Pseudogout

Background

Pseudogout is the popular term for calcium pyrophosphate crystal deposition disease (CPPD). There are two types of the disease.

TYPES CHARACTERIZATION

Hereditary Crystals develop early in life and associated with severe osteoarthritis

Sporadic (Idiopathic) See disease associations

The disease affects the articular matrix, menisci, and intervertebral discs. Joint involvement may last form days to weeks and may be monoarticular or polyarticular. It affects the knees, wrists, elbows, shoulders, and ankles.

OUTLINE

Epidemiology

Disease Associations

Pathogenesis

Laboratory/Radiologic/
Other Diagnostic Testing

Gross Appearance and Clinical Variants

Histopathological Features and Variants

Special Stains/
Immunohistochemistry/
Electron Microscopy

Differential Diagnosis

Prognosis

Treatment

Commonly Used Terms

Internet Links

EPIDEMIOLOGY CHARACTERIZATION

SYNONYMS Chondrocalcinosis

INCIDENCE Occurs in 30-60% of individuals 85 years and older

AGE RANGE-MEDIAN >50 years

SEX (M:F)
Equal

DISEASE ASSOCIATIONS CHARACTERIZATION

Previous joint damage

Hyperparathyroidism

Hemochromatosis

Hypomagnesemia

Hypothyroidism

Ochronosis

Diabetes

PATHOGENESIS CHARACTERIZATION

Linkage of disease with chromosome 8q Found in a family with hereditary type

Enzyme defects hypothesized Altered activity of matrix enzymes that produce and degrade pyroposphate with accumulation and crystallization with calcium

Effects of pyrophosphatase on dissolution of calcium pyrophosphate dihydrate crystals.

Xu Y, Cruz T, Cheng PT, Pritzker KP.

Department of Pathology, Mount Sinai Hospital, Toronto, ON, Canada.

J Rheumatol 1991 Jan;18(1):66-71 Abstract quote

Understanding the dissolution mechanisms involved in calcium pyrophosphate dihydrate (CPPD) crystals may prove important for the development of therapy for CPPD arthropathy.

We demonstrate that yeast pyrophosphatase effectively dissolved CPPD crystals in solutions. Maximum enzymatic dissolution of CPPD crystals was achieved at neutral pH and when the enzyme had access to the crystal surface. The enzymatic dissolution of CPPD crystals was highly dependent on ambient [Mg++] and [Ca++]. The stimulating effects of Mg++ on crystal dissolution in the presence of the enzyme is due to stimulation of pyrophosphatase activity and to enhanced direct release of pyrophosphate ions from the crystal surface.

The inhibiting effect of Ca++ on crystal dissolution by the enzyme is mainly due to the suppression of pyrophosphatase activity.

Polyamines enhance calcium pyrophosphate dihydrate crystal dissolution.

Shinozaki T, Pritzker KP.

Connective Tissue Research Group, Mount Sinai Hospital, Toronto, Canada.

J Rheumatol 1995 Oct;22(10):1907-12 Abstract quote

OBJECTIVE. Alkaline phosphatase (ALP), an enzyme with pyrophosphatase (PP(i)ase) activity, can dissolve calcium pyrophosphate dihydrate (CPPD) crystals. We investigated the CPPD crystal dissolution activity of polyamines, substrates known to enhance PP(i)ase activity.

METHODS. An in vitro model system for crystal enzyme interaction was used to assess CPPD crystal dissolution both biochemically and morphologically.

RESULTS. We demonstrated biochemically and morphologically that polyamines such as spermine and spermidine can enhance CPPD crystal dissolution activity of ALP. Polyamines enhanced ALP induced CPPD crystal dissolution and ALP PP(i)ase activity differentially. By scanning electron microscopy, we observed that polyamines enhanced dissolution stereoselectively at the small end faces (optical 010 faces) of CPPD crystals, indicated by the presence of etch pits.

CONCLUSION. Polyamines assist ALP to promote the stereoselective dissolution of CPPD crystals. In addition to implications for CPPD crystal dissolution, as ALP is present intracellularly, these studies suggest that polyamines and ALP have synergistic effects when ALP PP(i)ase activity is required for intracellular energy metabolism.

GROSS APPEARANCE/
CLINICAL VARIANTS CHARACTERIZATION

General Chalky white deposits in the joint

HISTOLOGICAL TYPES CHARACTERIZATION

General Crystals form oval blue-purple aggregates
Weakly birefringent
Occasionally deposited in masses resembling tophi

Most calcium pyrophosphate crystals appear as non-birefringent.

