Blood Phenylalanine Levels in Patients with Phenylketonuria from Europe between 2012 and 2018: Is It a Changing Landscape?

BACKGROUND: In 2011, a European phenylketonuria (PKU) survey reported that the blood phenylalanine (Phe) levels were well controlled in early life but deteriorated with age. Other studies have shown similar results across the globe. Different target blood Phe levels have been used throughout the years, and, in 2017, the European PKU guidelines defined new targets for blood Phe levels. This study aimed to evaluate blood Phe control in patients with PKU across Europe. METHODS: nine centres managing PKU in Europe and Turkey participated. Data were collected retrospectively from medical and dietetic records between 2012 and 2018 on blood Phe levels, PKU severity, and medications. RESULTS: A total of 1323 patients (age range:1-57, 51% male) participated. Patient numbers ranged from 59 to 320 in each centre. The most common phenotype was classical PKU (n = 625, 48%), followed by mild PKU (n = 357, 27%) and hyperphenylalaninemia (HPA) (n = 325, 25%). The mean percentage of blood Phe levels within the target range ranged from 65 ± 54% to 88 ± 49% for all centres. The percentage of Phe levels within the target range declined with increasing age (<2 years: 89%; 2-5 years: 84%; 6-12 years: 73%; 13-18 years: 85%; 19-30 years: 64%; 31-40 years: 59%; and ≥41 years: 40%). The mean blood Phe levels were significantly lower and the percentage within the target range was significantly higher (p < 0.001) in patients with HPA (290 ± 325 µmol/L; 96 ± 24%) and mild PKU (365 ± 224 µmol/L; 77 ± 36%) compared to classical PKU (458 ± 350 µmol/L, 54 ± 46%). There was no difference between males and females in the mean blood Phe levels (p = 0.939), but the percentage of Phe levels within the target range was higher in females among school-age children (6-12 years; 83% in females vs. 78% in males; p = 0.005), adolescents (13-18 years; 62% in females vs. 59% in males; p = 0.034) and adults (31-40 years; 65% in females vs. 41% in males; p < 0.001 and >41 years; 43% in females vs. 28% in males; p < 0.001). Patients treated with sapropterin (n = 222) had statistically significantly lower Phe levels compared to diet-only-treated patients (mean 391 ± 334 µmol/L; percentage within target 84 ± 39% vs. 406 ± 334 µmol/L; 73 ± 41%; p < 0.001), although a blood Phe mean difference of 15 µmol/L may not be clinically relevant. An increased frequency of blood Phe monitoring was associated with better metabolic control (p < 0.05). The mean blood Phe (% Phe levels within target) from blood Phe samples collected weekly was 271 ± 204 µmol/L, (81 ± 33%); for once every 2 weeks, it was 376 ± 262 µmol/L, (78 ± 42%); for once every 4 weeks, it was 426 ± 282 µmol/L, (71 ± 50%); and less than monthly samples, it was 534 ± 468 µmol/L, (70 ± 58%). CONCLUSIONS: Overall, blood Phe control deteriorated with age. A higher frequency of blood sampling was associated with better blood Phe control with less variability. The severity of PKU and the available treatments and resources may impact the blood Phe control achieved by each treatment centre.

Limited Role of Endogenous Vasopressin/Copeptin in Stimulation of ACTH-Cortisol Secretion during Glucagon Stimulation Test in Humans.

Copeptin is a stable part of a vasopressin precursor that closely mirrors arginine vasopressin (AVP) secretion. It is known that AVP/copeptin is also released in response to nonosmotic stimuli, such as stress evoked during anterior pituitary dynamic testing. In order to examine the role of AVP in challenging the hypothalamo-pituitary-adrenal axis, we assessed adrenocorticotropic hormone (ACTH), cortisol, copeptin and growth hormone (GH) during a glucagon stimulation test (GST) in 10 patients with satisfactory initial cortisol concentrations (mean ± SD: 20.34 ± 5.10 µg/dL) and failure to show any further cortisol increment on stimulation. For comparison, we measured copeptin in two subjects during an insulin tolerance test (ITT). During GST, there was an increase in copeptin (p = 0.02, average individual increase of 98%, range 10% to 321%). There was a robust increase in GH (p = 0.002, average increase 3300%), a decline in cortisol (p = 0.02, average decline 21.8%) and a fall in ACTH (p = 0.06). The relative increase in copeptin during ITT (176% and 52.2%) overlapped with increments observed during GST; however, here there was an increase in cortisol (20.45→24.26 µg/dL and 4.23→29.29 µg/dL, respectively). There was a moderate correlation between copeptin and GH concentrations (r = 0.4235, p = 0.0007). These results confirm that AVP is not crucial for ACTH-cortisol stimulation, though it might be an important factor in GH secretion.

