a late stage of critical illness operationally defined when patients have a tracheostomy placed, usually by ICU day 14 or so and based on a general consensus that further prolongation of critical illness is likely [1]. The CCI metabolic profile, referred to as CCI syndrome (CCIS), results from failure to downregulate the immune-neuroendocrine axis and is characterized by nutrient deficiencies and dysmetabolism [2]. Amino acid nutriture has gained popular attention within ICU nutrition circles, based on recent controversies, such as glutamine deficiencies and therapeutic interventions [3]. Furthermore, special clinical scenarios, such as renal replacement therapy and propofol infusion, have implicated micronutrient and mitochondrial physiology, respectively. Specifically, large doses of propofol (i.e. the propofol infusion syndrome) alter fatty acid (FA) oxidation www.co-clinicalnutrition.com

and impair oxidative phosphorylation reflected by increased circulating malonylcarnitine and acylcarnitine [4]. Carnitine (or L-carnitine) is a promotor of several biochemical reactions that include the removal of intramitochondrial and inhibitory acyl groups, the regulation of extra-mitochondrial long chain FA (LCFA) activation and delivery of the

a Center for Molecular Diseases, Lausanne University Hospital, bAdult Intensive Care & Burns, Lausanne University Hospital, Lausanne, Switzerland and cDivision of Endocrinology, Diabetes, and Bone Disease, Icahn School of Medicine at Mount Sinai, New York, New York, USA

Correspondence to Mette M. Berger, Adult Intensive Care & Burns, CHUV BH 08.612, Rue du Bugnon 46, 1011 Lausanne, Switzerland. E-mail: [email protected] Curr Opin Clin Nutr Metab Care 2014, 17:200–209 DOI:10.1097/MCO.0000000000000037 Volume 17 Number 2 March 2014

Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.

Carnitine deficiency in chronic critical illness Bonafe´ et al.

KEY POINTS Carnitine deficiency probably occurs in chronic critically ill patients more often than known until now and causes major alterations of mitochondrial energy metabolism, resulting in deleterious clinical consequences. Patients become at risk of deficiency by then end of the first month of chronic acute illness already, particularly if they depend on continuous renal replacement or on parenteral nutrition. In the patients at risk, a systematic supplementation of 0.5–1 g/day should be considered.

activated LCFA to the intramitochondrial enzymes of beta-oxidation. It therefore plays a critical role in cellular energy metabolism. The main function of carnitine is LCFA esterification and transport through the mitochondrial membrane wherein these substrates undergo beta-oxidation. LCFAs are linked to Coenzyme A (CoA) in the cytosol; carnitine maintains the CoA pool by esterifying LCFA facilitating their diffusion through the mitochondrial membrane. In the mitochondria, LCFAs are again esterified with CoA and oxidized by specific dehydrogenases on the basis of FA chain length and chemical features (Fig. 1). The carnitine cycle allows the entrance of LCFA into mitochondria, while medium-chain fatty acids easily cross mitochondrial membranes without the carnitine shuttle. The carnitine cycle comprises a first esterification to long-chain fatty acyl-CoA by carnitine-palmitoyl transferase 1 (CPT1) on the outer mitochondrial membrane that liberates cytosolic CoA and forms fatty acylcarnitine; acylcarnitines are transported through the inner mitochondrial membrane by the translocase (TRANS) and further esterified into fatty acyl-CoA in the mitochondrial matrix by carnitine-palmitoyl transferase 2 (CPT2). Acyl-CoA can hence undergo betaoxidation through the dehydrogenases specific for different chain length. Beta-oxidation results in electron transfer and generation of high-energy substrates for respiratory chain ATP synthesis (FADH, NADH). Acetyl-CoA can enter the TCA cycle (Krebs cycle) and/or undergo ketone synthesis. The TCA cycle generates NADH, whereas ketone synthesis allows regeneration of NAD by NADH consumption. With high glucose availability, the TCA cycle is replenished, citrate exits the mitochondria and regulates fatty acid synthesis through cytosolic malonyl-CoA, a potent inhibitor of CPT1 and promoter of fatty acid synthesis. In carnitine deficiency, beta-oxidation is impaired and the CoA pool is

