High Yield Overview

PSEUDOGOUT AND CPPD DISEASE

Calcium Pyrophosphate Dihydrate | Positively Birefringent | Rhomboid Crystals

CPPDCalcium pyrophosphate dihydrate

PositiveBirefringence under polarized light

KneeMost commonly affected joint

65+Age group most affected (years)

CPPD DISEASE PHENOTYPES

Asymptomatic Chondrocalcinosis

PatternIncidental radiographic finding

TreatmentNo treatment required

Acute CPP Crystal Arthritis

PatternPseudogout attack

TreatmentNSAIDs, colchicine, steroids

Chronic CPP Crystal Arthropathy

PatternOA-like chronic arthritis

TreatmentSupportive, joint replacement

Crowned Dens Syndrome

PatternCervical spine involvement

TreatmentNSAIDs, collar, rarely surgery

Critical Must-Knows

CPP crystals are rhomboid/rod-shaped and positively birefringent (blue parallel to polarizer)
Chondrocalcinosis on X-ray is pathognomonic but not synonymous with symptomatic disease
Knee is the most commonly affected joint (50% of cases)
Associated conditions: Hemochromatosis, hyperparathyroidism, hypomagnesemia, hypothyroidism
No specific disease-modifying therapy exists unlike gout

Examiner's Pearls

"
Positively birefringent = blue when parallel to polarizer axis
"
Chondrocalcinosis on knee X-ray: triangular fibrocartilage, hyaline cartilage
"
Always screen for metabolic causes in patients younger than 55 years
"
Crowned dens syndrome mimics meningitis - look for calcification around odontoid

Clinical Imaging

Imaging Gallery

Plain radiographs of the affected knee (a) before TKA, (b) after TKA, and (c) during the occurrence of pseudogout.Credit: Open-i / NIH via Open-i (NIH) (Open Access (CC BY))

US aspect of CPPD deposits (arrows) in the hyaline cartilage (HC) of the femur in a knee joint and in the fibrocartilage (FC) of a medial meniscus.Credit: Filippou G et al. via ScientificWorldJournal via Open-i (NIH) (Open Access (CC BY))

Findings of the histologic examination of synovial tissue after the onset of pseudogout. (a, c) Hematoxylin-eosin (H&E)–stained section at low magnification. (b, e, f) H&E-stained section at h — Findings of the histologic examination of synovial tissue after the onset of pseudogout. (a, c) Hematoxylin-eosin (H&E)–stained section at low magCredit: Open-i / NIH via Open-i (NIH) (Open Access (CC BY))

Intraoperative findings at the pseudogout attack.Credit: Open-i / NIH via Open-i (NIH) (Open Access (CC BY))

Critical CPPD Exam Points

Crystal Identification

CPP crystals: Rhomboid or rod-shaped, positively birefringent (blue parallel, yellow perpendicular). MSU crystals (gout): Needle-shaped, negatively birefringent (yellow parallel). This is the fundamental diagnostic distinction tested in exams.

Associated Metabolic Conditions

Screen for underlying causes in young patients (less than 55 years): Hemochromatosis (ferritin, transferrin saturation), hyperparathyroidism (calcium, PTH), hypomagnesemia, hypothyroidism (TSH). These are frequently asked in vivas.

Radiographic Features

Chondrocalcinosis: Linear calcification in fibrocartilage (menisci, TFCC, symphysis pubis) and hyaline cartilage. Pyrophosphate arthropathy: Subchondral cysts, osteophytes, joint space narrowing - often in unusual OA locations.

Key Differences from Gout

No urate-lowering equivalent exists for CPPD - treatment is symptomatic only. Joint distribution differs - knee more common than 1st MTP. Chronic form resembles OA rather than erosive arthritis. Attacks often less intense than gout.