Addison's disease concomitant with corticotropin deficiency and pituitary CRH resistance - a case report.

A 36-year-old woman was found to have a low morning ACTH concentration despite a history of Addison's disease. Past medical history: At the age of 23 years the subject developed Graves's disease, which was treated with radioiodine. At about the same time, she claimed to have two episodes of pancreatitis treated with cholecystectomy. About seven months later she was euthyroid on L-thyroxine (TSH 1.51 mIU/mL) but was admitted with hypotension, hyponatraemia (sodium 109 mmol/L), and low morning cortisol (119 nmol/L). Further investigations confirmed primary adrenal failure with ACTH concentration of 779 pg/mL (ref. range 0-60) prior to the dose of hydrocortisone. About nine years later she complained about tiredness. Clinically she was normotensive and not pigmented. BMI 22.3 kg/m². Periods were regular. ACTH concentration was surprisingly low (ACTH 8.53 pg/mL, ref. range 0-46), despite very low cortisol (3.37 nmol/L). She was admitted for further assessment. INVESTIGATIONS: Pituitary MRI scan was unremarkable. An insulin tolerance test was performed and showed a clear increase of ACTH (from 15.2 to 165 pg/mL). There was, however, hardly any increase of ACTH after CRH stimulation (from 6.05 pg/mL to 10.2 pg/mL), thus demonstrating central CRH resistance. In summary, this patient developed secondary adrenal failure in the setting of previous Addison's disease. Interestingly, hypoglycaemia (but not CRH) provided a stimulus for ACTH release, thus demonstrating CRH resistance. The case confirms that besides CRH, other factors are responsible for stimulation of the ACTH-cortisol axis during insulin tolerance test.

Copeptin as a marker of an altered CRH axis in pituitary disease.

BACKGROUND: Copeptin (pre-proAVP) secreted in equimolar amounts with vasopressin closely reflects vasopressin release. Copeptin has been shown to subtly mirror stress potentially mediated via corticotrophin-releasing hormone. To further test a potential direct interaction of corticotrophin-releasing hormone with copeptin release, which could augment vasopressin effects on pituitary function, we investigated copeptin response to corticotrophin-releasing hormone. PATIENTS AND METHODS: Cortisol, adrenocorticotropin and copeptin were measured in 18 healthy controls and 29 subjects with a history of pituitary disease during standard corticotrophin-releasing hormone test. RESULTS: Patients with previous pituitary disease were subdivided in a group passing the test (P1, n = 20) and failing (P2, n = 9). The overall copeptin response was higher in controls than in subjects with pituitary disease (area under the curve, p = 0.04 for P1 + P2) with a maximum increase in controls from 3.84 ± 2.86 to 12.65 ± 24.87 pmol/L at 30 min, p < 0.05. In contrast, both groups of pituitary patients lacked a significant copeptin response to corticotrophin-releasing hormone, and even in P1, where adrenocorticotropin concentrations increased fourfold (mean, 21.48 vs. 91.53 pg/mL, p < 0.01), copeptin did not respond (e.g., 4.35 ± 5.81 vs. 5.36 ± 6.79 pmol/L, at 30 min, p = ns). CONCLUSIONS: Corticotrophin-releasing hormone is able to stimulate copeptin release in healthy controls suggesting a direct interaction of corticotrophin-releasing hormone and vasopressin/vasopressin. Interestingly, this relation is altered already in the group of pituitary patients who pass the standard corticotrophin-releasing hormone test indicating (1) the corticotrophin-releasing hormone-adrenocorticotropin-cortisol response is largely independent from the vasopressin system, but (2) the corticotrophin-releasing hormone-vasopressin interaction reflected by copeptin may be much more sensitive to reveal subtle alterations in the regulation of pituitary function.