Threonine alpha-hydroxyisocaproic acid

Threonine Alpha-Hydroxyisocaproic Acid (α-HICA / HICA)

Identity, Chemical Nomenclature, and Natural Sources

Threonine alpha-hydroxyisocaproic acid, more commonly abbreviated as α-HICA or simply HICA, is the same compound referred to in the scientific literature as 2-hydroxyisocaproic acid, leucic acid, and DL-2-hydroxy-4-methylvaleric acid. The compound is also referred to as 2-hydroxy-4-methylvaleric acid, DL-leucic acid, 2-hydroxy-4-methylpentanoic acid, and alpha-hydroxyisocaproic acid — a leucine metabolite bearing a hydroxy substituent at the 2-position and a methyl substituent at the 4-position. Its CAS registry number is 13748-90-8 for the L-enantiomer. L-alpha-Hydroxyisocaproic acid (L-HICA) is an organic compound characterized by its hydroxyl and carboxylic acid functional groups; it is a chiral molecule, meaning it exists in two enantiomeric forms, with the L-form being the biologically active enantiomer. The compound is typically a white crystalline solid and is soluble in water, which is considered to enhance its bioavailability.

HICA (or leucic acid) is a metabolite of the branched-chain amino acid (BCAA) leucine. This compound is produced as a by-product of the leucine degradation pathway in humans and certain microorganisms; in humans, it is produced in tissues including connective tissues and muscles, and is regarded as a physiological agent present in the human body at low concentrations. The healthy adult contains approximately 0.1–0.25 mmol/L HICA in their plasma. Plasma HICA levels increase after exercise or during prolonged fasting due to the breakdown of proteins for energy.

Occurrence in Foods

HICA is an end-product of the microbial metabolism of leucine and is therefore found in many fermented foods, including wine, soy sauce, certain cheeses, kimchi, and yogurt. The variability of HICA levels in commercial yogurts may reflect the diversity of activities of hydroxyisocaproate dehydrogenase enzymes in the diverse Lactobacillus strains used in fermentation. HICA is produced by several species of lactic acid bacteria (LAB) during fermentation of animal proteins and during food fermentation, including Lactobacillus plantarum, Lactococcus lactis, Lactobacillus brevis, and Leuconostoc mesenteroides.

HICA production by lactic acid bacteria shows a positive correlation with hydroxyisocaproate dehydrogenases (HicDs), which play a key role in the production of HICA from leucine and ketoisocaproic acid; HICA contents in kimchi vary with Leuconostoc and Lactobacillus content during early-stage fermentation, and addition of lactic acid bacteria enhances the HICA content of kimchi. In fermented dairy research, Lactobacillus rhamnosus was found to be the most effective probiotic for 2-hydroxyisocaproic acid formation in yogurt; pH adjustment to pH 6, addition of leucine (1%) and whey protein (20%) to the milk, and extended fermentation time (21 hours) increased the 2-hydroxyisocaproic acid concentration to 4,651 mg/kg dry weight.

Common Forms and Preparations

The amino acid derivative 2-hydroxyisocaproic acid (HICA) is used commercially as a nutritional additive intended to increase muscle mass. It is sold primarily as the sodium salt of HICA in powdered form. In the key published clinical study, subjects in the HICA group received 583 mg of the sodium salt of HICA (corresponding to 500 mg of HICA) mixed with liquid three times a day. Supplement products market HICA in capsule and powder formats, often in conjunction with other leucine metabolites such as HMB or branched-chain amino acids.

Traditional and Historical Use

HICA does not have a discrete history of traditional botanical or herbal use, as it is not a plant extract but rather an endogenous human metabolite and a fermentation by-product. Its scientific investigation as a potential ergogenic supplement is entirely modern in origin. Interest in HICA as a dietary supplement arose specifically from laboratory research into leucine metabolism and the functional properties of leucine metabolites, beginning in earnest in the late 20th century.

HICA cannot be degraded by many bacterial species, and its production may represent a survival strategy for Lactobacillus, because HICA displays antibacterial activity. Its presence in fermented beverages such as wine has been documented analytically: among the acids identified in wine, 2-hydroxyisocaproic acid is present in smaller amounts alongside acetic, lactic, succinic, and other organic acids. Similarly, early Japanese food science research identified HICA as a flavour constituent of sake, and organic acid analyses of white riesling grape wines also detected it — though these were analytical characterisations rather than intentional use of the compound.