depleted, resulting in hypoglycemia and energy failure if glucose intake is low (e.g. fasting in inborn errors of fatty acid oxidation). If glucose (þ insulin) intake is high (as in critically ill patients), fatty acylCoA are routed towards triglyceride synthesis. In both cases, CoA depletion causes mitochondrial dysfunction, reduced ATP production and increased oxidative stress. Intracellular availability of L-carnitine and activity of carnitine palmitoyl-transferase 1 (CPT1) in skeletal muscle seem to be the main regulating factors of FA oxidation. When FA oxidation of any chain length is impaired primarily (genetic defects) or secondarily (medications), acyl-CoAs accumulate and deplete the CoA intramitochondrial pool, hence causing a generalized mitochondrial dysfunction with impaired energy metabolism and multiorgan failure. In such situations, administration of carnitine allows restoring CoA intracytosolic and intramitochondrial CoA pools thus improving energy metabolism. Furthermore, carnitine forms esters with accumulating FA and other organic acids, thus allowing their detoxification and urinary excretion. Carnitine also stimulates pyruvate dehydrogenase activity and tricarboxylic acid (TCA) cycling, as well as promoting branchedchain amino acids oxidation in muscle [5 ]. By contrast, carnitine is not required for transport of medium chain FAs in the liver, although it stimulates their oxidation in the muscle. Carnitine is a quaternary amine (3-hydroxy-4trimethylaminobutyric acid) mainly derived by diet. Endogenously, carnitine is synthesized from the essential amino acids lysine and methionine in most tissues, as the first enzymatic steps are widely expressed. However, the terminal gamma-butyrobetaine hydroxylation reaction is restricted to liver, kidney and brain in humans [5 ]. As carnitine is efficiently reabsorbed in the renal tubule by a specific transporter, and is present in large amounts in meat and other sources of animal proteins [6], carnitine deficiency is rare in well nourished, nonstressed, omnivorous adult people. Carnitine is also a strong antioxidant molecule, acting as a mitochondrial reactive oxygen species (ROS) scavenger. Oxidative stress is one of the main pathological mechanisms of tissue damage in several inborn errors of metabolism [7], as well as critical illness [8 ]. This study highlights the importance of carnitine status in critically ill patients, outlines some pitfalls for suspecting carnitine deficiency based on common biochemical markers and provides a framework for incorporating carnitinebased therapeutics in critical care medicine based on the current literature.

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Free fatty acid

Plasma

Cytosol

Medium-chain fatty acid

Long-chain fatty acid

+

Fatty acyl-CoA

Triglycerides

Glucose

Triglycerides

Glucose

(+ insulin)

L-carnitine

CPT1

Malonyl-CoA

Outer membrane

Fatty acylcarnitine

Acetyl-CoA

TRANS

Citrate

Inner membrane

Fatty acylcarnitine

Mitochondria

CPT2

Fatty acyl-CoA FADH, NADH e–

β-OXIDATION

NADH

Acetyl-CoA

Ketones

Citrate

TCA cycle

Pyruvate ATP

Pyruvate

– FADH NADH e

RESPIRATORY CHAIN

FIGURE 1. Physiological carnitine cycle (carnitine-palmitoyl transferase 1 and 2 (CPT1 and CPT2).

CARNITINE DEFICIENCY Profound carnitine deficiency causes hypoketotic hypoglycemia due to FA oxidation impairment, but also muscle weakness, rhabdomyolysis, cardiomyopathy, arrhythmia and sudden death [9]. Carnitine deficiency has been reported in children with genetic conditions involving enzymes and transporters of the carnitine-acylcarnitine shuttle (Fig. 1). Secondary carnitine deficiency is much more common than primary defects. In children, inborn errors of metabolism with accumulation of toxic organic acids are associated with carnitine depletion due to its consumption in esterified compounds aimed at detoxification (methylmalonylcarnitine, proprionylcarnitine and so on). In adults, carnitine deficiency is most commonly iatrogenic (Table 1), following the use of valproate or other drugs

