Alkaptonuria: clinical manifestations and an updated approach to treatment of a rare disease

Abstract

Alkaptonuria (AKU) is a rare autosomal recessive disorder with a global incidence of 1 in 250 000 to 1 million people worldwide. It results from a deficiency of the enzyme homogentisic acid (HGA) oxidase which when absent, leads to an accumulation of HGA. Without this enzymatic degradation, HGA deposits in connective tissues resulting in pigmentation (ochronosis), plaque formation and accelerated cartilage destruction. With this, many patients who suffer from AKU develop ochronotic arthropathies, tendon ruptures, fractures, and chronic joint pain. Similarly, patients can develop cardiac valvular dysfunction and interstitial renal disease. Our two cases highlight the array of pathologies seen in AKU and, in light of newly published research, give us a platform from which we can discuss the developments in management of this rare disease.

Background

Alkaptonuria (AKU) is a rare autosomal recessive disorder with a global incidence of 1 in 250 000 to 1 million people worldwide.¹ This disease has a rich history with many case reports describing patients with features of AKU even as far back as 1584 when Scribonius described a boy with ‘urine as black as ink’.² In 1904, it was first described as an inborn error of metabolism by Sir Archibald E. Garrod in his Croonian Lecture series and was the first disease seen to follow the classic Mendelian recessive inheritance pattern.^{3 4}

The disease results from a deficiency of homogentisic acid oxidase (HGD, EC 1.13.11.5), which leads to the accumulation of homogentisic acid (HGA). ^{5 6} Although some HGA is eliminated in urine, a large amount builds up systemically and can be associated with severe debilitating health consequences. Black urine is a common symptom of AKU and is often used as a diagnostic tool.^{1 7 8}

Other pathognomonic symptoms are absent until at least a person’s mid-20s; however, it is seen that some of the most debilitating aspects of the disease are the associated ochonotic arthropathies, tendonopathies and joint pain.

The nature of this disease causes rapid and progressive connective tissue degeneration and as such many of these patients will require a joint replacement at some point in their life.^{9 10} Given this, significant efforts have been made over the last number of years to find a disease modifying drug that can curtail the effects of this disease. In light of new research, we use these two extraordinary cases from two separate Irish institutions to highlight the newly approved treatment option of Nitisinone, available for this rare and chronic disease.

Case presentation

Case 1

The first patient, a 70-year-old woman was referred to the Midland Regional Hospital Tullamore (MRHT) Orthopaedic Department by her General Practitioner (GP) for severe right hip pain.

She had a multimorbid past medical history which included the diagnosis of AKU in 2005 but had also previous bilateral knee replacements, bilateral rotator cuff tendonopathies and bilateral glenohumeral and acromioclavicular joint arthritis. She was osteoporotic and was attending another tertiary centre for management of primary biliary cirrhosis.

Her overall burden of disease is summarised in table 1.

Table 1.

Overall burden of alkaptonuria for patient

Musculoskeletal	Other features
Cartilage damage (ochronosis)	Scleral pigmentation
Osteoarthritis and associated arthroplasty	Auricular cartilage pigmentation
Tendinopathies	Dark black urine
Osteoporosis

She was on no medical management for her AKU and her medications mainly included mild analgesia for joint pain.

On exam she was seen to have pigmentation of her sclera and auricular cartilage (figure 1) and she reported her urine as black in colour.

Figure 1.

Ocular and auricular cartilage.

In the outpatient’s department, pelvic, thoracic and lumbar spine X-rays were arranged. These demonstrated osteoarthritic degeneration of her right hip and calcific deposits in her spine (figure 2).

Figure 2.

Lateral lumbar spine X-ray showing calcific deposits.

Further imaging was recommended and 1 week later she underwent an MRI of her pelvis and hips, which surprisingly demonstrated an impacted subcapital fracture of the right hip (figure 3). This was in the absence of trauma and the rapidly progressive femoral head collapse was deemed pathological due to her AKU.

Figure 3.

X-ray pelvis 10 days apart.

She attended the emergency department in MRHT and a pelvic X-ray was repeated (as shown figure 3). She was admitted under the care of the orthopaedic service and underwent right total hip replacement (THR).

Intraoperatively, the femoral head was essentially absent, and the cardinal ‘black bone’ features of AKU were clearly evident (figure 4).

Figure 4.

Pigmented femoral head.

The procedure itself was uneventful and she returned to the ward with routine postoperative instructions. She received daily input from the physiotherapy service and was discharged home very well the fifth postoperative day.