CPPD vs Gout: Key Differentiators

Feature	CPPD (Pseudogout)	Gout (MSU)
Crystal shape	Rhomboid/rod-shaped	Needle-shaped
Birefringence	Positive (BLUE parallel)	Negative (YELLOW parallel)
Classic joint	Knee, wrist	1st MTP (podagra)
Radiographic sign	Chondrocalcinosis	Punched-out erosions
Metabolic associations	Hemochromatosis, HPT, hypoMg	Diet, alcohol, CKD
Disease-modifying therapy	None available	Allopurinol, febuxostat

Mnemonic

RHOMBUSCPPD Crystal Features

Rhomboid crystal shape

Rectangular or rod-like morphology

Hyaline cartilage calcification

Parallel lines on X-ray

Old age predominance

Increases with age over 65

Meniscal calcification

Triangular fibrocartilage involvement

Blue when parallel

Positive birefringence

Underlying metabolic causes

Hemochromatosis, HPT, hypoMg

Synovitis acute attacks

Pseudogout presentation

Memory Hook:RHOMBUS-shaped crystals glow BLUE parallel!

Mnemonic

HHHHMetabolic Causes of CPPD

Hemochromatosis

Iron overload - check ferritin

Hyperparathyroidism

Elevated calcium and PTH

Hypomagnesemia

Low magnesium promotes crystal formation

Hypothyroidism

Check TSH

Memory Hook:The 4 H's of metabolic CPPD - Hunt for Hidden causes!

Mnemonic

KWISTChondrocalcinosis Locations

Knee menisci

Most common location

Wrist TFCC

Triangular fibrocartilage complex

Intervertebral discs

Annulus fibrosus

Symphysis pubis

Fibrocartilage of pelvis

Triangular ligament

Hip labrum and other fibrocartilage

Memory Hook:Know Where It Shows on Targeting X-rays!

Overview and Epidemiology

Calcium pyrophosphate deposition (CPPD) disease is a crystal arthropathy caused by the deposition of calcium pyrophosphate dihydrate (CPP) crystals in articular and periarticular tissues. It encompasses a spectrum from asymptomatic chondrocalcinosis to acute pseudogout attacks to chronic pyrophosphate arthropathy.

Epidemiology:

Prevalence increases markedly with age: rare before age 50, present in greater than 40% of those over 84 years
Male to female ratio: approximately equal (slight female predominance in some studies)
Radiographic chondrocalcinosis: 15% at age 65-74, 44% at age 85 and older
Only 25% of those with radiographic chondrocalcinosis are symptomatic

Risk Factors:

Age: Strongest risk factor - prevalence doubles each decade after 60
Prior joint injury: Meniscectomy, joint trauma
Osteoarthritis: Strong association, chicken-and-egg relationship
Metabolic conditions: Hemochromatosis, hyperparathyroidism, hypomagnesemia, hypothyroidism
Familial: Rare autosomal dominant forms (ANKH gene mutations)

Age Rule

CPPD in a patient under 55 should trigger investigation for underlying metabolic disease. This is a common exam question - always screen young patients for the 4 H's: Hemochromatosis, Hyperparathyroidism, Hypomagnesemia, Hypothyroidism.

Pathophysiology

Understanding the pathophysiology of CPPD is essential for both diagnosis and management. The disease results from aberrant pyrophosphate metabolism leading to crystal formation in cartilage.

Pyrophosphate Metabolism

Normal physiology:

Inorganic pyrophosphate (PPi) is produced during ATP hydrolysis
PPi is normally converted to orthophosphate by pyrophosphatases
Balance between PPi generation and breakdown maintains normal levels
Chondrocytes are the primary source of articular PPi

Pathological crystal formation:

Excess PPi combines with calcium to form CPP crystals
Crystals deposit preferentially in fibrocartilage (menisci, TFCC) and hyaline cartilage
Crystal shedding into joint space triggers acute inflammation

Mechanisms of Crystal Formation

Elevated extracellular PPi:

Increased ANKH transporter activity (exports PPi from cells)
Decreased tissue non-specific alkaline phosphatase (TNAP) activity
Chondrocyte senescence with altered metabolism

Factors promoting crystallization:

Elevated calcium concentrations (hyperparathyroidism)
Increased PPi (ANKH mutations, hemochromatosis)
Decreased PPi degradation (hypomagnesemia - Mg is TNAP cofactor)
Cartilage matrix changes with aging

Inflammatory Response

Crystal-induced inflammation:

CPP crystals shed from cartilage into joint space
Crystals phagocytosed by synovial macrophages
NLRP3 inflammasome activation (similar to gout)
IL-1beta release triggers neutrophil influx
Acute synovitis develops

Why Hypomagnesemia Causes CPPD

Magnesium is an essential cofactor for pyrophosphatases that break down PPi. Low magnesium leads to PPi accumulation and crystal formation. This explains the association with diuretic use and alcoholism.

