CPPD / BCP

CPPD
    • Clinical Presentations CPPD NEJM 2016
      • Asymptomatic or Presymptomatic CPPD
      • Acute CPP Arthritis 
      • Chronic CPP Arthritis (Shoulder, Knee, Wrist)
      • Pseudo RA (less symmetrical than RA)
      • Pseudo-Neurotrophic or Charcot's Arthropathy
      • Spinal (The crowned dens syndrome)
      • Tumoral deposits in tissue 
    • Familial CPPD - CCAL2 locus on chromosome 5p causing gain of ANKH protein, and CCAL1 locus on chromosome 8 a gain-of-function mutation in the TNFRSF11B (osteoprotegerin) gene) CPPD NEJM 2016
    • Usually associated with following Metabolic Disease CPPD NEJM 2016
      • Hyper: 
        • Hyperparathyroidism (alters Ca metabolism, but association is more complex as persists even after correction)
        • Familial hypocalciuric hypercalcemia (increased Ca)
        • Hemochromatosis (inhibitory action of Iron on Pyrophosphotase, or high level of PTH in cartilage ?? )
      • Hypo: 
        • Hypothyroidism, 
        • Hypophosphatasia, 
        • Hypomagnesemia (Mg increases solubility of CPP crystals, and also  acts as cofactor for pyrophosphotase)
          • Gitlemans variant of Barters syndrome 
        • Alkaline phosphatase deficiency (causes high ePP)
      • Medicines: Loop diuretics, pamidronate, intrarticular hyarulonic acid, GM-CSF prep
    • Pathogenesis: CPP Deposition in the pericellular matrix of cartilage is the first step. 
  • CCP crystals deposit exclusively in articular hyaline cartilage, and fibrocartilage, and at site of chondroin metaplasia including in the synovium.
  • PPi generation: from ATP and other nucleoside triphophosphate by ectoenzyme ectonucleotide PP / phosphodiesterase 1 (ENPP1)
  • PPi transport: iATP to eATP by ANKH 
  • PPi degradation: PPi to Pi by TNAP (ectoenzyme tissue non-specific ALP (alkaline phosphatase) 
  • Then, CCP crystals form when eg Magnesium is low which normally surpasses CCP crystal formation 


  • Calcium Pyrophosphate Deposition Disease NEJM 2016
    • Diagnosis: 
      • positively birefringent, rhomboid- shaped crystals in synovial fluid from the affected joint CPPD NEJM 2016
      • Under compensated polarizing light microscopy, which is typically performed with a red filter, CPP crystals appear blue when they are parallel to the axis of the polarizer and yellow when they are perpendicular.CPPD NEJM 2016
      • Monosodium urate crystals appear yellow when they are parallel to the axis of the polarizer and blue when they are perpendicular.  LL -- LL (parallel, yellow) CPPD NEJM 2016
      • for < 60 yrs with sx of arthritis test for  iron studies, including measurement of iron, transferrin, and ferritin levels, as well as measurement of levels of serum calcium, alkaline phosphatase, and parathyroid hormone CPPD NEJM 2016
    • Clinical Pearls
      • Unusual sites of OA, such as elbow, the shoulder, or ankle joint should lead to further investigation for the evidence of CPPD or BCP crystal disease Cur Rheum Rep 2006
      1. Other useful radiographic clues that assist in differentiating primary osteoarthritis from CPPD disease include the following:
        1. HAS  Cyst Articular destruction and Tendon Calcification
        1. 1. hooklike osteophytes; 
        2. 2. axial skeletal involvement, such as annulus fibrosis calcification, severe disk degeneration with the vacuum phenomenon and subchondral erosions, and the vacuum phenomenon of sacroiliac joints; 
        3. 3. radiocarpal- or patello- femoral-predominant narrowing of the joint Space;
        4. 4. subchondral cyst formation; 
        5. 5. severe articular destruction, such as subchondral collapse, bony fragments, and microfractures; and 
        6. 6. tendon or fascial calcifications, such as at the Achilles tendon, plantar fascia, gastrocnemius, quadriceps, rotator cuff, or triceps at the elbow or shoulder. CPPD NEJM 2016
  • Basic Calcium Phosphate Deposition Disease:
    • Can lead to highly destructive inflammatory arthritis (Milwaukee shoulder)
    • The predominant mineral type in basic calcium phosphate (BCP)-associated musculoskeletal pathology is carbonated hydroxyapatite, although the term "basic calcium phosphate" refers to a trio of submicron-sized calcium phosphate crystals
    • These include partially carbonate-substituted hydroxyapatite, octacalcium phosphate, and tricalcium phosphate (whitlockite). The terms "calcium phosphate" and "hydroxyapatite" are often used synonymously with the more accurate term "basic calcium phosphate." BCP crystals are similar in composition to both the normal mineral found in bones and teeth and the pathologic mineral found in atherosclerotic plaques and calcinosis cutis.
    • OA with BCP crystals and MSS likely represent points on the same spectrum of disease pathogenesis rather than different syndromes.
    • The causes of pathologic basic calcium phosphate (BCP) crystal formation are not fully understood [5]. BCP mineral formation often occurs at sites of local tissue damage associated with injury or inflammation. Once formed, BCP crystals can produce symptoms and mediate tissue damage by several mechanisms, including the induction of a vigorous inflammatory response, biomechanical disruption, and by direct interactions with connective tissue cells, producing destructive cytokines and prostaglandins in the absence of inflammation
    • Diagnosis: 

      Osteoarthritis with BCP crystals – by clinical history consistent with noninflammatory arthritis in large joints. These patients have subacute or chronic pain in one of more large joints, which is worse with activity, increases as the day progresses, and is not associated with prolonged (>30 minutes) morning stiffness. The presence of intraarticular BCP crystals may be suspected when there is an unusually rapid pace of progression or very aggressive joint and soft tissue destruction. The diagnosis is further supported by the presence of noninflammatory synovial fluids without visible MSU or CPP crystals.

      Milwaukee shoulder syndrome – MSS is diagnosed based upon a clinical history of severe noninflammatory shoulder arthritis and an examination that often shows large effusions and shoulder instability. The diagnosis is further supported by synovial fluid aspirates showing cell counts of <1000 cells/mm3 and no MSU or CPP crystals. Radiographs can provide additional validation by demonstrating large effusions, massive rotator cuff damage, and extensive cartilage loss and bony changes.

      These diagnoses can be further supported by the identification of BCP crystals with alizarin red S staining of synovial fluid, if sufficient expertise in such staining and appropriate reagents are available (see 'Alizarin red S' below). This would be most helpful in patients with unusually aggressive or rapidly progressive osteoarthritis (OA), particularly in the shoulder. Ideally, analytic techniques to identify the chemical composition of crystals, such as spectroscopy or x-ray diffraction, could be employed to confirm the diagnosis, but these techniques are generally not available in routine clinical practice. (See 'Other techniques' below.)

Crystallopathies 







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