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Pseudogout in a patient who had parathyroidectomy for primary hyperparathyroidism and who possesses amino acid variant H63D in one copy of HFE or haemochromatosis related gene.

Dr I Talapatra (MRCP, UK) and Dr IPM O’Connell (MRCP, UK)
Department of Medicine, Royal Albert Edward Infirmary, Wigan, UK

Abstract:

We describe below a gentleman who initially presented with asymptomatic hypercalcemia secondary to primary hyperparathyroidism. He underwent successful surgery for it. He was later diagnosed to be a heterozygous carrier for the amino acid variant H63D of HFE or haemochromatosis related gene. Thereafter he developed acute arthritis of right knee and shoulder which was diagnosed as pseudogout. Pseudogout, a form of crystal induced arthropathy, is known to have associations with metabolic diseases like hyperparathyroidism and haemochromatosis. There have been also a few case reports of pseudogout following parathyroidectomy.

Key words: Haemochromatosis, Hyperparathyroidism, Pseudogout

Case Report:

A 66 year old gentleman was referred to the clinic with high calcium level. He was asymptomatic. His blood pressure was 124/86 mm Hg. His two brothers had prostate carcinoma. He used to consume alcohol in excess. His investigation results showed an adjusted calcium (calcium adjusted for albumin concentration) of 3.03 mmol/l (normal: 2.05-2.60 mmol/l), phosphate 0.67 mmol/l (normal 0.8-1.45 mmol/l) and alkaline phosphatase of 155 U/L (normal 64-300 U/L). his parathyroid hormone level (PTH) was 8 pmol/l (normal 1.1-6.9 pmol/l but a level >2.7 pmol/l in presence of hypercalcaemia is inappropriately high and suggests hyperparathyroidism). His renal , thyroid and liver function tests were normal, haemoglobin was 14.7 g/dl(normal 13.5-16.6 g/dl), haematocrit was 0.421 (normal: 0.380-0.5), white cell count and platelets were normal, red cell folate and serum vitamin B12 levels were normal but ferritin was 412 ng/ml (normal 16-323 ng/ml).

The following tests were requested from the clinic : repeat bone profile, 24 hours urinary calcium, creatinine clearance, X ray KUB (kidney, ureter, bladder), Myeloma screen (serum protein electrophoresis for M Paraprotein and urine test for Bence Jones protein) , angiotensin converting enzyme (ACE) and DEXA (dual energy X ray absorbimetry) scan of lumbar spine, wrist and hip. The patient was advised to drink plenty of water, to avoid dehydration, to avoid immobilisation as far as possible and to avoid excess intake of dairy products. His repeated adjusted calcium two weeks later was 2.79 mmol/l, ionised calcium was 1.47 mmol/l (normal 1.05-1.30), PTH was 6.81 pmol/l, urinary calcium was 12.70 mmol/24 hours (normal 2.50-7.50 mmol/24 hours), creatinine clearance was 79.2 ml/min (normal 95-140 ml/min) , ACE was 37 IU/L (normal 15-55 IU/L) and his myeloma screen was negative. The patient was diagnosed with primary hyperparathyroidism. His X ray KUB did not show any evidence of renal stones. However his DEXA scan showed evidence of forearm osteoporosis ( T score of wrist/ distal was -3.40). The patient had high calcium, which together with high urinary calcium and the presence of osteoporosis satisfied three NIH criteria for referral for parathyroidectomy. His ultrasound of the neck showed a left superior parathyroid adenoma and he underwent left upper parathyroidectomy. The patient’s serum calcium level settled to normal and his urinary calcium was 3.60 mmol/24 hours after four months. His serum calcium level continued to remain normal and he underwent a repeated DEXA scan two years later which showed that his forearm osteoporosis was persisting and he was commenced on Calcichew D3 (each tablet containing 12.6 mmol of calcium and 200 units or 5 ug of colecalciferol) two tablets daily. He underwent genetic tests for high ferritin level and was found to be a heterozygous carrier for the amino acid variant H63D of HFE gene (20% of this population have increased risk of developing classical Hereditary haemochromatosis).
The patient developed acute swelling of the right knee and shoulder a year later for which the right knee was aspirated . X rays showed degenerative changes. His ESR was 71 mm/hr and rheumatoid factor was negative. The joint aspirate showed rhomboid shaped, positively birefringent intra and extra cellular pyrophosphate crystals suggesting an acute attack of pseudo gout. He was treated with diclofenac.
The patient’s latest blood results showed an adjusted calcium of 2.24 mmol/l, Iron level 11 umol/l (normal 11-32), Transferrin 2.3 g/l ( normal 2.0-3.2), Transferrin saturation 19.1 % (normal 23-53), haemoglobin 13.4 g/dl and serum ferritin of 695 ug/l (normal 30-400 ug/l; new reference range). His 24 hours urinary calcium was 5.11 mmol.

