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.

The pathology of alkaptonuric ochronosis. Hum Pathol. 1989 Jan;20(1):40-6.

The gross and microscopic pathology of alkaptonuric ochronosis is presented from a study of pathologic specimens from six cases in our files and from a review of the literature. Emphasis is placed on the most clinically relevant organ systems involved by ochronosis: musculoskeletal, cardiovascular, genitourinary, eye, and skin. Recent electron microscopic discoveries from several affected organs, including the synovium, articular cartilage, cardiovascular system, eye, and skin, are included in this report. In addition, the molecular pathology of alkaptonuria is briefly discussed. The pathologic literature regarding alkaptonurin ochronosis is fragmented, as most cases of this rare entity are reported individually or as small series of cases. A comprehensive review of alkaptonuria has not appeared since the clinicopathologic review of the world literature by O'Brien et al in 1963. The purpose of this report is to present an updated and unified pathologic study of alkaptonuric ochronosis.

Ochronosis or alkaptonuria is a rare inherited disease. It is characterized by the deposition of dark pigments in collagen-rich tissues, which leads to clinical manifestations such as arthropathy. The ochronotic pigment can be found in the sclera, the conjunctiva, and the limbic cornea. Vision is usually not affected. We report the case of 47-year-old patient who complained of lower back pain. Ophthalmologic examination showed dark pigments in the conjunctiva. The increased levels  of homogentisic acid in urine confirmed the diagnosis of  ochronosis.

The rare hereditary metabolic disorder alcaptonuria is characterized by the inability to metabolize homogentisic acid, an intermediary compound in the catabolism of the aromatic amino acids phenylalanine and tyrosine. The essentially complete deficiency of homogentisic acid oxidase causes a striking accumulation of homogentisic acid and a derived melanin-like pigment in the connective tissues; the latter is termed ochronosis. Urinary homogentisic acid is oxidized rapidly and becomes a brown or black pigment if alkali is added. Older alcaptonurics have intensely pigmented (ochronotic) connective tissues, primarily the cartilaginous joint surfaces, ribs, intervertebral disks, ear cartilage, etc. They also have an unusual type of arthritis affecting the large weight-bearing joints, i.e. hips, knees and spine, but not the small joints of the hands and feet, as in rheumatoid arthritis. A mechanistic explanation for ochronotic arthritis has not been worked out, but it is clear that accumulation of homogentisic acid in the connective tissues directly or indirectly leads to the arthritic changes. A detailed analysis of the events leading to alcaptonuric arthritis should be worthwhile since it is a model form of arthritis secondary to a well-defined metabolic disorder that must persist for many years before the arthritic complications appear. Possibly other, more common types of arthritis, develop secondarily to metabolic disturbances that involve chemical mediators less obvious, or less easily detected, than homogentisic acid.

Ochronotic arthropathy: pathological evidence of acute destruction of the hip joint.Clin Rheumatol. 2007;26(7):1189-91.

Alcaptonuria is a hereditary disease, also known as black hip, where there is an accumulation of homogentisic acid pigmentation in joint cartilages. We describe a 74-year-old woman who showed acute destruction of her left hip joint. She received a total hip arthroplasty on her right side in July 2000, and was diagnosed with ochronosis. Her postoperative follow-up was at our institutions outpatient department. She first complained of increasing groin pain in July 2005, after which she had a left total hip arthroplasty in October 2005. Histopathologically, samples from this patient showed "fragmentation and cleft formation" in the cartilage of the femoral head. In addition, the samples revealed a remarkable degradation of proteoglycan, which is the secondary most abundant constituent of extra cellular matrix. These findings suggested that "cleft formation", where cracks develop toward the center, caused an acute destructive arthropathy with morphological fragility suggestive of ochronosis.

A 64-year-old man with alkaptonuric ochronosis required aortic valve replacement for severe aortic stenosis and single-vessel aortocoronary artery bypass grafting for a subtotally occluded obtuse marginal branch of the circumflex coronary artery. Operative findings included ochronosis of a partly calcified aortic valve and the aortic intima. The aortic valve and a punch biopsy specimen of the ascending aorta were removed at surgery and were studied with transmission electron microscopy and light microscopy. The ultrastructural studies of the aortic valve revealed intracellular and extracellular deposits of ochronotic pigment. A portion of the extracellular ochronotic pigment represented degenerated cells. Large deposits of extracellular ochronotic pigment were associated with areas of valvular calcification. Electron microscopic study of the aorta disclosed ochronotic pigment in macrophages and smooth-muscle cells. Aggregates of extracellular ochronotic pigment in the intima and media appeared to be in locations of necrotic cells. Light microscopy also showed intracellular and extracellular deposits of ochronotic pigment. Our study suggests that extensive extracellular deposits of ochronotic pigment in the aortic valve may serve as a stimulus for dystrophic calcification. This may play a role in the development of aortic valve calcification and aortic stenosis associated with alkaptonuric ochronosis. To our knowledge, this is the first ultrastructural study of the aortic valve and aorta in alkaptonuric ochronosis.

