Ochronotic Chondropathy: A Case Report

Abstract

Endogenous ochronosis, also known as alkaptonuria, is a rare disease known for its bluish-black discoloration of the skin, sclerae, and pinnae, as well as urine that turns black upon standing. Though rarely fatal, joint degradation is a common sequela, and many patients require multiple large joint arthroplasties throughout their lifetime. Though many aspects of the pathophysiological mechanisms of the disease have been described, questions remain, such as how the initiation of ochronotic pigmentation is prompted and the specific circumstances that make some tissues more resistant to pigmentation-related damage than others. In this report, we present the case of an 83-year-old female previously diagnosed with alkaptonuria including high-quality arthroscopic images displaying the fraying of articular cartilage. We also offer a summary of the latest literature on the pathophysiological mechanisms of the disease, including cellular-level changes observed in ochronotic chondrocytes, biochemical and mechanical alterations to the cartilaginous extracellular matrix, and patterns of pigmentation and joint degradation observed in humans and mice models. With these, we present an overview of the mechanisms of ochronotic chondropathy and joint degradation as the processes are currently understood. While alkaptonuria itself is rare, it has been termed a "fundamental disease," implying that its study and greater understanding have the potential to lead to insights in skeletal biology in general, as well as more common pathologies such as osteoarthritis and their potential treatment mechanisms.

Keywords: HGA; alkaptonuria; cartilage; chondrocyte; chondropathy; homogentisic acid; joint degradation; ochronosis; ochronotic pigmentation.

Figure 1

(A) Sagittal computed tomogram of the cervical spine of the patient taken 6 years ago when she was 77 years old. Destruction of intervertebral disc cartilage is apparent (white arrows). (B) Sagittal computed tomogram of the cervical spine of the same patient five years later, when she was 82 years old, showing progressive disc degeneration (black arrows) resulting from advancing disc cartilage destruction and reactive bone formation over the 5-year period. Vacuum phenomena are also apparent in the inferior two disc spaces.

Figure 2

Lateral chest X-ray of the patient taken 2 years ago when she was 81 years old. The spine exhibits degeneration of the intervertebral disc cartilage with end-plate sclerosis (white arrow) and osteophytes typical of lumbar spondylosis (black arrow). The intervertebral bodies may be osteoporotic.

Figure 3

Arthroscopic images obtained during the patient’s arthroscopy 23 years earlier, when she was 60 years old, revealing ochronosis of the medial femoral condyle with brownish-black discoloration. (A) Damage to the superficial articular surface can be seen (arrow). (B) Destruction of the deeper layers of articular cartilage is evident resulting in an insufficient bearing surface.

Figure 4

Anteroposterior radiograph of the patient’s knee taken 14 years ago when she was 69 years old. The medial tibiofemoral compartment articular cartilage has been destroyed (black arrow) and reactive bone and osteophytes have formed. Varus knee angulation has resulted. The radiographic appearance is typical of osteoarthritis which can result from a variety of chondral insults including genetic, inflammatory, septic, and mechanical conditions.

Figure 5

Diagrammatic representation of the exposed collagen hypothesis as described by Gallagher et al. The top panel shows collagen in its native state, surrounded by a protective layer of proteoglycans (PGs) disallowing the binding of HGA. The middle panel shows the periodic binding of HGA after protective PGs have been lost from collagen due to mechanical loading, aging, degeneration, or some other insult. The bottom panel shows the deposition of ochronotic pigment onto the exposed collagen, making it stiffer and leading to a downward spiral of further pigmentation and damage. Note that while the middle panel displays HGA itself binding the collagen, it is not currently known whether it is HGA, its oxidized intermediate benzoquinone acetic acid, or ochronotic pigment that first binds to collagen. Adapted with permission from Ref. [19]. 2016, Seminars in Cell & Developmental Biology.

Figure 6

From Hughes et al.: Progression of ochronotic pigment in articular cartilage in a 66-week-old BALB/c Hgd^−/− mouse. (A) A diagram displaying the progression of ochronotic pigmentation as observed in chondrocytes in the region of articular calcified cartilage. (i) A healthy, unpigmented chondrocyte; (ii) chondrocyte displaying pericellular pigmentation, the initial pigmentation to be observed; (iii) chondrocyte displaying progression to intracellular pigmentation as is typically observed after pericellular pigmentation; (iv) chondrocyte displaying more dramatic intracellular pigmentation and associated pyknosis. (B) Chondrocytes of the medial femoral condyle of the knee displaying ochronotic pigmentation (arrows) as observed without staining. (C) Chondrocytes in the articular calcified cartilage displaying the four steps of pigmentation (i–iv) as described in the diagram in (A), observed with Schmorl’s staining. Scale bar in (B,C) = 50 µm. Adapted with permission from Ref. [40]. 2021, Calcified Tissue International.