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Imaging of Crystal Disorders:

Calcium Pyrophosphate Dihydrate Crystal Deposition Disease, Calcium Hydroxyapatite Crystal Deposition Disease and Gout Pathophysiology, Imaging, and Diagnosis

      Keywords

      Key points

      • Including calcifications on radiographic reports is essential, as they may become symptomatic.
      • The 3 manifestations of calcium pyrophosphate dihydrate crystal deposition disease: chondrocalcinosis, acute calcium pyrophosphate crystal arthritis, and pyrophosphate arthropathy may overlap or be seen in isolation.
      • In crystal deposition diseases a cascade of reactions leading to joint inflammation can be age related, triggered by a trauma or disease, and result in sometimes rapid joint destruction.
      • Ultrasound-guided barbotage procedure is straightforward and accelerates the natural course of hydroxyapatite crystal deposition disease.
      • Dual-energy computed tomography is rapid, noninvasive, and enables diagnosis and follow-up of gout, in multiple joints on a single scan without the use of contrast agents.

      Introduction

      In the elderly population a variety of calcifications and crystal depositions can be appreciated on conventional imaging. These might be asymptomatic but may become symptomatic in time and deserve to be mentioned in the radiological report. The clinical presentation of crystal deposition diseases is variable and diagnosis might be challenging.
      • Steinbach L.S.
      Calcium pyrophosphate dihydrate and calcium hydroxyapatite crystal deposition disease: imaging perspectives.
      ,

      Resnick D. Calcium hydroxyapatite crystal deposition disease. In: Diagnosis of bone and joint disorders. 4th edition. Articular diseases, vol 1. Philadelphia (PA): WB Saunders; 2002. p. 1619–1657.

      The purpose of this review article is to explain the disease spectrum and pathophysiology of calcium pyrophosphate dihydrate crystal deposition disease (CPPD), hydroxyapatite crystal deposition disease (HADD), and gout; to describe imaging findings; and to learn about differential diagnoses, choice of imaging modalities, and possible clinical consequences. Pearls and pitfalls relevant to point of care are provided.

      Calcium pyrophosphate dihydrate crystal deposition disease

      Introduction

      CPPD is caused by the deposition of calcium pyrophosphate (CPP) crystals predominantly in, but also around, joints, and it is common in elderly persons.
      • Steinbach L.S.
      Calcium pyrophosphate dihydrate and calcium hydroxyapatite crystal deposition disease: imaging perspectives.
      ,

      Resnick D. Calcium hydroxyapatite crystal deposition disease. In: Diagnosis of bone and joint disorders. 4th edition. Articular diseases, vol 1. Philadelphia (PA): WB Saunders; 2002. p. 1619–1657.

      There is no gender difference. Its prevalence increases with age: using radiographic knee chondrocalcinosis as diagnostic criterion, it is uncommon in those younger than 55 years and increases to 20% to 30% in those older than 80 years.
      • Steinbach L.S.
      Calcium pyrophosphate dihydrate and calcium hydroxyapatite crystal deposition disease: imaging perspectives.
      ,
      • Felson D.T.
      • Anderson J.J.
      • Naimark A.
      • et al.
      The prevalence of chondrocalcinosis in the elderly and its association with knee osteoarthritis: the Framingham Study.
      • Neame R.L.
      • Carr A.J.
      • Muir K.
      • et al.
      UK community prevalence of knee chondrocalcinosis: evidence that correlation with osteoarthritis is through a shared association with osteophyte.
      • Richette P.
      • Bardin T.
      • Doherty M.
      An update on the epidemiology of calcium pyrophosphate dihydrate crystal deposition disease.
      The mechanism of CPP crystal accumulation in cartilage is unknown. The theory is that it is secondary to cartilage damage: age related, posttraumatic, or disease induced.
      • Steinbach L.S.
      Calcium pyrophosphate dihydrate and calcium hydroxyapatite crystal deposition disease: imaging perspectives.
      There is a positive association with osteoarthritis; however, CCPD deposition is not considered a risk factor for progressive cartilage loss.
      • Richette P.
      • Bardin T.
      • Doherty M.
      An update on the epidemiology of calcium pyrophosphate dihydrate crystal deposition disease.
      Less commonly genetic or various metabolic disorders such as hereditary hemochromatosis, primary hyperparathyroidism, and hypomagnesemia are the cause,
      • Steinbach L.S.
      Calcium pyrophosphate dihydrate and calcium hydroxyapatite crystal deposition disease: imaging perspectives.
      ,
      • Huaux J.P.
      • Geubel A.
      • Koch M.C.
      • et al.
      The arthritis of hemochromatosis. A review of 25 cases with special reference to chondrocalcinosis, and a comparison with patients with primary hyperparathyroidism and controls.
      and this should be considered in case of CPP deposition when younger than 55 years or excessive polyarticular involvement.
      • Richette P.
      • Bardin T.
      • Doherty M.
      An update on the epidemiology of calcium pyrophosphate dihydrate crystal deposition disease.
      Its clinical expression is variable; patients may present with chondrocalcinosis, acute CPP crystal arthritis (also called pseudogout), or pyrophosphate arthropathy, as a result of chronic CPP arthritis
      • Ea H.-K.
      • Lioté F.
      Diagnosis and clinical manifestations of calcium pyrophosphate and basic calcium phosphate crystal deposition diseases.
      ,
      • Zhang W.
      • Doherty M.
      • Bardin T.
      • et al.
      European League Against Rheumatism recommendations for calcium pyrophosphate deposition. Part I: terminology and diagnosis.
      (Fig. 1). There is no medical treatment of CPPD, and in case of progressive degenerative changes, joint replacement might be an option.
      • Steinbach L.S.
      Calcium pyrophosphate dihydrate and calcium hydroxyapatite crystal deposition disease: imaging perspectives.
      Treatment of acute or chronic arthritis in CPPD is based on expert opinion and evidence based on treatment of gout. A recent review article showed that the administration of nonsteroidal antiinflammatory drugs (NSAIDs), colchicine, and corticosteroids has not been evaluated by randomized controlled trials.
      • Parperis K.
      • Papachristodoulou E.
      • Kakoullis L.
      • et al.
      Management of calcium pyrophosphate crystal deposition disease: A systematic review.
      • Chondrocalcinosis: the asymptomatic form of this crystal arthropathy is probably the most common with absence of symptoms in at least 10% to 20%
        • Steinbach L.S.
        Calcium pyrophosphate dihydrate and calcium hydroxyapatite crystal deposition disease: imaging perspectives.
        (Fig. 2).
        Figure thumbnail gr2
        Fig. 2Granular calcifications of hyaline cartilage parallel to the cortical bone in femorotibial and patellofemoral joints A, B. Fibrocartilage calcifications in the menisci and proximal patella enthesopathy.B
      • Acute CPP crystal arthritis (pseudogout syndrome): CPPD was first recognized as a source of acute crystal-induced peripheral-joint inflammation. Most cases develop spontaneously, but there are situations that trigger arthritis, for instance joint trauma, medical illness, surgery, or a blood transfusion.

