The nutritional status of people with alkaptonuria: An exploratory analysis suggests a protein/energy dilemma

Abstract

Background Alkaptonuria (AKU) is a disorder of tyrosine/protein metabolism leading to accumulation of homogentisic acid. Clinical management historically recommended reducing dietary protein intake, especially in childhood, which has since been discredited in the literature. For the first time, analysis of baseline cross‐sectional nutritional surveillance data from a large cohort of AKU patients is presented, which has clinical implications in all aspects of treatment planning. Method Seventy‐four patients (mean 55 years) admitted to the National Alkaptonuria Centre (NAC), underwent a global nutritional assessment, which included objective anthropometry, bioimpedance measures, habitual nutritional intake using a 7‐day food diary and key nutritional biomarkers, including 24 hours urinary nitrogen, serum albumin, total protein and total 25‐hydroxy vitamin D. All data was compared with cohort norms or recommended nutrient intakes for health (RNI). The potential beneficial impact of protein and anti‐inflammatory nutrients such as vitamin C, selenium, and zinc were statistically interrogated against the AKU severity score index (AKUSSI)—a validated measure of disease progression stratified by age. Results Fifty percent of AKU patients reported some level of protein restriction at some point in their lives. In comparison with national data sets, AKU patients present with significantly lower than predicted mid‐upper arm circumference, grip strength, BMI, total energy and protein intake, and higher than predicted percentage body fat. They therefore meet the ESPEN criteria as “clinically undernourished.” Severity fluctuates over the life course. No statistical association is identified between protein intake, expressed as %RNI or g/kg, or anti‐inflammatory nutrients, including vitamin C as a high dose supplement on the severity of the disease, when correlated against the validated AKUSSI score. Conclusion AKU patients are at risk of protein depletion associated with a “perfect storm” of risk factors: historical, poorly evidenced recommendations to reduce total protein intake; limited mobility as the condition progresses, compromising muscle integrity; frequent hospital admissions for major surgery associated with multiple joint replacements, creating pinch points of high metabolic demand and the potential impact of the disease itself. As this is the first time this risk has been identified, the authors consider the dietetic implications of nitisinone treatment, which requires dietary protein control to manage the acquired tyrosinaemia. The lack of statistically significant evidence to support dietary manipulation of any kind to impede disease progression in AKU is demonstrated.

Effects of a protein‐restricted diet on body weight and serum tyrosine concentrations in patients with alkaptonuria

“…But there is no evidence that this has any effect on disease progression. 17 The protein restriction introduced in our study led to a statistically significant decrease in u‐HGA 24 in the untreated patients by about 8% on average at Month 12, which cannot be assumed to be of any clinical relevance, especially as there was a simultaneous (unexplained) 6% increase in s‐HGA. For comparison, treatment with nitisinone 10 mg/day reduced u‐HGA 24 and s‐HGA by, on average, 99.7% and 98.8%, respectively.…”

Association of alkaptonuria and low dose nitisinone therapy with cataract formation in a large cohort of patients

“… 42 A recent analysis of the diet in the NAC patients showed significant malnutrition including sarcopenia even before nitisinone therapy and a nutrition deficiency contribution to cataract in AKU cannot be excluded. 42 , 43 …”

Characterizing the alkaptonuria joint and spine phenotype and assessing the effect of homogentisic acid lowering therapy in a large cohort of 87 patients

“…A dedicated senior dietician delivered the lower-protein diet responding to serum tyrosine measurements during their annual visit to the NAC with the following tyrosine thresholds (all in μmol/L): <501-no action, continued on 1 g/kg body weight; 501-700reduced intake to 0.9 g/kg body weight; 701-900reduced intake to 0.8 g/kg body weight; >901-began tyrosine/phenylalanine-free meal exchanges in addition to reduced intake to 0.8 g/kg body weight; corneal keratopathy-discontinued nitisinone for 2 months and dietary intake reassessed before restarting nitisinone. 28 Over 7 years of nitisinone therapy, only three patients experienced corneal keratopathy. 29,30 Linear regression analysis in the current dataset provides a direct link between ochronosis and spondyloarthropathy in AKU.…”