The compound's potential application in medicine was anticipated in patent filings from the late 1970s and 1990s, which documented the use of alpha-hydroxy acid analogues of amino acids for the promotion of protein synthesis and suppression of urea formation. Finnish sports-nutrition researchers, particularly Antti Mero and colleagues, were among the first to formally investigate HICA as a standalone supplement for athletes, publishing a pilot study with wrestlers and a subsequent double-blind, placebo-controlled trial with soccer players in the 2000s and 2010 respectively.

Key Constituents and Active Compounds

HICA is itself the sole active compound of interest in preparations bearing its name; it is not an extract of a complex botanical matrix. Its structural relationship to leucine is central to understanding its proposed biological activities.

Relationship to the Leucine Metabolic Pathway

HICA is an end product of leucine metabolism in human tissues such as muscle and connective tissue. The first intermediate yielded by leucine metabolism, alpha-ketoisocaproic acid (KIC), is formed when leucine is reversibly transaminated within the muscle by mitochondrial branched-chain amino transferase (mBCAT). A proportion of KIC is then a substrate for the branched-chain alpha-keto acid dehydrogenase complex (BCKDC), which irreversibly and oxidatively decarboxylates KIC to form isovaleryl-CoA. Separately from this major oxidative route, another fraction of KIC is reduced by lactate dehydrogenase (LDH) or a specific KIC reductase to form alpha-hydroxyisocaproic acid (HICA), also known as leucic acid.

Alpha-HICA (also known as leucic acid or DL-2-hydroxy-4-methylvaleric acid), an end product of leucine metabolism, is found in muscle and is generally considered to have anticatabolic actions. Because a dietary substitution of alpha-HICA for leucine supports normal growth, it is possible that at least part of the anabolic effect of leucine is mediated via this metabolite.

Mechanisms of Action

Anticatabolic and Muscle-Protein Effects

According to clinical and experimental studies, HICA can be considered an anti-catabolic substance; there is evidence of a direct in vitro inhibitory effect of HICA on various matrix metalloproteinase (MMP) enzymes, which are responsible for degradation of various connective and protein tissues. HICA can inhibit various matrix metalloproteinase enzymes that are responsible for degrading connective and protein tissues.

There is ongoing debate as to whether HICA positively regulates skeletal muscle protein synthesis, resulting in the gain or maintenance of skeletal muscle. Cell culture research published in Nutrients in 2021 helped to clarify this controversy. The phosphorylation of AMPK or ERK1/2 was significantly altered 30 minutes after HICA treatment under normal conditions; however, the basal protein synthesis rates measured by a deuterium-labelling method were significantly lowered by HICA treatment under both normal and cachexic conditions. Conversely, myotube atrophy induced by TNFα/IFNγ co-exposure was significantly improved by HICA pretreatment, and this improvement was accompanied by the inhibition of iNOS expression and IL-6 production. Moreover, HICA also suppressed the TNFα/IFNγ co-exposure-induced secretion of 3-methylhistidine, a validated biomarker of myofibrillar protein degradation. These findings suggest HICA's primary muscle-preserving mechanism under inflammatory conditions is anti-catabolic (suppressing proteolysis) rather than anabolic (directly stimulating protein synthesis).

Antibacterial Mechanism

HICA exhibits its antibacterial activity via penetration of bacterial cell membranes, causing depolarisation, permeabilisation, rupture of membranes, subsequent leakage of cellular contents, and cell death. HICA is effective in controlling the growth of both Gram-positive and Gram-negative bacteria, including a multi-drug resistant Pseudomonas aeruginosa strain. HICA cannot be degraded by many bacterial species, and its production may therefore represent a survival strategy for Lactobacillus.

Antifungal Mechanism

Testing of HICA's efficacy against 19 clinical and reference isolates representing five Candida and three Aspergillus species with variable azole antifungal sensitivity profiles, using a microdilution method at concentrations of 18, 36, and 72 mg/mL, demonstrated that HICA at 72 mg/mL was fungicidal against all Candida and Aspergillus fumigatus and Aspergillus terreus isolates.