        Resnick D. Calcium hydroxyapatite crystal deposition disease. In: Diagnosis of bone and joint disorders. 4th edition. Articular diseases, vol 1. Philadelphia (PA): WB Saunders; 2002. p. 1619–1657.

        ,
        • Zhang W.
        • Doherty M.
        • Bardin T.
        • et al.
        European League Against Rheumatism recommendations for calcium pyrophosphate deposition. Part I: terminology and diagnosis.
        The European League Against Rheumatism has made recommendations for the diagnosis of CPPD based on rapid development of inflammatory symptoms, the location of arthritis (knee, shoulders, wrist), age of the patient (>65 years), imaging findings, and absence of another disease (eg, rheumatoid arthritis and septic arthritis).
        • Zhang W.
        • Doherty M.
        • Bardin T.
        • et al.
        European League Against Rheumatism recommendations for calcium pyrophosphate deposition. Part I: terminology and diagnosis.
        The theory of pathogenesis of acute arthritis and synovitis in CPPD is shown in the drawing of Fig. 3A, B . The shedding of CPP crystals into the joint is key in this process. This acute onset of CPP arthritis is self-limiting.
        • Zhang W.
        • Doherty M.
        • Bardin T.
        • et al.
        European League Against Rheumatism recommendations for calcium pyrophosphate deposition. Part I: terminology and diagnosis.
        Figure thumbnail gr3
        Fig. 3Pathogenesis of CPPD (A, B) and gout (C). (A) Acute CPPD attack hypothesis. Crystal deposits around chondrocytes (chondrocalcinosis) lead to cell death, cartilage loss, and deposit coalescence. Crystal shedding results in arthritis. (B) Pyrophosphate arthropathy pathogenesis. Cartilage loss and crystal shedding with synovial depositions result in synovitis. In time degenerative cysts and progressive cartilage and bone destruction is seen. (C) Gout. MTP1 is preserved; MSU crystals erode the bone in intra- and extraarticular eccentric locations, leading to overhanging margins.
        (Adapted from Resnick D. Gouty arthritis. In: Diagnosis of bone and joint disorders, 4th edition (Articular diseases, vol 1). Philadelphia: WB Saunders; 2002. P.1519-1559.)
      • Pyrophosphate arthropathy: the clinical presentation often simulates osteoarthritis. CPPD flares may occur, and a chronic and progressive form of arthritis develops. Its presence is often bilateral and symmetric. Preferential locations include the knee, hip, metacarpophalangeal joints, elbow, ankle, wrist, and glenohumeral joints.
        • Steinbach L.S.
        Calcium pyrophosphate dihydrate and calcium hydroxyapatite crystal deposition disease: imaging perspectives.
      Figure thumbnail gr1
      Fig. 1All 3 CPPD stages may be present in one patient. Diagnosis may become more difficult when 2 or only 1 stage is seen.
      (Adapted from Resnick D. Calcium pyrophosphate dihydrate crystal deposition disease. In: Diagnosis of bone and joint disorders, 4th edition (Articular diseases, vol 1). Philadelphia: WB Saunders; 2002. p.1560-1618.)

      Imaging Findings and Pathology

      • Radiography
      Chondrocalcinosis is most frequently seen in knees, wrists, symphysis pubis, elbows, and hips.

