Hyperuricemia and chondrocalcinosis: A clinical challenge for diagnosis and treatment
Hyperuricemia is a common condition in the adult population, especially in the elderly and in those with comorbid conditions , and is a key factor associated with the risk of developing gout . Chondrocalcinosis is a frequent finding in older patients, and the pathophysiologic foundation for the development of acute pyrophosphate arthritis (pseudogout) . The coexistence of both conditions, although plausibly frequent , has not been widely explored in the literature, and is a challenge for diagnosis and treatment decision making.
A 67-year-old man was referred by his family physician due to recurrent acute arthritis and chondrocalcinosis of the knee. He had a history of hypertension treated with enalapril 5 mg/day and hydrochlorothiazide 25 mg/day, and hyperlipidemia treated with simvastatin 20 mg/day. He had a typical history of gout of the metatarsophalangeal joint three years previously, and was on allopurinol 100 mg/day along with colchicine 0.5 mg/day intermittently.
He had been evaluated at the emergency room due to sudden pain and swelling in the knee joint, with no systemic symptoms being present. Overall the patient’s previous medical history did not provide any further information.
Arthritis of the left knee joint was evident, with general and musculoskeletal examination disclosing no further information. Serum urate (sUA) level was 5.2 mg/dL (range 2.5–7.0 mg/dL), estimated glomerular filtration (CKD-EPI) was 63 mL/min, C-reactive protein 36 mg/L, leukocytes 12,300 (80% neutrophils). A plain x-ray of the knee joint showed chondrocalcinosis of the meniscal fibrocartilage and hyaline cartilage of the femoral condyles (see Figure 1).
Figure 1. Plain radiograph of the knee joint showing chondrocalcinosis involving both the meniscal fibrocartilage and hyaline cartilage of the femoral condyles.
The patient was discharged with a diagnosis of ‘pseudogout’; treatment included on-demand naproxen 500 mg up to twice a day, omeprazole 20 mg/day, and colchicine 1 mg/day. Allopurinol dose was considered to be optimal according to sUA level. The patient did well with prescribed treatment, but recurrence of swelling of the knee joint suggested referral to the rheumatology division.
At first visit, the patient had only mild pain and swelling of the knee joint. A closer analysis of the patient’s electronic file showed that sUA level prior to the initiation of allopurinol treatment was 8.2 mg/dL, and sUA level afterwards ranged from 6.8 to 7.5 mg/dL, apart from the measurement at the emergency room (during an episode of acute arthritis of a great joint), suggesting that deposition of urate crystals could also be at work.
Aspiration of the knee joint disclosed non-inflammatory synovial fluid showing small, strongly birefringent crystals with positive elongation typical of monosodium urate crystals, and also negatively birefringent or mildly birefringent crystals with negative elongation typical of calcium pyrophosphate crystals (see Figure 2). A further study showed normal iron saturation, calcium and phosphate levels within normal range, but low serum magnesium level (1.62 mg/dL, range 1.7–2.5).
Figure 2: Close-up view X400, polarized light with first order red compensator, showing small strongly birefringent crystals with positive elongation typical of monosodium urate crystals, and also negatively birefringent or mildly birefringent crystals with negative elongation typical of calcium pyrophosphate crystals. Observe that there are some crystals parallel to each other that shine bright blue – urate- and dull yellow –pyrophosphate.
Suggested treatment included withdrawal of hydrochlorothiazide and prescription of losartan 50 mg/day in order to reduce sUA levels and increase magnesium levels while controlling hypertension; colchicine 1 mg/day was prescribed, and allopurinol dose was increased to 150 mg/day, both for gout pyrophosphate arthritis prophylaxis. NSAIDs on demand were prescribed to abort incoming flares where necessary. sUA level at 6-month follow-up was 5.6 mg/dL (on target), and magnesium levels were 1.82 mg/dL (within normal range).