Anti-inflammatory Mechanism

Histopathological examination in a murine biofilm model showed an attenuated inflammatory response together with reduced expression of matrix metalloproteinase 9 (MMP-9) and myeloperoxidase (MPO) compared to chambers containing caspofungin and PBS; the expression of developmental endothelial locus-1 (Del-1), an antagonist of neutrophil extravasation, increased after treatment with HICA.

Scientific Evidence by Area of Use

1. Body Composition and Lean Mass in Athletes

Pilot Study in Wrestlers (Mero et al., unpublished; described in Mero et al. 2010)

The earliest human data on HICA supplementation comes from a pilot study in competitive wrestlers. National top wrestlers (n = 7; 79.7 ± 4.5 kg; 26 ± 6 years) took 0.496 g of HICA three times per day after intensive training sessions for 42 days; they had at least 10 training sessions a week, each lasting from 1.5 to 2.5 hours. For at least the 6-week period before and during the 42-day trial, daily diets and the number, intensity, and duration of daily training sessions were kept constant; according to DXA measurements, the mean body weight gain during the treatment period was 0.84 ± 1.0 kg; bone mass was not changed, but total lean soft tissue mass was increased statistically significantly. The most important finding of the pilot study was that subjects using HICA did not suffer from DOMS symptoms at all, or suffered markedly less than before the treatment. This study was uncontrolled, however, limiting its interpretation.

Randomised Double-Blind Placebo-Controlled Trial in Soccer Players (Mero et al. 2010, Journal of the International Society of Sports Nutrition)

Fifteen healthy male soccer players (age 22.1 ± 3.9 years) volunteered for a 4-week double-blind study during an intensive training period. The subjects in the HICA group (n = 8) received 583 mg of sodium salt of HICA (corresponding to 500 mg of HICA) mixed with liquid three times a day for 4 weeks; the placebo group (n = 7) received 650 mg of maltodextrin three times a day. Body composition was evaluated with DXA before and after the 4-week period.

HICA supplementation significantly increased body weight (p < 0.005) and whole lean body mass (p < 0.05) while fat mass remained constant; the lean body mass of lower extremities increased by 400 g in the HICA group but decreased by 150 g in the placebo group, and this difference was significant (p < 0.01). HICA supplementation also significantly decreased whole-body DOMS symptoms in the 4th week of treatment (p < 0.05) compared to placebo; muscle strength and running velocity did not differ between the groups. The authors concluded that a 4-week HICA supplementation of 1.5 g per day leads to small increases in muscle mass during an intensive training period in soccer athletes.

Evidence limitations: This study had only 15 participants and a 4-week duration, rendering it substantially underpowered and of short duration. The training of the soccer players consisted of resistance training (weights) only four times during 28 days, whereas 13 soccer units and three matches were included, meaning that substantial endurance and anaerobic exercise was performed and catabolic processes were likely strong. The observed lean mass increase — while statistically significant — is small, and no replication of this specific finding has been published by independent groups using the same design.

Randomised Double-Blind Controlled Pragmatic Trial in Resistance-Trained Men (Teixeira et al. 2019, European Journal of Sport Science)

In a double-blind randomised controlled pragmatic trial, Teixeira and colleagues evaluated the effects of α-HICA, HMB-FA, and HMB-Ca — all off-the-shelf leucine metabolite supplements — on resistance exercise training (RET)-induced changes in body composition and performance. Forty men were block-randomised to receive α-HICA (n = 10, FFM = 62.0 ± 7.1 kg), HMB-FA (n = 11, FFM = 62.7 ± 10.5 kg), HMB-Ca (n = 9, FFM = 65.6 ± 10.1 kg), or placebo (n = 10, FFM = 64.2 ± 5.7 kg). The training program consisted of whole-body resistance training thrice weekly for 8 weeks (7 exercises/session, 3–4 sets per session, at 70–80% 1RM). Body composition was assessed by DXA and total body water by whole-body bioimpedance spectroscopy at baseline and at the end of weeks 4 and 8.

Research in young resistance-trained participants did not provide support that α-HICA is anabolic over and above sufficient energy and protein intake in this group of trainees. The study found no statistically significant effect of α-HICA supplementation on training-induced changes in body composition. This represents the largest and most methodologically rigorous human RCT on HICA to date, and its null finding in a well-controlled resistance-training design stands in direct contrast to the positive lean mass result of the Mero 2010 soccer-player trial.