      Resnick D. Calcium hydroxyapatite crystal deposition disease. In: Diagnosis of bone and joint disorders. 4th edition. Articular diseases, vol 1. Philadelphia (PA): WB Saunders; 2002. p. 1619–1657.

      The intraarticular deposition of CPP crystals is almost exclusively seen into articular hyaline cartilage and fibrocartilage and is the most common cause of chondrocalcinosis (see Fig. 3). Examples of fibrocartilage calcifications include knee menisci, symphysis pubis, triangular cartilage of the wrist, annulus fibrosis of the intervertebral disc, and labra of hip and shoulder. However, not all calcifications are identified on radiographs; this can be based on low density of the calcifications or an already severely deranged joint at presentation.
      • Steinbach L.S.
      Calcium pyrophosphate dihydrate and calcium hydroxyapatite crystal deposition disease: imaging perspectives.
      ,
      • Resnick D.
      • Utsinger P.D.
      The wrist arthropathy of “pseudogout” occurring with and without chondrocalcinosis.
      Calcifications can also be seen in the synovial membrane (eg, the knee, wrist, metacarpophalangeal, and metatarsophalangeal [MTP] joints) and the joint capsules. In addition, periarticular calcifications in tendons, bursae, and ligaments can be observed, mimicking hydroxyapatite deposition.
      • Steinbach L.S.
      Calcium pyrophosphate dihydrate and calcium hydroxyapatite crystal deposition disease: imaging perspectives.
      ,

      Resnick D. Calcium hydroxyapatite crystal deposition disease. In: Diagnosis of bone and joint disorders. 4th edition. Articular diseases, vol 1. Philadelphia (PA): WB Saunders; 2002. p. 1619–1657.

      ,
      • Jacques T.
      • Paul M.
      • Badr S.
      • et al.
      Conventional radiology in crystal arthritis gout, calcium pyrophosphate deposition, and basic calcium phosphate crystals.
      In the spine all ligaments may be affected. Periodontoid deposition is called the crowned dens syndrome.
      The term pyrophosphate arthropathy is used for the structural joint changes in CPPD (see Fig. 3). Characteristics include the following:
      • Cystic degeneration and sclerosis (no erosions)
      • Fragmentation of bone and cartilage
      • Debris in synovial membrane
      • Ultrasonography (US)
        • US can show synovitis and can sensitively show CPP deposits in cartilage, with a typical appearance of hypoechoic (cartilage) and echoic (CPPD) layers, being part of the EULAR criteria.
          • Zhang W.
          • Doherty M.
          • Bardin T.
          • et al.
          European League Against Rheumatism recommendations for calcium pyrophosphate deposition. Part I: terminology and diagnosis.
      • Computed tomography (CT)
        • CT technique is able to accurately show calcifications but is rarely used additional for diagnosis or evaluation of a painful joint.
          • Steinbach L.S.
          Calcium pyrophosphate dihydrate and calcium hydroxyapatite crystal deposition disease: imaging perspectives.
      • MR Imaging
      The value of MR imaging is limited in the diagnosis of CPPD. The calcifications are low of signal intensity on all MR sequences and difficult to identify especially in ligaments, and correlation with conventional radiographs is necessary.
      • Reijnierse M.
      Radiographic/MR imaging correlation of paravertebral ossifications in ligaments and bony vertebral outgrowths: anatomy, early detection, and clinical impact.
      In cartilage, depositions can be recognized.
      • Beltran J.
      • Marty-Default E.
      • Bencardino J.
      • et al.
      Chondrocalcinosis of the hyaline cartilage of the knee: MRI manifestations.

      Diagnostic Criteria

      • The 3 manifestations of CPPD may overlap (see Fig. 1). Knowledge of the characteristics of CPPD arthropathy ensures an accurate diagnosis.

        Resnick D. Calcium hydroxyapatite crystal deposition disease. In: Diagnosis of bone and joint disorders. 4th edition. Articular diseases, vol 1. Philadelphia (PA): WB Saunders; 2002. p. 1619–1657.

        ,
        • Zhang W.
        • Doherty M.
        • Bardin T.
        • et al.
        European League Against Rheumatism recommendations for calcium pyrophosphate deposition. Part I: terminology and diagnosis.
        ,
        • Parperis K.
        • Papachristodoulou E.
        • Kakoullis L.
        • et al.
        Management of calcium pyrophosphate crystal deposition disease: A systematic review.