Chronic arthropathy:

Persistent low-grade inflammation damages cartilage
Crystal deposition alters cartilage biomechanics
Secondary osteoarthritic changes develop
Distinctive pattern of joint involvement

Clinical Presentation

Acute CPP Crystal Arthritis (Pseudogout)

Classic presentation:

Acute monoarticular arthritis mimicking gout or septic arthritis
Knee is the most common site (50% of attacks)
Less severe than gout - can usually weight-bear
Self-limiting over 1-3 weeks without treatment
May be triggered by illness, surgery, or trauma

Other common joints:

Knee - 50%
Wrist - 25%
Shoulder, ankle, elbow - remaining 25%
1st MTP (podagra) - uncommon unlike gout

Chronic CPP Crystal Arthropathy

Features:

Resembles osteoarthritis clinically and radiographically
Affects joints atypical for primary OA
MCP joints, wrists, shoulders, ankles - unusual OA sites
Progressive joint destruction possible
Morning stiffness and inflammatory features may be present

Crowned Dens Syndrome

Cervical spine involvement:

Calcification around the odontoid process
Acute severe neck pain, fever, elevated inflammatory markers
Mimics meningitis or retropharyngeal abscess
Diagnosis: CT showing periodontal calcification
Treatment: NSAIDs, usually self-limiting

Physical Examination

Inspection:

Swelling and erythema over affected joint (less marked than gout)
Joint effusion, particularly at knee
No tophi (unlike gout)

Palpation:

Warmth and tenderness over affected joint
Effusion detectable at knee (ballottement, patellar tap)
Crepitus in chronic arthropathy

Investigations

Laboratory Studies

Synovial fluid analysis (Gold Standard):

CPP crystal identification under polarized microscopy
Rhomboid or rod-shaped, positively birefringent crystals
Blue when parallel to the polarizer (opposite of gout)
WBC count: 10,000-50,000/microL (predominantly neutrophils)

Metabolic screen (if under 55 years or recurrent):

Ferritin and transferrin saturation - hemochromatosis
Calcium, PTH - hyperparathyroidism
Magnesium - hypomagnesemia
TSH - hypothyroidism

Other labs:

ESR, CRP - elevated during acute attack
Uric acid - may help differentiate from gout

Imaging

Plain Radiographs:

Chondrocalcinosis - linear calcification in cartilage
Fibrocartilage: Menisci (triangular), TFCC (linear), symphysis pubis
Hyaline cartilage: Parallel lines within cartilage
Pyrophosphate arthropathy: Subchondral cysts, osteophytes, joint space narrowing

Key radiographic locations:

Knee: Meniscal calcification, femoral condyle cartilage
Wrist: TFCC, scapholunate ligament
Pelvis: Symphysis pubis
Spine: Intervertebral disc calcification

Ultrasound:

Hyperechoic deposits within cartilage
Distinguishable from gout (cartilage surface vs within cartilage)

CT:

Best for crowned dens syndrome (periodontal calcification)
Useful for spinal involvement

Management

Acute Attack Management

First-line options:

NSAIDs: Indomethacin 50mg TDS, naproxen 500mg BD
Colchicine: 0.5mg BD-TDS - less effective than in gout but still useful
Corticosteroids: Intra-articular (preferred for monoarticular) or oral prednisolone

Joint aspiration:

Therapeutic as well as diagnostic
Large effusion aspiration provides significant relief
Send for crystals and culture (exclude sepsis)

Exclude Septic Arthritis

Acute pseudogout can mimic septic arthritis. Always send synovial fluid for Gram stain and culture. If any doubt, treat as septic until proven otherwise. Crystals and infection can coexist.

Refractory cases:

IL-1 inhibitors (anakinra) for patients unresponsive to conventional therapy
Systemic corticosteroids if polyarticular

This section covers the acute management of pseudogout attacks.

