Alkaptonuria – a review of surgical and autopsy pathology

Abstract

Alkaptonuria is a rare, inherited defect of homogentisic acid 1,2-dioxygenase that leads to the widespread deposition of polymeric homogentisic acid, and clinical symptoms from degeneration of joints and the aortic valve. Pathological descriptions are few and mainly those of late-stage changes related to joint or valve failure. In this review, the macroscopic and histopathological changes in the tissues in alkaptonuria are illustrated by the detailed autopsy study of a 74-year-old female who died from disseminated ovarian carcinoma. The pathology is discussed in the context of the literature and in relation to potential pathogenic mechanisms of tissue damage. This review highlights the heterogeneity of some of the manifestations. In symptomatic patients, degenerative changes in synovial and intervertebral joints are usually well advanced, while early changes include diffuse cartilage pigmentation and chondrocyte necrosis. The initial stage of pigment deposition in the cardiovascular system may be influenced by intravascular pressure and flow disturbances, whereas more intense pigmentation affects fibrolipid components of atheromatous plaques. Pigmentation of the aortic and mitral valve cusps and valve rings is a result of intracellular and extracellular pigment deposition and is associated with calcification and clinically significant aortic stenosis.

Reversible Keratopathy Due to Hypertyrosinaemia Following Intermittent Low-Dose Nitisinone in Alkaptonuria: A Case Report

“…Although joint disease is a major feature, virtually all connective tissues are affected leading to a variety of clinical features and complications (Helliwell et al 2008). A promising new agent, called nitisinone, is available for the treatment of AKU (McKiernan 2006).…”

Alkaptonuria

“…23 It may be that mechanical forces play a key role in mediating ochronosis given that there appears to be little pigmentation in the venous component of the circulation compared with the arterial side. 17 Interestingly, while HGD expression and HGA metabolism occur in the liver, there are no reports to demonstrate that these tissues-along with those of the pancreas, gastrointestinal, lymphoreticular, or endocrine organs-develop ochronosis. 17 The development of ochronotic arthropathy is the result of deposition of the HGA polymer within hyaline articular cartilage.…”

“…17 Interestingly, while HGD expression and HGA metabolism occur in the liver, there are no reports to demonstrate that these tissues-along with those of the pancreas, gastrointestinal, lymphoreticular, or endocrine organs-develop ochronosis. 17 The development of ochronotic arthropathy is the result of deposition of the HGA polymer within hyaline articular cartilage. Pigmentation is widespread, with all tissues of the joint organ being affected ( Table 1).…”

“…[14][15][16][17] Each feature presents at various stages in life, the earliest being detection of HGA in urine. 18 The passing of black urine is the only manifestation of the condition known in pediatrics, leading to 21% of patients being diagnosed with AKU before 1 year of age.…”

Misdiagnosis of alkaptonuria in an elderly patient

“…Both synovial and intervertebral joints are affected 9 . Usually, joint symptoms start between the ages of 40 and 50 years.…”