      Differential Diagnosis

      • Gout (see Fig. 3C)
        • Zhang W.
        • Doherty M.
        • Bardin T.
        • et al.
        European League Against Rheumatism recommendations for calcium pyrophosphate deposition. Part I: terminology and diagnosis.
        ,
        • Towiwat P.
        • Doyle A.J.
        • Gamble G.D.
        • et al.
        Urate crystal deposition and bone erosion in gout: “inside-out” or “outside-in”? A dual-energy computed tomography study.
      • Septic arthritis
      • Charcot arthropathy
      • Synovial osteochondromatosis
      • Degenerative joint disease
      • HADD

      Calcium hydroxyapatite crystal deposition disease

      Introduction

      Deposition of calcium HA crystals is predominantly periarticular in tendons and bursae but also in ligaments being the source of inflammatory periarthritis, such as bursitis or tendinitis.
      • Resnick D.
      Calcium hydroxyapatite crystal deposition disease.
      HADD is usually monoarticular; the shoulder is most frequently involved, affecting people between the age of 40 and 60 years.
      • Steinbach L.S.
      Calcium pyrophosphate dihydrate and calcium hydroxyapatite crystal deposition disease: imaging perspectives.
      The second most common site is the hip followed by elbow, wrist, hand, and knee, but any joint can be affected, including the cervical and lumbar spine.
      • Jacques T.
      • Paul M.
      • Badr S.
      • et al.
      Conventional radiology in crystal arthritis gout, calcium pyrophosphate deposition, and basic calcium phosphate crystals.
      ,
      • Reijnierse M.
      Radiographic/MR imaging correlation of paravertebral ossifications in ligaments and bony vertebral outgrowths: anatomy, early detection, and clinical impact.
      Intraarticular depositions can lead to arthritis or destructive arthropathy
      • Halverson P.B.
      • Carrera G.F.
      • McCarty D.J.
      Milwaukee shoulder syndrome. Fifteen additional cases and a description of contributing factors.
      ,
      • McCarthy D.J.
      • Swanson A.B.
      • Ehrhart R.G.
      Haemorraghic rupture of the shoulder.
      (Fig. 4). This arthropathy is more frequent in women in an older age group (50–90 years) and bilateral in 65% of cases.
      • McCarthy D.J.
      • Swanson A.B.
      • Ehrhart R.G.
      Haemorraghic rupture of the shoulder.
      Milwaukee shoulder syndrome is associated with rotator cuff pathology, and arthropathy in other joints, especially the knee, is reported, typically unicompartmental
      • Resnick D.
      Calcium hydroxyapatite crystal deposition disease.
      ,
      • Halverson P.B.
      • Carrera G.F.
      • McCarty D.J.
      Milwaukee shoulder syndrome. Fifteen additional cases and a description of contributing factors.
      (Fig. 5). The differential diagnosis includes CPPD arthropathy, neuropathic arthropathy, and infection.
      Figure thumbnail gr4
      Fig. 4Milwaukee shoulder syndrome. Posttraumatic left shoulder (A) of an 80-year-old woman without fracture and preexisting rotator cuff pathology. After 6 weeks (B) complete destruction of the humeral head and a large soft tissue mass with multiple bony fragments is seen. Axial CT image (C), T1TSE (D), and coronal T2fatsat MR images (E) show complete humeral head destruction with several bony fragments, surrounded by fluid and debris, extending into the subacromial bursa secondary to rotator cuff pathology.
      Figure thumbnail gr5
      Fig. 5Arthropathy of the right knee in same patient as . Intraarticular fluid, valgus deviation, and large lateral tibia plateau impression with demarcated sclerosis A. Multiple intraarticular bony fragments are present A, B.
      The cause and pathogenesis of calcium HA deposition is unknown. Several theories in the past included tendon degeneration, hypoxia, (repetitive) trauma, and aging.
      • Resnick D.
      Calcium hydroxyapatite crystal deposition disease.
      In case of bilateral and polyarticular presence, a genetic, neurologic, or metabolic origin can be considered.
      • Resnick D.
      Calcium hydroxyapatite crystal deposition disease.
      Most calcifications are incidental findings, and other pathology should be excluded before focusing on the calcific deposit as the source of complaints. Calcific tendinitis of the rotator cuff has a reported prevalence of 6.8% to 54% in patients with shoulder pain.
      • Uhthoff H.K.
      • Loehr J.W.
      Calcific tendinopathy of the rotator cuff : pathogenesis, diagnosis and management.
      • Speed C.A.
      • Hazleman B.L.
      Calcific tendinitis of the shoulder.
      • de Witte P.B.
      • Selten J.W.
      • Navas A.
      • et al.
      Calcific tendinitis of the rotator cuff: a randomized controlled trial of ultrasound-guided needling and lavage versus subacromial corticosteroids.
      It is considered a self-limiting disease with low-grade pain, and treatment is preferably conservative including physical therapy and NSAIDs.
      • de Witte P.B.
      • Selten J.W.
      • Navas A.
      • et al.
      Calcific tendinitis of the rotator cuff: a randomized controlled trial of ultrasound-guided needling and lavage versus subacromial corticosteroids.
      However, symptoms can be severe and long-lasting, and several treatments have been initiated including subacromial corticosteroid injections, high-energy extracorporeal shock wave therapy, barbotage, and surgery.
      • de Witte P.B.
      • Selten J.W.
      • Navas A.
      • et al.
      Calcific tendinitis of the rotator cuff: a randomized controlled trial of ultrasound-guided needling and lavage versus subacromial corticosteroids.
      ,
      • Louwerens J.K.G.
      • Sierevelt I.
      • Kramer E.T.
      • et al.
      Comparing ultrasound-guided needling combined with a subacromial corticosteroid injection versus high-energy extracorporeal shockwave therapy for calcific tendinitis of the rotator cuff: a randomized controlled trial.
      Barbotage and subacromial injections are among the most frequently applied treatments in calcific tendinitis of the rotator cuff.
      • Serafini G.
      • Sconfienza L.M.
      • Lacelli F.
      • et al.
      Rotator cuff calcific tendonitis: short-term and 10-year outcomes after two-needle us-guided percutaneous treatment-nonrandomized controlled trial.
      ,
      • de Witte P.B.
      • Kolk A.
      • Overes F.
      • et al.
      Rotator cuff calcific tendinitis: ultrasound-guided needling and lavage versus subacromial corticosteroids: five-year outcomes of a randomized controlled trial.