Ivorra J, Rosas J, Pascual E.

Seccion de Reumatologia, Hospital General Universitario de Alicante, and Universidad Miguel Hernandez, Alicante, Spain.

Ann Rheum Dis 1999 Sep;58(9):582-4 Abstract quote

OBJECTIVE: To determine the proportion of calcium pyrophosphate dihydrate (CPPD) crystals that appear as non-birefringent when observed under the polarised light microscope.

METHODS: Two observers examined independently 10 synovial fluid samples obtained during an episode of arthritis attributable to CPPD crystals. Ten synovial fluid samples from patients with acute gout were used as a reference. The examination was performed after placing a fluid sample in a Niebauer haemocytometric chamber; a crystal count was done first under ordinary light, then in the area corresponding to a 0.1 ml, under polarised light

RESULTS: The percentages of birefringence appreciated for CPPD were 18% (confidence intervals (CI) 12, 24) for observer 1, and 17% (CI 10, 24) for observer 2 (difference NS). The percentages of birefringence for monosodium urate were 127% (CI 103, 151) for observer 1 and 107% (CI 100, 114) for observer 2 (difference NS). Percentages above 100% indicate that crystals missed under ordinary light became apparent under polarised light.

CONCLUSION: Only about one fifth of all CPPD crystals identified by bright field microscopy show birefringence when the same synovial fluid sample is observed under polarised light. If a search for CPPD crystals is conducted under polarised light, the majority of the crystals will be missed. Ordinary light allows a better rate of CPPD crystal detection but observation under polarised light of crystals showing birefringence is required for definitive CPPD crystal identification.

SPECIAL STAINS/
IMMUNOPEROXIDASE/
OTHER CHARACTERIZATION

Special stains

Evaluation of Crystals in Formalin-Fixed, Paraffin-Embedded Tissue Sections for the Differential Diagnosis of Pseudogout, Gout, and Tumoral Calcinosis

Vinod Shidham, M.D., FIAC, MRCPath, Mamatha Chivukula, M.D., Zainab Basir, M.D. and Ganesh Shidham, M.D.

From the Department of Pathology (VSMC, ZB) and Division of Nephrology (GS), Medical College of Wisconsin, Milwaukee, Wisconsin

Mod Pathol 2001;14:806-810 Abstract quote

Hematoxylin-eosin (H&E)�stained sections may not allow proper evaluation of birefringence properties of the crystals in the lesions of pseudogout, gout, and tumoral calcinosis. This study was undertaken to verify the application of a special stain that could facilitate the evaluation of the birefringence properties of these crystals for definitive diagnosis.

We evaluated previously described nonaqueous alcoholic eosin staining (NAES) method based on the principle of using alcoholic eosin without hematoxylin and any other aqueous reagents for staining of formalin-fixed, paraffin-embedded tissue sections.

Two observers, in a blinded fashion, evaluated the sections stained with routine H&E and NEAS method without the knowledge about clinical diagnosis. All pseudogout (nine sections from seven cases) and gout (eight sections from five cases) lesions demonstrated birefringence in the sections stained with NAES method. H&E�stained sections showing the respective diagnostic histomorphology failed to demonstrate the birefringent crystals by polarizing microscopy in all the eight sections from gout and in seven of nine sections from pseudogout. Only two H&E�stained sections showed scant calcium pyrophosphate dihydrate (CPPD) crystals in pseudogout. None of the three sections from two cases of tumoral calcinosis showed birefringence with either stain.

We conclude that CPPD in pseudogout and monosodium urate in gout may not polarize in the routine H&E�stained sections. However, polarizing microscopy of sections stained with NAES method allowed demonstration of CPPD crystals with positive birefringence in pseudogout, MSU crystals with negative birefringence in gout, and calcium hydroxyapatite crystals without birefringence in tumoral calcinosis.

Section stained with NAES method is a significantly useful adjunct to the routine H&E stain for proper evaluation of the crystals under polarizing microscope in these lesions.

PROGNOSIS AND TREATMENT CHARACTERIZATION

Prognostic Factors 50% of patients experience significant joint damage

Treatment

Intravenous colchicine use in crystal-induced arthropathies: a retrospective analysis of hospitalized patients.

Maldonado MA, Salzman A, Varga J.

Rheumatology Division, University of Pennsylvania School of Medicine, Philadelphia 19104, USA.