Case Study in Type 1 Diabetic Patient with Muscle Atrophy (Teixeira et al. 2018, PubMed)

Research involving dietary supplement interventions for sarcopenia and osteopenia in type 1 diabetes patients is scarce; a case study of a type 1 diabetic patient was treated with supplemental alpha-hydroxy-isocaproic acid (α-HICA) for 120 days, with body composition assessed by DXA, blood markers, and maximum voluntary contraction parameters at baseline and after 120 days. The patient's baseline weight was 73.2 kg, which increased to 75.2 kg by the 120-day assessment, with salient mass distribution changes including increases of trunk fat mass (+0.4 kg), trunk fat-free mass (+0.2 kg), and a decrease of 8% in trunk fat mass contribution. Handgrip strength increased by 58.84 N, whereas isometric force in the leg press decreased by 347.15 N; amelioration of BMD Z-scores from −0.7 to 0.5 and T-scores from −1.0 to −0.9 were also noted. Hematologic measures and weekly nutritional counselling assessments revealed no signs of adverse effects. This is a single-subject, uncontrolled case study and cannot establish causality.

2. Delayed Onset Muscle Soreness (DOMS)

The most consistently positive human signal for HICA supplementation is a reduction in delayed onset muscle soreness. DOMS is the sensation of muscular discomfort and pain during active contractions that occurs in a delayed fashion after strenuous exercise; subjects with DOMS have painful, tender, and swollen muscles with reduced range of motion, especially after unaccustomed exercise. Both the wrestler pilot study and the Mero 2010 soccer-player RCT reported marked reductions in DOMS. In the soccer-player study, HICA supplementation significantly decreased whole-body DOMS symptoms in the 4th week of treatment (p < 0.05) when compared to placebo. The pilot study with wrestlers suggested that HICA alone was highly effective on DOMS symptoms. In humans, the available evidence suggests that HICA may relieve DOMS symptoms and can increase lean mass during training; HICA may therefore be beneficial for high-intensity training athletes who experience stiff and sore muscles, but more long-term and mechanistic studies are needed. The DOMS findings from human studies are limited to small samples and have not been independently replicated in larger trials.

3. Muscle Recovery After Immobilization (Animal Data)

Muscle disuse atrophy is observed routinely in patients recovering from traumatic injury; a study addressed the hypothesis that a diet containing 5% α-HICA — a leucine metabolite — would slow loss and/or improve recovery of muscle mass in response to disuse. Adult 14-week-old male Wistar rats were provided a control diet or an isonitrogenous isocaloric diet containing either 5% α-HICA or leucine; disuse atrophy was produced by unilateral hindlimb immobilisation (casting) for 7 days, and rats were also permitted to recover for 7 or 14 days after casting. Casting decreased gastrocnemius mass, which was associated with both a reduction in protein synthesis and S6K1 phosphorylation, as well as enhanced proteasome activity and increased atrogin-1 and MuRF1 mRNA. HICA was shown to increase protein synthesis and muscle mass in rats who were recovering from a period of induced atrophy. These are preclinical animal data and cannot be directly extrapolated to humans.

4. Anti-inflammatory Activity

In a murine chamber infection model, HICA demonstrated notable anti-inflammatory properties. A robust biofilm was formed for 5 days in a diffusion chamber implanted underneath mouse skin, and the biofilm was treated for 12 hours with HICA, while caspofungin and phosphate-buffered saline (PBS) were used as controls. Histopathological examination showed an attenuated inflammatory response together with reduced expression of MMP-9 and myeloperoxidase (MPO) compared to caspofungin and PBS controls; the expression of Del-1, an antagonist of neutrophil extravasation, was also increased after HICA treatment. Considering its anti-inflammatory and antimicrobial activity, HICA may have therapeutic potential in the treatment of chronic biofilm infections and inflammation, such as those seen with chronic wounds. These findings are from animal and in-vitro models; no human clinical trials have tested HICA specifically for anti-inflammatory outcomes.

5. Antimicrobial Activity

HICA has broad antibacterial activity. Results confirmed that HICA was effective in inhibiting the growth of tested Gram-positive and Gram-negative bacteria, including a multi-drug resistant P. aeruginosa strain. Antibacterial activity combined with its previously reported antifungal activity and safety profile suggests that HICA could be considered as a potential natural antimicrobial agent against food spoilage bacteria and pathogens. All antimicrobial investigations have been conducted in vitro or in animal models; no clinical human trials have investigated HICA as a therapeutic antimicrobial agent.