      Imaging Findings and Pathology

      • Radiographs
      Three stages of calcific deposits have been described: a formative, resting, and resorptive phase.
      • Uhthoff H.K.
      • Loehr J.W.
      Calcific tendinopathy of the rotator cuff : pathogenesis, diagnosis and management.
      ,
      • Speed C.A.
      • Hazleman B.L.
      Calcific tendinitis of the shoulder.
      Different types of calcific deposits can be classified according to Gärtner and correlated to these different phases.
      • Gärtners J.
      • Simons B.
      Analysis of calcific deposits in calcifying tendinitis.
      • Type I calcifications have a sharp border and a dense structure
      • Type II calcifications either have a sharp border and inhomogeneous structure or a vague border and a homogenous structure
      • Type III calcifications have a vague border, and are more or less transparent, with a cloudy appearance.
      In the phase of resorption, calcifications can migrate into the soft tissues: the tendon, bursa, joint, but also the bone. On radiographs faint small calcifications can be appreciated in the area of the bursa (Fig. 6). This chemical bursitis can be extremely painful and important to recognize. A calcification can also migrate into the bone, leading to cortical erosions (Fig. 7). In the resorptive phase the radiograph might not show calcific deposits, and other imaging modalities such as ultrasound and MR imaging might be of help.
      • Reijnierse M.
      Radiographic/MR imaging correlation of paravertebral ossifications in ligaments and bony vertebral outgrowths: anatomy, early detection, and clinical impact.
      • Ultrasonography
      Figure thumbnail gr6
      Fig. 6Large unsharply defined calcification (type II) in the supraspinatus tendon (A). Two days after barbotage the patient presented with severe shoulder pain. The calcification (B) shows resorption and fragmentation on ultrasound present in SSP tendon (C) and bursa (D).
      Figure thumbnail gr7
      Fig. 7Unremarkable radiograph (A). Ultrasound (B) of the supraspinatus insertion shows multiple small calcifications and a cortical break with intraosseous extension of calcifications. No bursitis. Coronal T1TSE (C) and T2fatsat MR images (D) show SSP enthesitis and several subchondral cysts and extensive bone marrow edema at the footprint.
      On US the calcifications will have a different appearance based on their content. A dense type I calcification will show acoustic shadowing, whereas a type II can be more clearly visualized with a hyperechoic margin (Fig. 8A). During a barbotage procedure the calcific deposit can show a change in echogenicity because crystals are washed out (Fig. 8D, E) and the posterior border can become visible.
      Figure thumbnail gr8
      Fig. 8Large subscapularis calcification with a hyperechoic demarcated rim and less hyperechoic content, surrounding hyperemia in longitudinal (left) and axial view (right) (A). Bursal injection of 1cc corticosteroid (40 mg/ml) and 4cc bupivacaine 5 mg/ml (B, C). Lavage of the calcification (D), with hypoechoic saline (E).
      US can visualize radiographic undetected calcifications because of size or density and determine their exact location (see Fig. 6). In addition, US-Doppler will show inflammation in bursae, tendons and joints (see Fig. 8A). Moreover, US is the ideal tool for an accurate bursal injection and barbotage procedure (Fig. 8; Figs. 9 and 10).
      Figure thumbnail gr9
      Fig. 9Anteroposterior and axial views of the right shoulder, before (A, B), after (C, D), and 6 weks after barbotage (E, F). The large calcification in the subscapularis tendon has decreased in size.
      Figure thumbnail gr10
      Fig. 10Syringe with saline and calcific deposits layered at the bottom (A). Dried amorphous white calcifications (B).
      Barbotage treatment is invasive, needs coordinating skills, and is time consuming. It can be painful during and after the intervention but is reported to accelerate the natural course of HADD in randomized controlled trials.
      • de Witte P.B.
      • Selten J.W.
      • Navas A.
      • et al.
      Calcific tendinitis of the rotator cuff: a randomized controlled trial of ultrasound-guided needling and lavage versus subacromial corticosteroids.
      ,
      • Serafini G.
      • Sconfienza L.M.
      • Lacelli F.
      • et al.
      Rotator cuff calcific tendonitis: short-term and 10-year outcomes after two-needle us-guided percutaneous treatment-nonrandomized controlled trial.
      ,
      • de Witte P.B.
      • Kolk A.
      • Overes F.
      • et al.
      Rotator cuff calcific tendinitis: ultrasound-guided needling and lavage versus subacromial corticosteroids: five-year outcomes of a randomized controlled trial.
      • CT and MR imaging are less frequently used in HADD
      However, in unclear diagnosis these modalities might be of help: CT in detecting small calcifications, intraosseous erosion, and for example, evaluation of deposits in the spine. On MR imaging calcifications are less evident; however, soft tissue involvement and bone marrow edema can be detected (see Fig. 7).
      • Reijnierse M.
      Radiographic/MR imaging correlation of paravertebral ossifications in ligaments and bony vertebral outgrowths: anatomy, early detection, and clinical impact.
      ,
      • Malghem J.
      • Omoumi P.
      • Lecouvet F.
      • et al.
      Intraosseous migration of tendinous calcifications: cortical erosions, subcortical migration and extensive intramedullary diffusion, a SIMS series.

