*From the Division of Pulmonary and Critical Care Medicine (Drs. Parambil, Daniels, and Utz) and Department of Cardiovascular Surgery (Dr. Zehr), Mayo Clinic, Rochester, MN.
Correspondences to: James P. Utz, MD, Division of Pulmonary and Critical Care Medicine, Desk East 18, Mayo Clinic, 200 First St SW, Rochester, MN 55905; e-mail: email@example.com
A 68-year-old white man was evaluated for failure to wean from mechanical ventilation after cardiac surgery. Bronchoscopy performed prior to percutaneous dilatational tracheotomy revealed circumferential strikingly dark-colored airways, most prominent in the trachea and mainstem bronchi, extending distally into all airways with overlying desiccated black secretions. Histologic examination of bronchial mucosal biopsy samples and the desiccated secretions showed acute bronchitis and necrotic debris, respectively. This finding and the patient’s history led to testing for plasma homogentisic acid, which was found to be elevated at 12.6 μg/mL, establishing the first diagnosis of alkaptonuria made using flexible bronchoscopy.
Alkaptonuria (ochronosis) is an inherited disorder of amino acid metabolism1affecting the degradation of phenylalanine and tyrosine.2 These amino acids are degraded along the tyrosine degradation pathway to acetoacetic acid and fumaric acid.2 In alkaptonuria, one of the enzymes in this pathway, homogentisate 1, 2-dioxygenase (HGO), is absent, leading to the accumulation of homogentisic acid (HGA).2HGA and its metabolites accumulate in collagenous tissues causing ochronosis, characterized by darkened cartilaginous tissues, arthritis and joint destruction, and deterioration of cardiac valves.3
Ochronotic pigmentation of the laryngeal and tracheal cartilages has been described at autopsy in case reports.4 We report the first case of alkaptonuria diagnosed premortem by flexible bronchoscopy.
A 68-year-old white man was admitted to the hospital electively for cardiac valve replacement surgery. He had congestive heart failure due to severe aortic valve and mitral valve stenoses. His medical history was remarkable for multiple joint replacement surgeries since age 46 years for polyarticular erosive arthropathy presumed to be due to seronegative rheumatoid arthritis. On physical examination, there were no peripheral stigmata suggestive of ochronosis.
The patient underwent mitral valve and aortic valve replacements with St. Jude mechanical valves (St. Jude Medical Inc.; St. Paul, MN), and a tricuspid valve repair with a bilateral asymmetric Kay annuloplasty. On postoperative day 15, he was evaluated for failure to wean from mechanical ventilation due to post-pump ARDS and ventilator-associated pneumonia.
Bronchoscopy was performed prior to percutaneous dilatational tracheotomy. This revealed circumferential strikingly dark-colored airways, most prominent in the trachea and mainstem bronchi, extending distally into all airways with overlying desiccated black secretions (Fig 1
). Despite several attempts at cleaning the central airways with forceps extraction and copious saline solution irrigation, the mucosa remained hyperpigmented. Histologic examination of bronchial mucosal biopsy specimens and the desiccated secretions showed acute bronchitis and necrotic debris, respectively. Fontana-Masson staining disclosed that the pigmentation was negative for melanin. Microbiological studies of bronchial secretions revealed no growth of pathogenic organisms.
Given the patient’s history of polyarticular erosive arthropathy, cardiac surgery for valvular stenoses, and the dark-colored airways, testing for plasma HGA was performed. The level was elevated at 12.6 μg/mL, establishing the diagnosis of alkaptonuria. Despite initiating high-dose ascorbic acid treatment, the patient died from multisystem organ failure.
La Du and colleagues2 were the first to describe the metabolic derangement responsible for the observed phenotype of ochronosis by demonstrating the deficiency of HGO activity in the liver of a patient with alkaptonuria. Elevation in urinary HGA excretion by a factor of 100 to 600 or the detection of HGA in plasma is considered diagnostic for alkaptonuria.4Our patient was anuric due to acute tubular necrosis. However, HGA was detected in plasma, thereby establishing the diagnosis of alkaptonuria. Prior to the development of gas chromatographic-mass spectrophotometric assays to measure urine and plasma HGA levels,5 alkaptonuria was diagnosed based on the property of urine HGA to turn dark on prolonged exposure to room air or with the addition of sodium hydroxide.1 On prolonged exposure of urine to room air or by alkalinizing urine, HGA in the urine oxidizes to benzoquinones, which in turn form melanin-like polymers,5 and turns black within minutes.
Case reports of ochronotic pigmentation of the laryngeal and tracheal cartilages have been described at autopsy in patients with an established diagnosis of alkaptonuria, suggesting that HGA and its metabolites accumulate in these tissues.4 In alkaptonuria, the deficiency of HGO causes excretion of large quantities of HGA daily in the urine and other bodily secretions such as cerumen and sweat.4As mentioned earlier, a milieu that facilitates the oxidation of HGA is necessary for the generation of benzoquinones and melanin-like polymers.5There are several opportunities for the generation of oxygen-free radicals in a patient receiving mechanical ventilation and high concentrations of oxygen. Healthy volunteers breathing pure oxygen develop hyperoxic tracheobronchitis mediated through the production of reactive oxygen species with erythema and edema of large airways observed bronchoscopically, and is thought to reflect oxygen toxicity on the tracheal and bronchial mucosa.6 Hyperoxia also promotes the insudation of inflammatory cells, which are also sources of oxygen-derived free radicals.6 Therefore, the oxidation of HGA and its metabolites by reactive oxygen species can lead to the diffusely dark-colored pigmentation of the cartilaginous tracheobronchial tree and its secretions.
This case is the first report of alkaptonuria diagnosed premortem using flexible bronchoscopy. The bronchoscopic finding of circumferential diffusely hyperpigmented airways should raise the suspicion of alkaptonuria and further investigation for this diagnosis can be performed by testing urine or plasma for HGA levels.
Abbreviations: HGA = homogentisic acid; HGO = homogentisate 1, 2-dioxygenase
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