6. Clinical Biomarker Role: Metabolic Disease States

Elevated levels of HICA have been reported in the urine of patients with dihydrolipoyl dehydrogenase deficiency. HICA is also a key player in disease states such as Maple Syrup Urine Disease (MSUD), where its levels can become markedly elevated, leading to serious health issues. Elevated 2-hydroxyisocaproic acid in urine has also been linked to short bowel syndrome and may be an indicator of oxidative stress. In organic acid analysis panels, HICA measurement can thus serve as an indirect indicator of aberrant branched-chain amino acid catabolism.

Body Systems and Health Areas Associated with HICA

• Skeletal muscle / musculoskeletal system: According to clinical and experimental studies, HICA can be considered an anti-catabolic substance. Its primary proposed role is in preserving lean muscle mass during periods of intense exercise, injury-related disuse, or catabolic illness.
• Connective tissue: There is evidence of a direct in-vitro inhibitory effect of HICA on various matrix metalloproteinase enzymes responsible for degradation of various connective and protein tissues.
• Immune and inflammatory system: Myotube atrophy induced by TNFα/IFNγ co-exposure was significantly improved by HICA pretreatment, and this improvement was accompanied by inhibition of iNOS expression and IL-6 production.
• Antimicrobial defence: HICA demonstrates both antibacterial and antifungal properties in laboratory studies, with activity against clinically relevant organisms including Candida spp., Aspergillus spp., and multi-drug resistant bacteria.
• Bone: In the case study of a type 1 diabetic patient, improvements in BMD Z-scores were observed over 120 days, though this represents a single uncontrolled observation.
• Amino acid metabolism: HICA is a metabolic end-product formed from α-ketoisocaproic acid, which is formed when leucine is broken down by the enzyme BCAT; this process occurs in human tissues such as muscle and connective tissue.

Dosage Forms and Reported Dosages

HICA is available commercially as a dietary supplement in powdered and capsule form, typically as the sodium salt to improve stability and solubility. The following dosages are drawn directly from published studies:

• Soccer player RCT (Mero et al. 2010): Subjects received 583 mg of the sodium salt of HICA (corresponding to 500 mg of HICA) mixed with liquid, three times per day for 4 weeks, for a total of 1,500 mg HICA daily.
• Wrestler pilot study: National top wrestlers (n = 7) took 0.496 g of HICA three times per day after intensive training sessions for 42 days. This corresponds to approximately 1,488 mg per day.
• Type 1 diabetes case study: The type 1 diabetic patient was treated with supplemental α-HICA for 120 days, though the specific daily dose in milligrams is not stated in the available abstract data.
• Animal study (Lang et al. 2013): Adult 14-week-old male Wistar rats were provided an isonitrogenous isocaloric diet containing 5% α-HICA. This was a dietary-substitution model not directly translatable to human supplemental dosing.

The most commonly cited human clinical dose of 1,500 mg per day — administered in three divided doses of 500 mg each — is derived from the Mero 2010 trial. No dose-response studies establishing an optimal dose range in humans have been published. No pharmacokinetic studies characterising human absorption, distribution, metabolism, or excretion (ADME) of supplemental HICA at these doses are available in the peer-reviewed literature.

Safety Considerations and Interactions

Observed Safety in Clinical Studies

In the soccer-player study, no changes in blood pressure, heart rate, or laboratory blood values were associated with the use of HICA, suggesting that its use is safe. In the case study of the type 1 diabetic patient, full hematologic measures and weekly nutritional counselling assessments revealed no signs of adverse effects with 120-day supplementation. HICA has been used for muscle recovery by professional athletes and for veterinary purposes such as in animal feed, thus demonstrating its biocompatibility and safety profile.

Relevance to Inborn Errors of Metabolism

Individuals with rare genetic disorders affecting branched-chain amino acid metabolism, such as Maple Syrup Urine Disease (MSUD), must avoid HICA, as their bodies cannot properly process leucine or its downstream metabolites. Elevated levels of HICA in the body may indicate the presence of a metabolic disorder like MSUD; MSUD leads to the accumulation of branched-chain amino acids and their metabolites, which can result in severe neurological damage if untreated. Elevated levels of HICA have also been reported in the urine of patients with dihydrolipoyl dehydrogenase deficiency.