Clin Exp Rheumatol 1997 Sep-Oct;15(5):487-92 Abstract quote

OBJECTIVES: To assess current prescribing patterns, and adherence to recommended practice guidelines, for the use of intravenous colchicine in the treatments of crystal-induced arthropathies.

METHODS: Medical records of patients at an urban academic medical center who received intravenous colchicine were reviewed. Information about colchicine dosing and clinical outcomes, with particular attention to interventions by Rheumatologists, was obtained. All hospitalized patients with confirmed or suspected crystal-induced arthropathies treated with intravenous colchicine during a 48-month period were included in this retrospective study. The demographic profile, medical history and clinical data were reviewed.

RESULTS: Intravenous colchicine dosing schedules generally followed recommended guidelines. There was no significant difference between patients evaluated by a Rheumatologist, and those that were not, in the cumulative colchicine dose received, clinical response, or length of hospitalization. Relative contraindications to intravenous colchicine were present frequently, but no morbidity or mortality directly attributable to intravenous colchicine was recorded. Patients evaluated by a Rheumatologist prior to receiving intravenous colchicine were significantly more likely to have the diagnosis of a crystal-induced arthropathy confirmed by the identification of crystals from synovial fluid, and less likely to have received oral colchicine prior to intravenous colchicine, than patients who were not evaluated by a Rheumatologist.

CONCLUSIONS: Increased involvement of Rheumatologists, and increased awareness of the appropriate indications and guidelines for the safe administration of intravenous colchicine are recommended.

Dissolution of calcium pyrophosphate crystals by polyphosphates: an in vitro and ex vivo study

. Cini R, Chindamo D, Catenaccio M, Lorenzini S, Selvi E, Nerucci F, Picchi MP, Berti G, Marcolongo R.

Department of Chemical and Biosystem Sciences and Technologies, University of Siena, Italy.

Ann Rheum Dis 2001 Oct;60(10):962-7 Abstract quote

OBJECTIVE: To determine the dissolving ability (DA) of linear pentasodium tripolyphosphate (PSTP), cyclic trisodium metaphosphate (TSMP), polymeric sodium metaphosphate (SMP) on synthetic crystals of calcium pyrophosphate dihydrate (CPPD) and on crystalline aggregates of menisci from patients with chondrocalcinosis (CC).

METHODS: Synthetic CPPD crystals were mixed with phosphate buffered saline (PBS), which contained the different polyphosphates, for one hour at 37 degrees C. The calcified menisci were obtained from the knees of four female patients with CPPD disease who underwent total arthroscopic meniscectomy for degenerative meniscal lesions. Meniscal cryosections and fragments were incubated in SMP (15 mg/ml PBS) at 37 degrees C for one hour and 24 hours, respectively. Histological evaluation on meniscal samples after polyphosphate incubation was carried out by ordinary transmitted light microscopy and polarised light microscopy. The dissolution of CPPD crystals by polyphosphates was assessed by atomic absorption spectroscopy, which determined the amount of calcium liberated from synthetic crystals and meniscal fragments. Cytotoxicity of SMP was evaluated by tetrazolium salt assay and by an ultrastructural study on cultured chondrocytes.

RESULTS: SMP and PSTP showed higher DA on CPPD crystals than TSMP. Analysis of the DA values at increasing concentrations of SMP showed that a concentration of 15 mg/ml completely dissolved 2.0 mg CPPD crystals. The solution of meniscal CPPD crystals showed a significant increase of calcium concentration after three hours and 24 hours of SMP incubation (p=0.0001; Kruskal-Wallis analysis of variance) compared with fragments incubated in PBS control solution. Macroscopic and microscopic evaluation of meniscal specimens showed a notable reduction of CPPD deposits. A 50% inhibitory dose on cultured chondrocytes was reached at the maximum concentration of SMP used in this work (15 mg/ml); ultrastructural analysis did not show morphological alterations in the treated cells.

CONCLUSION: The results of this study indicate that linear polyphosphates are effective in dissolving both synthetic and ex vivo CPPD crystal aggregates. This suggests a potential therapeutic use for these molecules in the treatment of symptomatic CC.