Surgical Management

Indications for Surgery

End-stage arthropathy: Joint destruction requiring arthroplasty
Mechanical symptoms: Loose bodies, meniscal pathology
Carpal tunnel syndrome: From crystal deposition
Crowned dens syndrome: Rarely requires surgical decompression

Joint Arthroplasty in CPPD

Considerations:

CPPD arthropathy is an indication for joint replacement
Outcomes generally good but some studies show higher complication rates
Ensure acute attack is not present at time of surgery

Preoperative planning:

Screen for metabolic conditions
Assess other joints for involvement
Consider prophylactic colchicine perioperatively

Outcomes:

Total knee arthroplasty: Good outcomes reported
Total hip arthroplasty: Comparable to primary OA
Shoulder arthroplasty: Higher complication rates in some series

Key points:

Crystal disease does not preclude arthroplasty
May have higher manipulation rates post-TKA
Consider perioperative colchicine for flare prophylaxis

This section covers arthroplasty considerations in CPPD.

Complications

Disease Complications

Chronic erosive arthropathy: Progressive joint destruction
Spinal stenosis: From disc calcification and hypertrophy
Tendon rupture: Rare but reported with periarticular deposits
Neurological compression: Carpal tunnel, cervical myelopathy

Surgical Complications

Acute flare: Perioperative pseudogout attack
Stiffness: May be more common after TKA
Wound healing: Generally not affected unlike gout with tophi
Recurrent symptoms: Crystal deposition continues

Evidence Base

Chondrocalcinosis Prevalence Study

Felson DT et al. • Osteoarthritis Cartilage (2016)

Key Findings:

Chondrocalcinosis prevalence increases markedly with age
Present in 8.1% at age 60-74 years
Increases to 17% in those over 75 years

Metabolic Associations with CPPD

Abhishek A et al. • Arthritis Rheumatol (2017)

Key Findings:

Strong association with hemochromatosis
Hyperparathyroidism significantly associated
Hypomagnesemia promotes crystal formation

Colchicine Prophylaxis in CPPD

III

Zhang W et al. • Ann Rheum Dis (2011)

Key Findings:

Low-dose colchicine may reduce attack frequency
Evidence extrapolated from gout trials
Limited CPPD-specific RCT data available

TKA Outcomes in CPPD

III

Heyse TJ et al. • Knee Surg Sports Traumatol Arthrosc (2014)

Key Findings:

Overall TKA outcomes comparable to primary OA
Higher rate of manipulation under anesthesia
Crystal disease does not preclude arthroplasty

Exam Viva Scenarios

Practice these scenarios to excel in your viva examination

VIVA SCENARIOStandard

Scenario 1: Acute Pseudogout Attack

EXAMINER

"A 72-year-old woman presents with acute onset pain and swelling of her right knee. She had a hip replacement 3 days ago. Examination shows a warm, swollen knee with an effusion. She is afebrile."

EXCEPTIONAL ANSWER

Thank you. This presentation raises concern for either acute pseudogout or septic arthritis following recent surgery. Post-surgical stress is a known trigger for pseudogout attacks. My immediate priority is to aspirate the knee and send fluid for crystal analysis and culture. I would expect to find positively birefringent rhomboid crystals if this is pseudogout. However, I would treat as potentially septic until cultures return negative. If crystals are confirmed and cultures negative, I would treat with intra-articular corticosteroid injection or systemic steroids given recent surgery and likely NSAID contraindications.

KEY POINTS TO SCORE

Post-surgical stress triggers pseudogout

Must exclude septic arthritis - aspirate and culture

Crystals are positively birefringent, rhomboid

Treat with steroids if NSAIDs contraindicated

COMMON TRAPS

✗Assuming pseudogout without excluding infection

✗Missing the post-surgical trigger

✗Confusing crystal birefringence

LIKELY FOLLOW-UPS

"What if the patient is febrile?"

"How do you differentiate CPPD from gout crystals?"

"What prophylaxis would you consider for future attacks?"

VIVA SCENARIOStandard

Scenario 2: Young Patient with CPPD

EXAMINER

"A 48-year-old man presents with recurrent episodes of knee pain and swelling. X-rays show chondrocalcinosis. His father had similar problems. He also reports fatigue and impotence."

EXCEPTIONAL ANSWER

Thank you. CPPD disease in a patient under 55 years is unusual and mandates investigation for underlying metabolic causes. The symptoms of fatigue and impotence, combined with a family history, raise strong suspicion for hemochromatosis. I would order ferritin and transferrin saturation as the initial screen. I would also check calcium and PTH for hyperparathyroidism, magnesium for hypomagnesemia, and TSH for hypothyroidism. If hemochromatosis is confirmed, I would refer to hepatology for phlebotomy treatment and screen family members. For his joint symptoms, I would treat acute attacks with NSAIDs or colchicine and consider low-dose colchicine prophylaxis.