Aortic valve stenosis due to alkaptonuria.J Heart Valve Dis. 2008 Jan;17(1):127-9.

Cardiovascular disease is a less-well appreciated aspect of alkaptonuria. A 69-year-old man presented with shortness of breath and exertional chest pain. He had a previous diagnosis of alkaptonuria (endogenous ochronosis), confirmed on the basis of urine coloration, skin pigmentation and ochronotic arthropathy in the knees. Echocardiography and coronary angiography revealed severe aortic valve stenosis and concomitant coronary artery disease. The patient underwent biological aortic valve replacement (AVR) and coronary artery bypass grafting (CABG). Operative findings included ochronosis of a severely calcified aortic valve and the aortic intima, and bioprosthetic AVR and CABG were successfully performed.

Aortic stenosis in cardiovascular ochronosis. J Clin Pathol. 2007 Jan;60(1):92-3.

Alkaptonuria (endogenous ochronosis) is a rare metabolic disorder caused by a deficiency of homogentisic acid oxidase, an enzyme responsible for the metabolic degradation of tyrosine. Patients with alkaptonuria commonly present with joint pain owing to degenerative arthritis. Other affected patients may present with pigmentation of the ear cartilage and sclera. This article reports a case of aortic stenosis associated with ochronosis in a 48-year-old man who presented with severe cardiac failure. He had no previous diagnosis of alkaptonuria, which was confirmed by mass spectrometry analysis of urine. The pathogenesis of cardiovascular ochronosis is unclear, but is probably related to the extensive extracellular deposits of ochronotic pigment in the cardiac tissue.

Alkaptonuria and renal failure: a case report and review of the literature.Mod Pathol. 1992 Jul;5(4):464-71.

In alkaptonuric ochronosis, the absence of homogentisic acid oxidase results in the accumulation of homogentisic acid in the body. Associated renal failure is rare and usually occurs in the later stages of the disease. We report a 19-yr-old girl who presented initially with severe renal failure, without family or past history of illness. There was no significant proteinuria or hematuria. No clinical evidence of pigmentation such as skin and subcutaneous cartilages was noted. However, pigment deposits were identified in the renal biopsy specimens obtained within a week after admission and another after a month. Two months later the peritoneal dialysis fluid and skin progressively darkened, suggesting ochronosis. This was confirmed by the detection of homogentisic acid in the serum and urine. The patient expired in renal failure. Renal biopsy tissues showed diffuse chronic tubulo-interstitial disease characterized by widespread tubular atrophy, interstitial fibrosis, and a moderate degree of inflammation. Many tubular cells contained brown, coarsely granular ochronotic pigment (OP) and a few pigment casts were in the lumina. Similar deposits were also in the interstitium and within histiocytes. Ultrastructural studies of the glomeruli revealed small sparse OP deposits in the visceral and parietal epithelial cells, mesangial cells, and rare extracellular and basement membrane deposits. The tubulointerstitial changes were varied: atrophy and dilatation of tubules, varying degrees of lysosomal OP and degeneration of tubular cells, casts containing OP with crystalline material, histiocytes distended with OP, and free interstitial pigment deposition.

Diagnosis of alcaptonuria: rapid analysis of homogentisic acid by HPLC. Clin Chim Acta. 1990 Jul;189(1):7-11.

The clinical and biochemical features of five cases of alcaptonuria were reported. The concentration of homogentisic acid was determined in urine and also in plasma using a rapid, sensitive and specific HPLC method. In all five cases, the concentrations of homogentisic acid were elevated in urine rising up to 46.5 mmol/24 h. In plasma, homogentisic acid levels ranged from 33 to 38 mumols/l. In healthy individuals, homogentisic acid was not detectable in plasma and urine. The method described represents a very useful and suitable analytical tool for the diagnosis of alcaptonuria.