Outcome and follow-up
The patient was fully informed that although our expectation would be complete remission of gout flares in the long term, acute pyrophosphate arthritis flares could unexpectedly occur; although normalization of magnesium levels is associated with clinical improvement, chondrocalcinosis would nevertheless remain.
After a 2-year follow-up period in which the patient remained asymptomatic, the patient was discharged to the primary care team.
Gout is the most common cause of inflammatory arthritis , with acute pyrophosphate arthritis probably second, especially in the elderly . Both hyperuricemia and chondrocalcinosis are so prevalent in the elderly [1,3], that there is good possibility of their coexistence . The appearance of acute arthritis, especially when not showing a typical gouty-joint distribution (1st metatarsophalangeal joint or tarsus) would raise a clinical question. Microscopic confirmation of diagnosis should be considered in order to discern which underlying crystal is involved in acute joint inflammation.
This is not just an academic argument, as treatment would be based on the underlying condition. Treatment of hyperuricemia could therefore be prescribed, maybe for life, in a patient suffering from pyrophosphate arthritis and showing hyperuricemia. On the other hand, no treatment would be prescribed in a patient with gout showing asymptomatic chondrocalcinosis.
Other issues arise from this case. Firstly, the patient had always been over the therapeutic serum urate target, which may be associated with long-term persistence of urate crystals , while most guidelines and recommendations suggest sUA should be maintained at levels <6 mg/dL . Secondly, treatment with thiazide diuretics may have an impact on sUA levels, but also on magnesium levels, which are associated with increased risk of pyrophosphate arthritis . Thirdly, although the clinical profile of the patient may help differentiate gout from ’pseudogout‘, the term pseudogout indicates that it mimics the clinical characteristics of gout. Indeed, a recent study showed that hyperuricemia during acute arthritis characterized gout, while monoarticular joint distribution and periarticular soft tissue swelling were indications for pseudogout . In this case, lower (normal) sUA levels were found during the acute flare, resulting in no change in urate-lowering medication dosage. Although coexistence of both urate and pyrophosphate crystals in the same synovial fluid sample seems to be uncommon, development of pyrophosphate arthritis in patients with a previous diagnosis of gout is not .
The patient gave written informed consent to use his clinical data and anonymized imaging for investigation and educational purposes, as required by the local Ethics and Investigation Committee.
About the author
- Kumar AUA, Browne LD, Li X et al. Temporal trends in hyperuricaemia in the Irish health system from 2006-2014: A cohort study. PLoS One 2018; 13: e0198197.
- Dalbeth N, Phipps-Green A, Frampton C et al. Relationship between serum urate concentration and clinically evident incident gout: an individual participant data analysis. Ann Rheum Dis 2018; 77: 1048–1052.
- Richette P, Bardin T, Doherty M. An update on the epidemiology of calcium pyrophosphate dihydrate crystal deposition disease. Rheumatology (Oxford) 2009; 48: 711–715.
- Perez Ruiz F, Herrero-Beites AM, Alonso-Ruiz A, Calabozo M. Calcium Pyrophosphate Crystal Arthritis (CPPA) Is a Frequent Cause of "Refractory Gout". Arthritis Rheum 2010; 62(Suppl 10): S362–S363. (Abstract)
- Li-Yu J, Clayburne L, Sieck M et al. Treatment of chronic gout. Can we determine when urate stores are depleted enough to prevent attacks of gout? J Rheumatol 2001; 28: 577–580.
- Kleiber Balderrama C, Rosenthal AK, Lans D, Singh JA, Bartels CM. Calcium Pyrophosphate Deposition Disease and Associated Medical Comorbidities: A National Cross-Sectional Study of US Veterans. Arthritis Care Res (Hoboken) 2017; 69: 1400–1406.
- Muangchan C, Bhurihirun T. An investigation of the independent risk factors that differentiate gout from pseudogout in patients with crystal-induced acute arthritis: a cross-sectional study. Rheumatol Int 2018; 38: 89–95.