KEY POINTS TO SCORE

CPPD under 55 requires metabolic investigation

Fatigue and impotence suggest hemochromatosis

Screen: ferritin, calcium/PTH, magnesium, TSH

Family history suggests hereditary cause

COMMON TRAPS

✗Treating as idiopathic CPPD without metabolic screen

✗Missing hemochromatosis symptoms

✗Not considering familial forms

LIKELY FOLLOW-UPS

"What other organs does hemochromatosis affect?"

"How do you manage hemochromatosis?"

"Are there genetic tests for familial CPPD?"

VIVA SCENARIOStandard

Scenario 3: Crystal Identification

EXAMINER

"You are shown a polarized microscopy image of synovial fluid showing rhomboid crystals that appear blue when aligned parallel to the polarizer. What is your diagnosis?"

EXCEPTIONAL ANSWER

Thank you. These are calcium pyrophosphate dihydrate crystals diagnostic of pseudogout or CPPD disease. The key features are the rhomboid or rod-shaped morphology and positive birefringence - appearing blue when parallel to the polarizer axis. This is in contrast to MSU crystals in gout which are needle-shaped and negatively birefringent, appearing yellow when parallel. The mnemonic I use is 'Blue Parallel in Pseudogout' or 'Positive is Blue.' I would correlate with radiographs looking for chondrocalcinosis to support the diagnosis.

KEY POINTS TO SCORE

CPP crystals: rhomboid, positively birefringent

Blue when parallel to polarizer = positive birefringence

Gout: needle-shaped, negatively birefringent (yellow parallel)

Look for chondrocalcinosis on X-rays

COMMON TRAPS

✗Confusing positive and negative birefringence

✗Mixing up crystal shapes

✗Not correlating with radiographic findings

LIKELY FOLLOW-UPS

"What causes false negative crystal analysis?"

"Can you have both crystal types in one joint?"

"What is the sensitivity of crystal analysis?"

VIVA SCENARIOAdvanced

Scenario 4: Crowned Dens Syndrome

EXAMINER

"An 80-year-old woman presents with acute severe neck pain, fever, and neck stiffness. She is being investigated for possible meningitis. CT cervical spine shows calcification around the odontoid process."

EXCEPTIONAL ANSWER

Thank you. This presentation is consistent with crowned dens syndrome, a manifestation of CPPD disease affecting the atlantoaxial junction. The calcification around the odontoid process on CT is characteristic. This condition mimics meningitis or retropharyngeal abscess with neck pain, fever, and stiffness, but the CSF will be normal. Management is with NSAIDs and a soft collar. It is typically self-limiting over 1-3 weeks. Systemic steroids can be used if NSAIDs are contraindicated. Surgery is rarely needed unless there is significant spinal cord compression. I would also screen for other manifestations of CPPD and metabolic causes given her age.

KEY POINTS TO SCORE

Crowned dens syndrome is CPPD of atlantoaxial junction

Mimics meningitis - acute neck pain, fever, stiffness

CT shows periodontal calcification

Treatment: NSAIDs, collar - usually self-limiting

COMMON TRAPS

✗Treating as meningitis without considering CPPD

✗Missing the calcification on imaging

✗Ordering unnecessary lumbar puncture

LIKELY FOLLOW-UPS

"When would surgery be indicated?"

"How do you differentiate from cervical discitis?"

"What is the natural history?"

Australian Context

In Australia, CPPD disease is common in the aging population, with prevalence increasing in line with demographic shifts. The condition is frequently encountered in orthopaedic practice, particularly in patients presenting for knee arthroplasty.

PBS-listed medications:

Colchicine: PBS listed for prophylaxis and acute attacks of crystal arthropathies
NSAIDs: Various PBS listed for acute inflammatory conditions
Corticosteroids: Available for systemic or intra-articular use

Management should include screening for metabolic causes in younger patients, with referral to endocrinology or hepatology as appropriate. The Australian Rheumatology Association guidelines emphasize the importance of excluding septic arthritis in acute presentations and the lack of disease-modifying therapies for CPPD unlike gout.