      Gout

      Introduction

      With a prevalence of approximately 1% to 7%, gout has become a major cause for musculoskeletal pain and arthritis.

      Resnick D. Gouty arthritis. In: Diagnosis of bone and joint disorders. 4th edition. Articular diseases, vol 1. Philadelphia (PA): WB Saunders; 2002. p. 1519–1559.

      • Dehlin M.
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      Global epidemiology of gout: prevalence, incidence and risk factors.
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      Epidemiology of gout: an update.
      Its prevalence and incidence seem to be increasing across the globe, especially in industrialized nations and in male population.
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      • et al.
      The rising incidence of gout and the increasing burden of comorbidities: a population-based study over 20 years.
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      • et al.
      The rising prevalence and incidence of gout in British Columbia, Canada: Population-based trends from 2000 to 2012.
      • Zobbe K.
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      • et al.
      Secular trends in the incidence and prevalence of gout in Denmark from 1995 to 2015: a nationwide register-based study.
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      Contemporary epidemiology of gout in the UK general population.
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      • et al.
      Contemporary Prevalence of Gout and Hyperuricemia in the United States and Decadal Trends: The National Health and Nutrition Examination Survey, 2007-2016.
      Sustained elevation of serum urate levels results in a deposition of monosodium urate (MSU) especially in or around joints, which can lead to formation of tophi and joint damage.
      • Girish G.
      • Melville D.M.
      • Kaeley G.S.
      • et al.
      Imaging 2ppearances in gout.
      MSU deposits may be intratendinous, peritendinous, or at the enthesis as well.
      • de Ávila Fernandes E.
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      • Mitraud S.A.
      • et al.
      Sonographic description and classification of tendinous involvement in relation to tophi in chronic tophaceous gout.
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      • et al.
      Ultrasound scans and dual energy CT identify tendons as preferred anatomical location of MSU crystal depositions in gouty joints.
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      • Risin M.
      • et al.
      Gouty flexor tenosynovitis of the digits: report of three cases.
      • Gerster J.C.
      • Landry M.
      • Rappoport G.
      • et al.
      Enthesopathy and tendinopathy in gout: computed tomographic assessment.
      Peripherally located structures and structures of the lower limbs are especially frequently affected by gout, with a predilection for the first MTP joint; this is classically described as podagra and is reported in up to 80% of untreated patients.
      • Perez-Ruiz F.
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      • Chinchilla S.P.
      • et al.
      Clinical manifestations and diagnosis of gout.
      A recent survey showed that gout presented with single joint involvement in more than 90% of patients, whereas fewer than 1% of patients presented with gout affecting more than 4 joints.
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      • Lancrenon S.
      • Lanz S.
      • et al.
      GOSPEL: prospective survey of gout in France. Part I: design and patient characteristics (n = 1003).
      Clinical presentation typically consists of recurrent episodes of acute arthritis with a rapid onset of severe pain, swelling, and erythema. Gout further has a strong association with cardiovascular diseases.
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      • Widmann G.
      • et al.
      Ultrasonography and dual-energy computed tomography: impact for the detection of gouty deposits.
      Elevation of serum urate levels can have several causes: exogenous, due to excessive intake of purines (eg, meat, seafood, alcohol), or endogenous, for example, cell lysis during chemotherapy or myeloproliferative disorders.
      • Choi H.K.
      • Atkinson K.
      • Karlson E.W.
      • et al.
      Purine-rich foods, dairy and protein intake, and the risk of gout in men.
      Insufficient uric acid clearance also plays a major role in the development of elevated serum urate, either from chronic kidney disease, drug interactions, or genetic predispositions.
      • Jacques T.
      • Michelin P.
      • Badr S.
      • et al.
      Conventional radiology in crystal arthritis: Gout, calcium pyrophosphate deposition, and basic calcium phosphate crystals.
      Demonstrating MSU crystals in joint fluid or in a tophus by puncture with polarizing microscopy is still the gold standard for the diagnosis of gout
      • McQueen F.M.
      • Chhana A.
      • Dalbeth N.
      Mechanisms of joint damage in gout: evidence from cellular and imaging studies.
      (Fig. 11). However, this is invasive with potential contraindications, leading to the increasing role of US and dual-energy computed tomography (DECT) in gout detection.
      • Klauser A.S.
      • Gruber J.
      Response to: "Monosodium urate crystal deposition associated with the progress of radiographic grade at the sacroiliac joint in axial SpA: a dual-energy CT study.
      • Finkenstaedt T.
      • Manoliou A.
      • Toniolo M.
      • et al.
      Gouty arthritis: the diagnostic and therapeutic impact of dual-energy CT.
      • Bongartz T.
      • Glazebrook K.N.
      • Kavros S.J.
      • et al.
      Dual-energy CT for the diagnosis of gout: an accuracy and diagnostic yield study.
      Both US and DECT are included in the new 2020 American College of Rheumatology classification criteria, along with radiographs, elevated serum urate levels, clinical evidence of tophus, and MSU crystals in synovial fluid.
      Figure thumbnail gr11
      Fig. 11Needle-shaped crystals of monosodium urate (A), showing strongly birefringent crystals on polarization (B) Zeiss Axioskop and Leica DM2000 light microscope: 400x enlargement.

