Fatal oxidative haemolysis and methaemoglobinaemia in a patient with alkaptonuria and acute kidney injury

Abstract

Alkaptonuria (AKU) is a rare inherited disorder of tyrosine metabolism, which leads to an accumulation of homogentisic acid (HGA) and is associated with a progressive arthropathy. Fatal complications are unusual and usually result from cardiac disease or progressive renal impairment; rapidly fatal haematological complications are exceptionally rare and described in only a handful of case reports. This case involves a 63-year-old male with AKU and modest chronic kidney disease who developed rapidly fatal haemolysis and methaemoglobinuria following an episode of acute kidney injury triggered by an obstructing ureteric calculus and urosepsis. The patient succumbed despite aggressive antioxidant therapy with ascorbic acid and n-acetyl cysteine. A rapid build-up of HGA due to reduced renal clearance, triggering oxidative haemolysis and methaemoglobinuria is proposed as the mechanism. Alternative strategies to consider when conventional antioxidants fail are discussed including the potent inhibitor of HGA production, nitisonone.

Ochronosis Presenting as Methemoglobinemia

“…Although most complications of alkaptonuria are chronic in nature, there are reports of acute decompensation and death in patients with alkaptonuria and impaired renal function. More specifically, the development of methemoglobinemia in patients with alkaptonuria has been reported in the English literature in multiple adult patients . In all cases, methemoglobinemia followed a decline in renal function, leading to rapid accumulation of HGA in the serum.…”

“…In patients with alkaptonuria who develop renal disease, decreased urinary elimination of HGA can lead to rapid accumulation of HGA in the blood and tissues, causing diffuse skin pigmentation. Moreover, rapid accumulation of HGA and its byproducts in the serum can overwhelm the anti‐oxidant capacity of the body, resulting in oxidation of oxyhemoglobin to methemoglobin, inducing refractory methemoglobinemia .…”

Ochronotic pigmentation is caused by homogentisic acid and is the key event in alkaptonuria leading to the destructive consequences of the disease—A review

“…Stone formation featuring OP has been found in kidney, prostate, gall bladder, and salivary gland, resulting in symptomatic obstruction of these organs . Renal failure can ensue both due to obstruction and renal parenchymal ochronosis, sometimes leading to fatal intractable hemolytic anemia …”

Nitisinone: a review

“…86 Acute metabolic decompensation, including oxidative hemolysis and/or methemoglobinemia, has also been reported. 99,100 There is currently no licensed pharmacological treatment for AKU, except palliative treatments.…”

“…13,24,25,[102][103][104] It is postulated that treatment with nitisinone should be started as early as possible before renal functions decline and other potentially fatal acute complications develop. 99,100 Nitisinone and neuroblastoma Neuroblastoma, the most common solid neoplasm of childhood outside of the central nervous system, is a neural crest-derived neoplasm. The overall outcome is excellent for children with localized disease.…”