typically interfering with mitochondrial metabolism and carnitine intracellular pool. Patients with HIV have been recently recognized as being at risk for carnitine deficiency and mitochondrial dysfunction, due to the specific toxicity of the pharmacological treatments controlling the disease [10]. For years, nephrologists have been using carnitine therapy (20 mg/kg) in dialyzed patients with cardiomyopathy, muscle weakness and erythropoietin unresponsive anaemia [11]. The rationale for carnitine supplementation is that this small molecule is highly dialyzable and low plasma carnitine levels are prevalent in dialysis patients, many of whom have hypertriglyceridemia. Nevertheless, prospective trials are sparse [12 ,13]. Given the current knowledge about the pivotal role of carnitine in intermediate metabolism with pleiotropic effects in different tissues, carnitine &

Table 1. Critical care conditions at risk of carnitine deficiency Condition

Mechanism

Acute renal failure with continuous renal replacement therapy

Carnitine loss in the effluent

Energy protein malnutrition

Insufficient intake

Prolonged parenteral nutrition

Insufficient supplementation

Critically ill HIV patients

Specific toxicity of the antiretroviral therapy

Prolonged status epilepticus treated with valproate

Drug toxicity

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supplements have been proposed in several clinical conditions, such as myopathies and cardiomyopathies of different causes [14–16], male infertility [17], cardiovascular diseases [18–20], peripheral atherosclerotic artery disease [21], Alzheimer’s disease [22 ], Huntington’s disease [23], peripheral nerve trauma [24] and other chronic illnesses [25]. Nevertheless, sufficient clinical evidence is still lacking to support many of these approaches. In critical illness, studies in animal models, and less extensively in humans, have suggested the possible role of carnitine in different settings [26]. Low plasma carnitine has been observed in critically ill patients with trauma, sepsis, acute organ failure, pharmacological therapy (e.g. zidovudine, pivampicillin and valproate), low dietary intakes and severe protein-energy malnutrition [27]. Limited clinical evidence has implicated carnitine supplements with improved outcome in sepsis [5 ] and in acute heart failure [28]. Carnitine is typically not included in parenteral nutrition formulations, and therefore, acquired carnitine deficiency may occur when parenteral nutrition is the exclusive nutritional source for prolonged periods. In patients undergoing major surgery, outcomes may improve with glutamine and carnitine supplements in the perioperative period, with the rationale of attenuating the adverse effects of prolonged fasting around surgery [29–31]. Carnitine supplements have also been suggested for the treatment of acute hepatic encephalopathy [32]. No specific studies in critically ill patients with burns have been reported in recent years and despite growing attention to micronutrient supplements in these patients, there is no recommendation about carnitine monitoring and supplementation. &

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A CASE OF PROLONGED HAEMOFILTRATION WITH SEVERE AMYOTROPHY A 34-year-old man sustained an 85% body surface area burn trauma with severe inhalation injury. The initial body weight was 74 kg (BMI 22.8 kg/m2). During the initial resuscitation phase, which included laparostoma for an abdominal compartment syndrome, he developed several organ failures from which he eventually recovered by the end of the first week, except for renal failure. This prompted the use of continuous venovenous haemofiltration (CVVH) that was continued until day 180. He was trached on day 25. Surgical treatment, including early debridement and temporary wound closure with conventional dressings before grafting of cultured keratinocytes, allowed almost total wound healing by day 190. During