      Imaging Findings

      • Radiography
      Radiographs are indicated to search for imaging evidence of MSU crystal deposition but have limited value for the diagnosis of gout flare. The radiographic changes take several years to develop, thus helpful in supporting diagnosis of chronic gout. In patients with 4 years duration of disease, sensitivity and specificity for erosions were 0.12 and 0.96.
      • Richette P.
      • Doherty M.
      • Pascual E.
      • et al.
      2018 updated European League Against Rheumatism evidence-based recommendations for the diagnosis of gout.
      Radiographic manifestations are classified into early, intermediate, and late stage.
      • Early findings are nonspecific soft-tissue swelling in the affected joint secondary to synovitis, capsular distension, and periarticular soft tissue edema. Fine lacy periosteal reaction may be observed secondary to urate crystals in adjacent soft tissue.
      • Intermediate-stage features include faint calcification of affected soft tissues, intracortical erosions and irregularity, and osteochondral compression or cupping. The joint space is preserved until late in the disease.
      • Late stage is characterized by well-defined juxta-articular erosions with sclerotic rims and overhanging margins. Progressive erosions and intraarticular deposits may result in tapering deformities of the shafts, subluxation, and mutilating arthritis. Progressive joint space narrowing with secondary degenerative changes is a late manifestation. Rarely, ankylosis may occur. Appositional bone deposition may cause apparent expansion of bone ends with a bulbous appearance.
        • Bloch C.
        • Hermann G.
        • Yu T.F.
        A radiologic reevaluation of gout: a study of 2,000 patients.
        ,
        • Dhanda S.
        • Jagmohan P.
        • Quek S.T.
        A re-look at an old disease: a multimodality review on gout.
        • Ultrasonography
      US is an ideal first-line examination technique for suspected gout. MSU deposits can have several different appearances, including the “double contour sign” (DC-sign), “snow storm sign,” and delineation of tophi.
      • Taljanovic M.S.
      • Melville D.M.
      • Gimber L.H.
      • et al.
      High-Resolution US of Rheumatologic Diseases.
      • DC-sign
      An abnormal hyperechoic band over the superficial margin on the hypoechoic articular hyaline cartilage, which may be homogeneous or inhomogeneous, irregular or regular, and continuous or intermittent. There may be posterior acoustic shadowing, depending on both the amount and density of the MSU deposits.
      • Filippucci E.
      • Di Geso L.
      • Grassi W.
      Tips and tricks to recognize microcrystalline arthritis.
      The thickness of the DC sign should be similar to the cortex; however, in early stages it may be thinner (Fig. 12A, B ).
      • Snow-storm sign and tophi: hyperechoic microtophi appearing as white spots within the fluid collection generate the typical snow storm appearance. Larger, dense aggregates develop into hypoechoic to hyperechoic (mainly chronic tophi) inhomogeneous tophi, with a cloudy appearance and a hypoechoic or anechoic rim
        • Bruyn G.A.
        • Iagnocco A.
        • Naredo E.
        • et al.
        OMERACT Definitions for ultrasonographic pathologies and elementary lesions of rheumatic disorders 15 Years On.
        ,
        • de Ávila Fernandes E.
        • Kubota E.S.
        • Sandim G.B.
        • et al.
        Ultrasound features of tophi in chronic tophaceous gout.
        (Fig. 13).
        Figure thumbnail gr13
        Fig. 13Large gout tophus at the level of the Achilles tendon insertion on lateral radiograph of the right ankle (A). Longitudinal ultrasound (B) shows an inhomogeneous hyperechoic mass with a surrounding hypoechoic rim, without hyperemia (C).
      Figure thumbnail gr12
      Fig. 12(A) Double contour (DC) sign (arrows) in an axial US scan of the knee in a patient with gouty arthritis, with a hyperechoic band over the articular cartilage (hypoechoic) of the condyles. (B) DC sign in a sagittal US scan of an MCP joint with surrounding hypervascularization.
      Although those appearances are very specific for gout, data regarding specificity and sensitivity are highly variable depending the examined region. Although regions that can be easily assessed by US such as the MTP1 joint show great data, regions such as the hand and wrist show poor gout detection, as these joints are less accessible. In these joints US showed a sensitivity of 70.1% (extraarticular: 42.5%, P < .001; intraarticular: 80.3%, P = .14) and a specificity of 51%.
      • Klauser A.S.
      • Halpern E.J.
      • Strobl S.
      • et al.
      Gout of hand and wrist: the value of US as compared with DECT.
      • MR Imaging
      On MR imaging, tophi can be seen as amorphous or nodular regions of low-intensity signal on T1-weighted images, variable intensity on T2-weighted images and with variable enhancement after intravenous contrast media. Other MR imaging features of gout are synovial pannus, joint effusions, and soft-tissue edema.