Henry JB. Clinical Diagnosis and Management by Laboratory Methods. Twentieth Edition. WB Saunders. 2001.
Rosai J. Ackerman's Surgical Pathology. Ninth Edition. Mosby 2004.
Sternberg S. Diagnostic Surgical Pathology. Fourth Edition. Lipincott Williams and Wilkins 2004.
Robbins Pathologic Basis of Disease. Seventh Edition. WB Saunders 2005.
DeMay RM. The Art and Science of Cytopathology. Volume 1 and 2. ASCP Press. 1996.
Weedon D. Weedon's Skin Pathology Second Edition. Churchill Livingstone. 2002
Fitzpatrick's Dermatology in General Medicine. 5th Edition. McGraw-Hill. 1999.
Weiss SW and Goldblum JR. Enzinger and Weiss's Soft Tissue Tumors. Fourth Edition. Mosby 2001.

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TYPES	CHARACTERIZATION
Hereditary	Crystals develop early in life and associated with severe osteoarthritis
Sporadic (Idiopathic)	See disease associations

Epidemiology
Disease Associations
Pathogenesis
Laboratory/Radiologic/ Other Diagnostic Testing
Gross Appearance and Clinical Variants
Histopathological Features and Variants
Special Stains/ Immunohistochemistry/ Electron Microscopy
Differential Diagnosis
Prognosis
Treatment
Commonly Used Terms
Internet Links

EPIDEMIOLOGY	CHARACTERIZATION
SYNONYMS	Chondrocalcinosis
INCIDENCE	Occurs in 30-60% of individuals 85 years and older
AGE RANGE-MEDIAN	>50 years
SEX (M:F)	Equal

DISEASE ASSOCIATIONS	CHARACTERIZATION
Previous joint damage
Hyperparathyroidism
Hemochromatosis
Hypomagnesemia
Hypothyroidism
Ochronosis
Diabetes

PATHOGENESIS	CHARACTERIZATION
Linkage of disease with chromosome 8q	Found in a family with hereditary type
Enzyme defects hypothesized	Altered activity of matrix enzymes that produce and degrade pyroposphate with accumulation and crystallization with calcium
Effects of pyrophosphatase on dissolution of calcium pyrophosphate dihydrate crystals. Xu Y, Cruz T, Cheng PT, Pritzker KP. Department of Pathology, Mount Sinai Hospital, Toronto, ON, Canada.	J Rheumatol 1991 Jan;18(1):66-71 Abstract quote Understanding the dissolution mechanisms involved in calcium pyrophosphate dihydrate (CPPD) crystals may prove important for the development of therapy for CPPD arthropathy. We demonstrate that yeast pyrophosphatase effectively dissolved CPPD crystals in solutions. Maximum enzymatic dissolution of CPPD crystals was achieved at neutral pH and when the enzyme had access to the crystal surface. The enzymatic dissolution of CPPD crystals was highly dependent on ambient [Mg++] and [Ca++]. The stimulating effects of Mg++ on crystal dissolution in the presence of the enzyme is due to stimulation of pyrophosphatase activity and to enhanced direct release of pyrophosphate ions from the crystal surface. The inhibiting effect of Ca++ on crystal dissolution by the enzyme is mainly due to the suppression of pyrophosphatase activity.
Polyamines enhance calcium pyrophosphate dihydrate crystal dissolution. Shinozaki T, Pritzker KP. Connective Tissue Research Group, Mount Sinai Hospital, Toronto, Canada.	J Rheumatol 1995 Oct;22(10):1907-12 Abstract quote OBJECTIVE. Alkaline phosphatase (ALP), an enzyme with pyrophosphatase (PP(i)ase) activity, can dissolve calcium pyrophosphate dihydrate (CPPD) crystals. We investigated the CPPD crystal dissolution activity of polyamines, substrates known to enhance PP(i)ase activity. METHODS. An in vitro model system for crystal enzyme interaction was used to assess CPPD crystal dissolution both biochemically and morphologically. RESULTS. We demonstrated biochemically and morphologically that polyamines such as spermine and spermidine can enhance CPPD crystal dissolution activity of ALP. Polyamines enhanced ALP induced CPPD crystal dissolution and ALP PP(i)ase activity differentially. By scanning electron microscopy, we observed that polyamines enhanced dissolution stereoselectively at the small end faces (optical 010 faces) of CPPD crystals, indicated by the presence of etch pits. CONCLUSION. Polyamines assist ALP to promote the stereoselective dissolution of CPPD crystals. In addition to implications for CPPD crystal dissolution, as ALP is present intracellularly, these studies suggest that polyamines and ALP have synergistic effects when ALP PP(i)ase activity is required for intracellular energy metabolism.