This patient had progressed well since the THR and recently was seen in the outpatients department whereby she reported worsening pain in her left hip and as such is being worked up for an elective THR. This is likely to be done in the coming months. No further discussion about treatment for her AKU has been had thus far.

Case 2

A 55-year-old man was referred to St James’ Hospital (SJH), Dublin, for definitive management of a moderately differentiated adenocarcinoma of the distal oesophagus (T3, N1, M0).

Interestingly, he had the same pathognomonic eye, ear and urine features of AKU as our first patient (figure 1), as well as other cardinal features including aortic stenosis (AS; for which he previously underwent a metallic Aortic Valve Replacement), bilateral ruptured Achilles tendons in 1999 and 2003 and suffered from recurrent renal calculi. He had a right shoulder hemiarthroplasty in the 1990s (figure 5), previous bilateral knee replacements in the 2000s and an intertrochanteric left femur fracture in 2014 which was treated with cephalomedullary nailing (table 2). He had worked as a carpenter but had to retire when his symptoms became progressively worse in his early 30s.

Figure 5.

Erect chest X-ray highlighting prior surgeries.

Table 2.

Overall burden of alkaptonuria for patient

Musculoskeletal features	Other features
Cartilage damage (ochronosis)	Pigmentation of sclera
Calcified intervertebral discs	Aortic valve/coronary artery calcification
Ankylosis	Renal calculi
Lumbosacral back pain	Dark black urine
Osteoarthritis and associated arthroplasty	Skin pigmentation (axilla/inguinal)
Pseudogout	Pigmentation of ear cartilage

His overall burden of disease is summarised in table 2.

His PET CT postneoadjuvant therapy showed an interval decrease in bulk and metabolic activity of the tumour and as such was admitted under the Upper GI Service where he was prepared for an oesophagectomy as is the normal gold standard of care.

His preoperative course was slightly protracted given that he was initially switched to low molecular weight heparin in place of his warfarin (for which he was on for his metallic aortic valve) and also required urgent urological input for treatment of a symptomatic renal calculus which required ureteroscopy and extracorporeal shockwave lithotripsy. Unfractionated heparin was commenced 3 days prior to surgery.

At induction of anaesthesia, our anaesthetic colleagues interestingly reported observing pigmented tracheal rings on intubation.

During a two-stage (Ivor Lewis) oesophagectomy, the right lung is deflated and the hemithorax is entered by separating and resecting a small portion of rib. Entering the right hemithorax facilitates the gastric pull up and anastomosis for the neo-oesophagus. In our patient there was obvious black pigmentation of the bone and cartilage associated with alkaptonuria (figure 6).

Figure 6.

Pigmented cartilage and bone.

The surgery was uncomplicated. Following a short stay in the intensive care unit for observation, pain management and total parenteral nutrition, he was transferred to the ward where he made good postoperative progress and was discharged on postoperative day 8.

Following a period of 13 months disease free survival, this patient developed a widespread metastatic recurrence of oesophageal cancer and subsequently passed away.

Discussion

Arthropathies and tendonopathies associated with this disease significantly alter a patient’s quality of life. While usually asymptomatic in childhood and adolescence, the disease typically begins to manifest is in the third decade due to an accumulation of HGA.

Stiffness and pain in the lumbar spine are usually some of the first symptoms and clinically, AKU can resemble ankylosing spondylitis in the articular damage seen in the spine and large joints. It differs however in sparing the sacroiliac joints.^{11 12}

In the body HGA is deposited in the connective tissues as an oxidised and polymerised pigment.⁴ Postmortem examination by Helliwell et al demonstrated chondrocyte necrosis and significant cartilaginous pigmentation in their patient who had suffered from AKU and alluded to prior in vitro studies showing the toxic effects HGA has on chondrocytes.^{13 14} They attribute this toxic effect to the accelerated ochronotic arthropathies seen in this disease.

The same processes are also at the root of the development of the significant cardiac valvular pathologies seen.^{15 16} A large prospective cohort study conducted by the National Alkaptonuria Centre in the UK showed a 22.2% prevalence of AS in their population (n=81) with 6.2% of patients requiring aortic valve replacement. Again, the severity of disease and ochronosis burden were attributed with the development of AS.¹⁷

Biochemical assays of urinary collagen N-telopeptides (NTx) (a known marker of osteoclastic activity and bone resorption) in patients with AKU is raised.^{18 19} Although there is a wide variability of urinary NTx especially in young men,²⁰ in AKU, is thought to be due to a combination of these primary effects of ochronosis combined with the secondary effects of arthropathy-related disuse. Osteoporosis is a feature of this disease and can be indicative of those who may progress to pathological fractures.

