Incidentally Discovered Ochronosis Explaining Decades of Chronic Pain

Manipulating the metabolic pathway of phenylalanine with medication is a second option. An example of this is nitisinone, a US Food and Drug Administration-approved medication for treatment of tyrosinemia. It acts by inhibiting hydroxyphenylpyruvic acid dioxygenase, one of the enzymes that converts tyrosine into HGA, to prevent the buildup of damaging tyrosine byproducts. At low doses it has been effective in decreasing HGA concentrations in alkaptonuria and tyrosinemia.^10,11 Due to this mechanism of action, nitisinone directly causes increased tyrosine levels. Therefore, tyrosine toxicity, usually not predicted by tyrosine levels, has been associated with eye-related adverse effects (AEs), including keratopathy, diminished visual acuity, and corneal tissue damage.^1,2,10 Incidence of these AEs have not been clearly documented, but routine monitoring should include patient education on ocular symptoms and slit-lamp examinations.¹²

In addition, case reports have shown that high-dose ascorbic acid (vitamin C) promotes HGA, tyrosine, and phenylalanine excretion in urine, which may slow the progression of alkaptonuria, but clinical effect has not been proven.¹³ Additionally, high vitamin C intake is considered a risk factor for nephrolithiasis, which must be balanced with the increased risk of stone formation from HGA excretion.¹⁴ These dietary and medical options can be considered, especially in the setting of severe symptoms or complications, but the risks must be discussed with patients.

A second and commonly utilized strategy for caring for these patients is symptom management. As demonstrated through this case report, there is no clear medication that adequately addresses the pain caused by HGA deposition. Patients should be referred to a pain specialist to allow for single provider prescribing of pain medications. This patient found most relief and least AEs with tramadol but eventually self-discontinued due to diminishing pain relief. Given the eventual involvement of large joints, these patients will often require further symptom management with joint replacement surgery, usually much earlier than patients who undergo these surgeries for age-related osteoarthritis. The imperative aspect of symptom management is to engage patients in shared decision making with clear expectation setting.

Given the progressive nature of alkaptonuria, providers must monitor and address complications that are a result of this disorder. HGA becomes pathologic by binding to and weakening collagen fibers.⁵ This gradual buildup leads to degenerative changes in weight-bearing lower vertebrae and large joints that can become severe. Due to HGA’s interaction with collagen fibers, tendon involvement leading to inflammation, calcification, and rupture can result as patients enter the third stage, ochronotic arthropathy, of the disorder (Figure 3).¹⁵ Many of these arthropathies will require medical and surgical management and can be urgent in situations like tendon ruptures and meniscal tears. Understanding the pathophysiology of tendinopathies in patients with alkaptonuria also can aid orthopedic surgeons during the postoperative period where patients may be at risk for poor healing.⁵

A second area of complications includes CV involvement. This patient was diagnosed with premature atherosclerosis and underwent cardiac interventions, including coronary stent placement and valve replacements at age 63 years. This early cardiac involvement was likely due in part to the deposition of HGA and collagen injury in CV tissue leading to damage of the endocardium, aortic intima, heart valves, and coronary arteries.¹ HCPs should monitor for these manifestations with regular visits, chest computed tomography, and echocardiographic studies.²

The most classic aspect of this rare disorder is urine darkening due to the renal excretion of HGA and comprises the third area of complications. This process leads to chronically acidic urine—every urinalysis in this patient’s chart displayed the lowest pH measurable—and an increased risk for calcification and precipitation of solutes within the kidney and urinary tract (Figure 4). Both X-ray and ultrasound imaging should be used to identify kidney and prostate stones in the setting of abdominal or genitourinary pain or infection. Patients with diminished renal function may manifest a more severe and rapidly progressing form of alkaptonuria that exacerbates symptoms and complications, but direct damage to the kidneys by HGA is not evident.