Elevated Phenylalanine Levels – More Than a Biomarker?

Phenylalanine is an essential amino acid, obtained from the diet, that is used to synthesize proteins. During times of fasting, such as in critical illness, muscle is catabolized into its constitutive amino acids and serves as the primary source of serum phenylalanine, which is understood to be a marker of whole body proteolysis (1). There is evidence that chronically elevated levels of serum phenylalanine are cardiotoxic, leading to the development of coronary artery disease, increased heart failure hospitalizations, and even cardiac fibrosis (2–5). However, the association between acute elevations in phenylalanine and an increased risk of mortality in critically ill patients admitted to the cardiac intensive care unit (CICU) has only recently been studied. The authors have previously demonstrated an association between elevated phenylalanine levels (≥ 11.2 μmol/dL) on CICU admission with 1-year mortality (6).

In this edition of Critical Care Medicine, Wang et al (7) build upon their previous work, demonstrating that among critically ill patients admitted to the CICU without elevated phenylalanine levels (< 11.2 μmol/dL) on admission, those with a genetic predisposition towards developing hyperphenylalaninemia are at increased risk of mortality. They performed a single center prospective observational study in their tertiary level CICU where they enrolled 497 critically ill patients from 2017 – 2021. Consistent with their previous data, they found that patients experiencing stress hyperphenylalaninemia (SHP, defined as level ≥ 11.2 μmol/dL) on admission had higher 90-day mortality compared to those without SHP (< 11.2 μmol/dL). This is the first novel finding in this study, that there is the association between the development of SHP during the CICU admission and increased mortality.

There are genetic polymorphisms in phenylalanine metabolism, which they quantified by creating a genetic risk score (GRS). They then performed a subgroup analysis in patients without SHP on admission (defined as level of < 11.2 μmol/dL, n=383) and separated them into those with a genetic predisposition to developing SHP (GRS ≥ 2, n=165), and those without (GRS < 2, n=218). First, they found that a higher proportion of patients with a GRS ≥ 2 develop SHP during their CICU admission compared to those with a GRS < 2 (31.5% vs. 16.1%, p=0.001). The second novel finding of this study is that, after adjusting for confounders, a GRS ≥ 2 was associated with a higher hazard of mortality (HR: 1.74, 95% CI: 1.18 – 2.56, p=0.005) using multivariable cox-proportional hazard modeling. From this, the authors conclude that the development of SHP, due to a patient’s genetic predisposition, resulted in cardiotoxicity leading to an increased risk of mortality.

There is no clearly described causal pathway linking acutely elevated levels of phenylalanine to end organ injury resulting in death. Moreover, no observational study has been performed which measures all serum amino acid levels during critical illness. Human muscle contains all amino acids and during critical illness, catabolism of this tissue would likely lead to elevations in all amino acids (8,9). Without measuring the serum levels of other amino acids during critical illness, the significance of the observation between elevated GRS leading to SHP is uncertain, and the impact of genetic variants of phenylalanine metabolism are speculative.

While no data currently support a direct causal pathway between SHP during critical illness and end organ dysfunction leading to increased mortality (Figure 1, Pathway A), there are potential pathways that could explain why SHP manifests in critically ill patients seen in the CICU (Figure 1, Pathway B). Muscle catabolism, leading to elevated phenylalanine levels, occurs early during critical illness, and patients with multiorgan failure experience greater muscle loss compared to those with only single organ failure (10). Second, phenylalanine is metabolized and cleared by the body via two pathways. The first, accounting for most of its removal, is via hydroxylation into tyrosine by phenylalanine hydroxylase (PAH). Mutation of this enzyme results in the well-known inherited disorder, phenylketonuria. The second route is direct excretion of phenylalanine into the urine. While the mechanisms are not entirely understood, as renal failure progresses, conversion from phenylalanine to tyrosine is slowed and renal clearance of phenylalanine becomes non-existent, resulting in elevated phenylalanine levels (11). Note that in these two pathways of increased phenylalanine levels (increased muscle catabolism and impaired phenylalanine clearance), SHP is a result of critical illness, but may not result in or contribute to critical illness and end organ dysfunction leading to mortality.

Figure 1:

Directed acyclic graphs showing (Pathway A) stress hyperphenylalaninemia causally mediating the pathway between critical illness and organ dysfunction leading to mortality, or as a (Pathway B) byproduct of critical illness and not causally associated with organ dysfunction leading to mortality.

We agree with the authors that “SHP predicted mortality in patients facing critical illness,” as SHP can be predictive of increased end organ injury and mortality as illustrated in Figure 1 (Pathway A). However, the authors go further in their discussion and suggest targeting phenylalanine levels with tetrahydrobiopterin (BH4, a key cofactor for phenylalanine hydroxylase) supplementation as a potential therapy in acutely ill patients admitted to the CICU. This would be a reasonable next step if a casual pathway for SHP leading to adverse outcomes (Figure 1, Pathway B) were shown to be true. The only support for the presence of this pathway offered by the authors is that among patients without SHP on admission, those with a genetic predisposition for developing SHP (defined as a GRS >= 2) are more likely to develop SHP and have a higher risk of mortality. This evidence is largely useful for hypothesis generation at best. The authors themselves correctly state that “whether SHP or phenylalanine derived toxic metabolites play a direct role in poor outcomes needs further investigation.”

Wang et al provide preliminary evidence to support the association between the development of elevated phenylalanine levels during hospitalization and adverse outcomes in critically ill patients admitted to the CICU. Furthermore, there may be genetic polymorphisms that predispose critically ill patients to developing SHP leading to increased mortality risk. Predicting clinical outcomes in this diverse population and identifying novel pathways for therapies has been identified as a key priority in the field of critical care cardiology (12). Their investigation is a step in the right direction, but more work is needed to determine if there is a causal relationship between acute elevations in phenylalanine levels and end organ injury leading to mortality in this patient population. Ignoring this fundamental step risks repeating the mistakes in sepsis research in which multiple clinical trials investigated blockade of specific inflammatory biomarkers, and all have failed (13).

Abbreviation:

SHP

stress hyperphenylalaninemia