Therapeutic approaches to treat AKU have been of much debate for decades. Vitamin C had been trialled with some success, as had dietary restrictions of tyrosine, phenylalanine or total protein. The main issue with any of these methods is compliance and it is known to be extremely difficult for adults to sustain such a restricted diet.¹³,¹⁴

More recently the drug nitisonone has come into the forefront of therapy.²¹ Nitisinone inhibits 4‐hydroxyphenylpyruvate, the enzyme responsible for the production of HGA, and has been approved for the treatment of hereditary tyrosinaemia type 1 for many years.²² In 2002, Phornphutkul et al found that the drug reduced urinary HGA excretion by 69% or more in their patient cohort, providing proof of principle for the ability of nitisinone to lower HGA production and thus be applied to the setting of AKU.¹ Introne et al in their randomised controlled trial built on this concept and highlighted that a 2 mg daily dose of nitisinone was not only effective at reducing urinary HGA by 95% in AKU but also that the drug itself was tolerable as a regular medication with a low side effect profile.⁷

This was then progressed further by Dr Ranganath who has been evaluating the effectiveness of nitisinone in treating AKU. His first trial, SONIA 1, an international, multicentre, randomised controlled trial looked at the effect of different doses of once daily nitisinone on 24-hour urinary HGA excretion (u-HGA24) in patients with AKU. There was a definite correlation between higher nitisinone dose and lower urinary HGA levels showing a dose response relationship with an 8 mg dose showing a mean 24-hour urinary HGA level reduction by 98.8%.²³

This was followed up with the SONIA 2 trial, whose recently published results showed from an orthopaedic point of view, that a 10 mg once a day dose of nitisinone has a very positive effect on AKU related joint disease and can actually slow disease progression. Using the Clinical Alkaptonuria Severity Score Index as a measure, they demonstrated a number of positive clinical findings. Included in these are trends from the treatment arm highlighting the reduction of musculoskeletal pathologies (fractures and tendon/ligament/muscle ruptures), statistically significant differences in T-score of the hip after the 48 months, decreases in spinal pain and a reported increase in joint active and passive range of motion.²⁴ Given the impact of this study, a comprehensive summary of the findings are seen in table 3.

Table 3.

Summarised findings from SONIA 2 trial

	Clinical outcomes: control group versus 10 mg nitisione group	P value (if given)
Ear pigmentation	Decrease in progression with nitisinone	N/A
Bone mineral density	T-score better at 48 months compared with control group	0.05
Fractures	Trend towards an increase over time in the number of fractures in the control group compared with nitisinone treated patients	0.16
Tendon ligament and muscle rupture	Cumulative trend towards more ruptures in control group than treatment group	N/A
Joint pain	At month 48, there was a decrease in the number of joints with pain from baseline in the nitisinone group. An observed difference was seen at all post baseline visits	N/A
Spinal pain	There was a decrease in the number of spinal regions with pain in the nitisinone group at month 48 compared with baseline. Note: Comparisons between groups did not reach significance	0.05
Range of motion	Trend in favour of nitisinone in both the passive and the active range of motion of the joints at months 12, 24 and 36	N/A
Eye pigmentation	Lower progression than control group	0.0011

Based on the results of the SONIA 2, the European Medicines Agency authorised Swedish Orphan BIovitrum to use their product—Orfadin (Nitisinone) for the treatment of AKU on 22 October 2020. The European Commission thereafter approved its use for the treatment of adult patients with AKU.

In conclusion, AKU is a rare and fascinating disease which has both a heavy economic burden on healthcare services and a social burden on the quality of life of patients. Due to the pathophysiology of the disease these patients develop a number of orthopaedic issues and care should be taken to manage these patients in a holistic and multidisciplinary manner.

Nitisinone does indeed appear to be the cornerstone in providing a sustainable treatment option for these patients and hopefully future research will further change the face of AKU.

Learning points.

• Alkaptonuria (AKU) is a rare and fascinating disease which has both a heavy economic burden on healthcare services and a social burden on the quality of life of patients.

• The pathophysiology of the disease these patients develop a number of orthopaedic issues and care should be taken to manage these patients in a holistic and multidisciplinary manner.

• Nitisinone does indeed appear to be the cornerstone in providing a sustainable treatment option for these patients and hopefully future research will further change the face of AKU.

Ethics statements

Patient consent for publication

Consent obtained directly from patient(s).