GROSS APPEARANCE/ CLINICAL VARIANTS	CHARACTERIZATION
General	Chalky white deposits in the joint

PROGNOSIS AND TREATMENT	CHARACTERIZATION
Prognostic Factors	50% of patients experience significant joint damage
Treatment
Intravenous colchicine use in crystal-induced arthropathies: a retrospective analysis of hospitalized patients. Maldonado MA, Salzman A, Varga J. Rheumatology Division, University of Pennsylvania School of Medicine, Philadelphia 19104, USA.	Clin Exp Rheumatol 1997 Sep-Oct;15(5):487-92 Abstract quote OBJECTIVES: To assess current prescribing patterns, and adherence to recommended practice guidelines, for the use of intravenous colchicine in the treatments of crystal-induced arthropathies. METHODS: Medical records of patients at an urban academic medical center who received intravenous colchicine were reviewed. Information about colchicine dosing and clinical outcomes, with particular attention to interventions by Rheumatologists, was obtained. All hospitalized patients with confirmed or suspected crystal-induced arthropathies treated with intravenous colchicine during a 48-month period were included in this retrospective study. The demographic profile, medical history and clinical data were reviewed. RESULTS: Intravenous colchicine dosing schedules generally followed recommended guidelines. There was no significant difference between patients evaluated by a Rheumatologist, and those that were not, in the cumulative colchicine dose received, clinical response, or length of hospitalization. Relative contraindications to intravenous colchicine were present frequently, but no morbidity or mortality directly attributable to intravenous colchicine was recorded. Patients evaluated by a Rheumatologist prior to receiving intravenous colchicine were significantly more likely to have the diagnosis of a crystal-induced arthropathy confirmed by the identification of crystals from synovial fluid, and less likely to have received oral colchicine prior to intravenous colchicine, than patients who were not evaluated by a Rheumatologist. CONCLUSIONS: Increased involvement of Rheumatologists, and increased awareness of the appropriate indications and guidelines for the safe administration of intravenous colchicine are recommended.
Dissolution of calcium pyrophosphate crystals by polyphosphates: an in vitro and ex vivo study . Cini R, Chindamo D, Catenaccio M, Lorenzini S, Selvi E, Nerucci F, Picchi MP, Berti G, Marcolongo R. Department of Chemical and Biosystem Sciences and Technologies, University of Siena, Italy.	Ann Rheum Dis 2001 Oct;60(10):962-7 Abstract quote OBJECTIVE: To determine the dissolving ability (DA) of linear pentasodium tripolyphosphate (PSTP), cyclic trisodium metaphosphate (TSMP), polymeric sodium metaphosphate (SMP) on synthetic crystals of calcium pyrophosphate dihydrate (CPPD) and on crystalline aggregates of menisci from patients with chondrocalcinosis (CC). METHODS: Synthetic CPPD crystals were mixed with phosphate buffered saline (PBS), which contained the different polyphosphates, for one hour at 37 degrees C. The calcified menisci were obtained from the knees of four female patients with CPPD disease who underwent total arthroscopic meniscectomy for degenerative meniscal lesions. Meniscal cryosections and fragments were incubated in SMP (15 mg/ml PBS) at 37 degrees C for one hour and 24 hours, respectively. Histological evaluation on meniscal samples after polyphosphate incubation was carried out by ordinary transmitted light microscopy and polarised light microscopy. The dissolution of CPPD crystals by polyphosphates was assessed by atomic absorption spectroscopy, which determined the amount of calcium liberated from synthetic crystals and meniscal fragments. Cytotoxicity of SMP was evaluated by tetrazolium salt assay and by an ultrastructural study on cultured chondrocytes. RESULTS: SMP and PSTP showed higher DA on CPPD crystals than TSMP. Analysis of the DA values at increasing concentrations of SMP showed that a concentration of 15 mg/ml completely dissolved 2.0 mg CPPD crystals. The solution of meniscal CPPD crystals showed a significant increase of calcium concentration after three hours and 24 hours of SMP incubation (p=0.0001; Kruskal-Wallis analysis of variance) compared with fragments incubated in PBS control solution. Macroscopic and microscopic evaluation of meniscal specimens showed a notable reduction of CPPD deposits. A 50% inhibitory dose on cultured chondrocytes was reached at the maximum concentration of SMP used in this work (15 mg/ml); ultrastructural analysis did not show morphological alterations in the treated cells. CONCLUSION: The results of this study indicate that linear polyphosphates are effective in dissolving both synthetic and ex vivo CPPD crystal aggregates. This suggests a potential therapeutic use for these molecules in the treatment of symptomatic CC.