Endogenous Physiological Context

In humans, HICA is produced in tissues including connective tissues and muscles and is regarded as a physiological agent present at low concentrations; the healthy adult contains approximately 0.1–0.25 mmol/L HICA in plasma. The degree to which oral supplemental HICA raises plasma concentrations, and whether those concentrations reach the substantially higher levels used in in-vitro antimicrobial assays, has not been established in published pharmacokinetic data.

Limitations of the Safety Database

Human safety data derive from a small number of short-duration studies (4 weeks to 120 days) involving healthy male athletes and a single diabetic case study. No long-term (beyond 4 months) safety data exist. No studies have examined safety in female populations, children, the elderly, individuals with renal or hepatic compromise, or pregnant or lactating individuals. In-vitro antimicrobial data employed concentrations of HICA (up to 72 mg/mL) that are orders of magnitude higher than plasma concentrations achievable physiologically.

Drug Interactions

No peer-reviewed human data on HICA drug interactions have been published. Because HICA is a downstream metabolite of the essential amino acid leucine — itself subject to catabolism by the BCKDH enzyme complex — any pharmacological agent that modulates branched-chain amino acid metabolism could theoretically alter HICA disposition, but this has not been studied.

Summary of Evidence Strength

The overall evidence base for HICA as a dietary supplement is small and mixed. The most positive human signal — reduced DOMS — is supported by two studies in overlapping athlete populations from the same research group, one of which was uncontrolled. The one independent RCT in resistance-trained men (Teixeira et al. 2019) found no effect on body composition. Anticatabolic and anti-inflammatory mechanistic evidence is largely preclinical (cell culture and rodent models). Antimicrobial evidence is entirely in vitro or in vivo in animal models. More long-term and mechanistic studies in humans are needed before firm conclusions can be drawn.

References

• Mero AA et al. (2010). Effects of alfa-hydroxy-isocaproic acid on body composition, DOMS and performance in athletes. Journal of the International Society of Sports Nutrition. PMC2818616.
• Teixeira FJ et al. (2018). Effects of Alpha-hydroxy-isocaproic acid upon Body Composition in a Type I Diabetic Patient with Muscle Atrophy – A Case Study. PubMed PMID 29962922.
• Teixeira FJ et al. (2019). No effect of HMB or α-HICA supplementation on training-induced changes in body composition. European Journal of Sport Science. PubMed PMID 30588860.
• Lang CH et al. (2013). Chronic α-hydroxyisocaproic acid treatment improves muscle recovery after immobilization-induced atrophy. American Journal of Physiology-Endocrinology and Metabolism.
• Sumi K et al. (2021). α-Hydroxyisocaproic Acid Decreases Protein Synthesis but Attenuates TNFα/IFNγ Co-Exposure-Induced Protein Degradation and Myotube Atrophy via Suppression of iNOS and IL-6 in Murine C2C12 Myotube. Nutrients. PMC8308709.
• Sakko M et al. (2014). 2-hydroxyisocaproic acid is fungicidal for Candida and Aspergillus species. Mycoses. PubMed PMID 24125484.
• Pahalagedara ASNW et al. (2022). Antibacterial efficacy and possible mechanism of action of 2-hydroxyisocaproic acid (HICA). PLOS One.
• Nieminen MT et al. (2014). dl-2-Hydroxyisocaproic Acid Attenuates Inflammatory Responses in a Murine Candida albicans Biofilm Model. Clinical and Vaccine Immunology. PMC4178561.
• Park B et al. (2017). Identification of 2-hydroxyisocaproic acid production in lactic acid bacteria and evaluation of microbial dynamics during kimchi ripening. Scientific Reports. PMC5589888.
• Wikipedia. 2-Hydroxyisocaproic acid.
• Stout JR et al. (2015). A 14C-leucine ADME study in adult Sprague–Dawley rat reveals β-hydroxy-β-methylbutyrate as a metabolite. PMC4412734.
• Mero AA. (2018). Alfa-Hydroxy-Isocaproic Acid—Effects on Body Composition, Muscle Soreness, and Athletic Performance. Nutrition and Enhanced Sports Performance (2nd ed.). ScienceDirect.