the treatment course, he presented with several septic complications, most of them related to Pseudomonas aeruginosa burn wound infections. He expired on day 213 with refractory septic shock from skin origin due to a pan-resistant P. aeruginosa. The nutritional management incorporated tight glycemic control by continuous insulin administration since day 1 [33]. Enteral feeding was also initiated on day 1 and continued until day 160; parenteral nutrition was provided from day 160 to 180 due to sustained gut dysfunction from recurring peritonitis and ileal perforation. Fat content was low in both enteral and parenteral nutritional formulations. The custom-made parenteral nutrition included a medium-chain triglyceride (MCT)/longchain triglyceride (LCT) emulsion. Protein delivery varied over time between 1.5 and 2 g/kg/day. After day 180, he received combined one-third enteral (modular diet) and two-thirds parenteral nutrition. Lipid intake from sedation, mainly propofol, resulted in 10–15 g/day. Total fat intake remained less than 1 g/kg throughout the entire period. This patient presented many time-sensitive metabolic and nutritional challenges. His initial BMI was 22.8 kg/m2, and despite being fed commensurate with measured energy expenditures by repeated indirect calorimetry, he lost 18 kg (–25%) by day 60. This loss translated into severe amyotrophy (Figs. 2 and 3). He developed persistent high lactate levels from nonhypoxic origin and severe and sustained hypertriglyceridemia (Fig. 4). From day 25, plasma triglyceride levels increased above normal levels and peaked at days 44–80 to 14.2 mmol/l (Fig. 4). These metabolic anomalies prompted retrospectively analysis of the nutritional prescriptions to consider mitochondrial dysfunction. A comprehensive metabolic workup was performed on day 131 (Table 2). An amino acid profile showed a clear depletion of essential amino acids along with a steep increase in alanine. Total and free carnitines were found to be low. Urinary organic acids showed lactic aciduria with increased excretion of TCA cycle intermediates (succinate, methylsuccinate, fumarate and malate), increased dicarboxylic aciduria without consistent ketosis and marked increase of hydantoin-5-propionate and pyroglutamate excretion. Plasma amino acids showed massive increased alanine and essential amino acid depletion, particularly branched-chain amino acids. The plasma acylcarnitine profile revealed extremely low free carnitine (8 mmol/l) and increased acetylcarnitine (C2), and long-chain (C14 and C14OH) acylcarnitines. These results prompted intravenous carnitine supplementation (2 g/day, 33 mg/kg). This nutritional intervention was associated with clinical and biological

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FIGURE 2. Obvious amyotrophy in a previous healthy strong young man on days 55 and 190.

100

Actual BW (kg) 90 80 70 60 50 10.0

Copper IV intake (mg/d)

8.0

6.0

4.0

2.0

0.0 25

Copper (umol/l)

20 15 10 5

D210

D200

D190

D180

D170

D160

D150

D140

D130

D120

D110

D100

D090

D080

D070

D060

D050

D040

D030

D020

D010

D000

0

FIGURE 3. Weight curve and evolutions of copper intakes and plasma copper concentrations. 204


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20

Lactate (arterial: mmol/l) 15

10

5

0 CVVH 14

Triglycerides (mmol/l)

12 10 8 6 4 2 0 0

10 20 30 40 50 60 70 80 90 100 110 120 130 140 150 160 170 180 190 200 210

120

Lipid intake (total: g/day) 100 80 60 40 20 0

Time (days)

FIGURE 4. Plasma lactate and triglyceride levels with daily fat intakes during the stay (fat levels include lipids from propofol) (green line, CVVH; dotted line, carnitine supplements).

improvement: lower lactate and triglyceride levels, anabolism with a modest weight gain, and improved performance metrics (sitting up and walking a few steps). Unfortunately, this intervention failed to prevent his demise. Low plasma copper levels were also observed after day 50, which persisted despite large intravenous supplementation. Abundant haemofiltration

effluents are associated with increased copper losses [34] and standard nutritional formulations generally fail to compensate leading to true copper deficiency and associated hypertriglyceridemia (Fig. 5) [35]. Essential amino acid depletion, also linked to CVVH with standard nutritional intakes, further induced muscle catabolism and reduced glutathione synthesis, the latter already depleted

Table 2. Evolution of carnitine plasma levels

ICU day

Total carnitine (reference range) (29–70) mmol/l

D131

29

D171

116

D177

379

D183

725

D191

503

Free carnitine (18–48) mmol/l 11

Acyl-carnitine (7–26) mmol/l

Acyl-carnitine/free carnitine ratio (