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Discussion:
Gout and pseudogout are the 2 most common crystal-induced arthropathies. These are debilitating illnesses in which pain and joint inflammation are caused by the deposition of crystals within the joint space. Pseudogout is an inflammation caused by the deposition of rhomboid shaped calcium pyrophosphate dihydrate (CPPD) crystals (1). CPPD crystals are produced by nucleoside triphosphate pyrophosphohydrolase, a catalytic enzyme found in vesicles that develop within osteoarthritic cartilage (2). A genetic predisposition exists for the condition, but any process that leads to osteoarthritis also can be associated subsequently with pseudogout. The most common sites of pseudogout arthritis are the knee, wrist, and shoulder. Pseudogout is most commonly monarticular, however, polyarticular acute arthritis can occur as well and many different joints may be involved simultaneously or in rapid succession . Many cases are idiopathic, but pseudogout has also been associated with aging, trauma, and many different metabolic abnormalities like hyperparathyroidism and hemochromatosis (2).
How pseudogout is related to these metabolic diseases is not very clear. Accepted theory (3) relates CPPD crystal deposition to a disturbance in calcium or inorganic phosphate metabolism, leading to an excess of either in joints. For example, serum calcium changes acutely following parathyroidectomy, which has a well recognized association with pseudogout(4). These elevated levels, with or without changes in the matrix which promote crystal formation, are thought to lead to the formation of calcium pyrophosphate dihydrate crystals in cartilage.

Our patient had hyperparathyroidism for which he underwent surgery and he also possesses the H63D variant in one copy of HFE (haemochromatosis related gene).
Hyperparathyroidism (5,6,7) is one of the most important causes of hypercalcaemia. In 85% cases of hyperparathyroidism the cause is a single parathyroid adenoma (3) as it was in our patient. Of the various NIH (National Institute of Health, USA) criteria for referral for surgery(8,9) for hyperparathyroidism, our patient fulfilled at least three criteria . His serum calcium on presentation was greater than 0.25 mmol/l above the upper limit of normal, his urine calcium was greater than 10 mmol/24 hours and he had osteoporosis. The patient underwent successful parathyroid surgery and his serum and urinary calcium became normal following surgery.

C282Y or H63D point mutations of HFE gene are commonly observed in Hereditary haemochromatosis (10,11). Hereditary hemochromatosis (HH) is a heterogeneous recessive genetic disorder characterized by an unregulated absorption of intestinal iron. Excess iron accumulates in body tissues leading to complications such as cirrhosis, hepatocellular carcinoma, diabetes and heart failure over many years Two mutations associated with HH have been described in the HFE gene: a G A transition in position 845 (C282Y) and a C G transition in position 187 (H63D). Our patient is a heterozygous carrier of the amino acid variant H63D of HFE gene (one copy of the gene is defective and the other is normal). A carrier may be silent, asymptomatic or can have mild form of the disease or may develop florid HH depending on the mutation as sometimes occurs in diabetes, excess alcohol consumption or in presence of other unknown triggering factors.
This case emphasises the fact that in case of an acute attack of arthritis (usually monoarthritis), the joint should always be aspirated. The differential diagnosis lies between septic arthritis, gout and pseudogout. In our case the patient was already known to have other co-existent metabolic complications but these should be looked for as they are known to be associated with this form of crystal induced arthritis.

References:

(1) Joseph J, McGrath H. Gout or 'pseudogout': how to differentiate crystal-induced arthropathies. Geriatrics, 1995 Apr; 50(4): 33-39.
(2) Kaplan J. Gout and pseudogout. e-Medicine, June 2007
(3) McCarty D J, Koopman W J. Arthritis and allied conditions - a textbook of rheumatology. 13th ed. pp 2103-2126. Baltimore, London: Williams and Wilkins, 1997
(4) Kabayashi S, Sugenoya A, Takahashi S,et al. Two cases of acute pseudogout attack following parathyroidectomy. Endocrinol Jpn; 38: 309-314
(5)Salen PN. Hyperparathyroidism. e-Medicine, Nov 2006
(6)al Zahrani A, Levine MA: Primary hyperparathyroidism. Lancet 1997 Apr 26; 349(9060): 1233-8.
(7)Allerheiligen DA, Schoeber J, Houston RE, et al: Hyperparathyroidism. Am Fam Physician 1998 Apr 15; 57(8): 1795-802, 1807-8
(8)NIH conference. Diagnosis and management of asymptomatic primary hyperparathyroidism: consensus development conference statement. Ann Intern Med. 1991 Apr 1;114(7):593-7
(9)Parathyroidectomy in Asymptomatic PrimaryHyperparathyroidism: Improves "Bones"...Walker and Silverberg J Clin Endocrinol Metab.2007; 92: 1613-1615
(10)Feder,J.N., Gnirke,A., Thomas,W., Tsuchihashi,Z., Ruddy,D.A., Basava,A., Dormishian,F., Domingo,R.,Jr, Ellis,M.C., Fullan,A. et al. (1996) A novel MHC class I-like gene is mutated in patients with hereditary haemochromatosis. Nat. Genet; 13: 399–408
(11)Girouard J, Giguère Y, Delage R and Rousseau F. Prevalence of HFE gene C282Y and H63D mutations in a French–Canadian population of neonates and in referred patients. Human Molecular Genetics, 2002; 11(2): 185-189

First published June 2007

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