      • Poh Y.J.
      • Dalbeth N.
      • Doyle A.
      • et al.
      Magnetic resonance imaging bone edema is not a major feature of gout unless there is concomitant osteomyelitis: 10-year findings from a high-prevalence population.
      ,
      • Cimmino M.A.
      • Zampogna G.
      • Parodi M.
      • et al.
      MRI synovitis and bone lesions are common in acute gouty arthritis of the wrist even during the first attack.
      A particular advantage of MR imaging is the ability to assess bone involvement in detail, being more sensitive than both CT and US in detecting bone erosion in patients with gout. A main disadvantage is that MSU crystals cannot be directly observed by MR imaging, leading to poor specificity
      • Dalbeth N.
      • Doyle A.J.
      Imaging of gout: an overview.
      (Fig. 14).
      • Dual-energy Computed Tomography
      Figure thumbnail gr14
      Fig. 14Left foot dorsoplantar (A) and ¾ view (B) show erosive destruction in the tarsus and MTP joints. Sagittal MR images, T1TSE (C), T2TSE fatsat (D), and T1TSE fatsat after intravenous contrast (E) show multiple sharply delineated erosions in the tarsal bones. The moderately high T2 content shows a peripheral zone of enhancement. Absence of intraosseous edema. DECT, 3D-formatted (F), axial subtracted images in bone (G) and soft tissue (H) setting. Color-coded green MSU deposits in the erosions. 3D, 3-dimensional.
      The unique chemical composition of uric acid precipitates results in a distinct radiographic attenuation when compared with other materials, and this results in characteristic patterns of CT numbers at high versus low kilovolts (kV), allowing imaging software to differentiate MSU from other materials.
      • Bongartz T.
      • Glazebrook K.N.
      • Kavros S.J.
      • et al.
      Dual-energy CT for the diagnosis of gout: an accuracy and diagnostic yield study.
      ,
      • Johnson T.R.
      • Krauss B.
      • Sedlmair M.
      • et al.
      Material differentiation by dual energy CT: initial experience.
      The effectiveness of noncontrast DECT has been proved in several studies,
      • Finkenstaedt T.
      • Manoliou A.
      • Toniolo M.
      • et al.
      Gouty arthritis: the diagnostic and therapeutic impact of dual-energy CT.
      ,
      • Klauser A.S.
      • Halpern E.J.
      • Strobl S.
      • et al.
      Gout of hand and wrist: the value of US as compared with DECT.
      ,
      • Hu H.J.
      • Liao M.Y.
      • Xu L.Y.
      Clinical utility of dual-energy CT for gout diagnosis.
      • Choi H.K.
      • Al-Arfaj A.M.
      • Eftekhari A.
      • et al.
      Dual energy computed tomography in tophaceous gout.
      • Glazebrook K.N.
      • Guimarães L.S.
      • Murthy N.S.
      • et al.
      Identification of intraarticular and periarticular uric acid crystals with dual-energy CT: initial evaluation.
      • Strobl S.
      • Halpern E.J.
      • Ellah M.A.
      • et al.
      Acute gouty knee arthritis: ultrasound findings compared with dual-energy CT findings.
      • Teh J.
      • McQueen F.
      • Eshed I.
      • et al.
      Advanced imaging in the diagnosis of gout and other crystal arthropathies.
      and DECT is increasingly being used for the diagnosis and follow-up of gout, with a reported sensitivity of 78% to 100% and specificity of 89% to 100%
      • Dalbeth N.
      • Choi H.K.
      Dual-energy computed tomography for gout diagnosis and management.
      (Fig. 15). DECT scanning is rapid and noninvasive and enables multiple joints to be imaged on a single scan without the use of contrast agents.
      • Wang P.
      • Smith S.E.
      • Garg R.
      • et al.
      Identification of monosodium urate crystal deposits in patients with asymptomatic hyperuricemia using dual-energy CT.
      Data are acquired at 80 and 140 kV with a plot of the attenuation of each voxel at 80 kV (y-axis) against attenuation at 140 kV (x-axis). The pixels containing calcium and monosodium urate can be separated and presented as a color image for easy identification. Although the color coding can vary across manufacturers, the most common software color codes are green for MSU deposits, lavender for cortical bone, and pink for trabecular bone. These color-coded images are displayed as an overlay on either 2-dimensional conventional gray-scale CT images or as 3-dimensional volume-rendered images
      • Garner H.W.
      • Wessell D.E.
      Gout: update on dual-energy computed tomography with emphasis on artifact identification.
      (see Figs. 14 and 15; Fig. 16). DECT can therefore provide color-coded information about the composition of certain materials, including urate, calcium pyrophosphate (CPPD), and hydroxyapatite (HADD). Mallinson and colleagues concluded that nail bed deposits, submillimeter deposits, skin deposits, and deposits obscured by motion, beam hardening, and vascular artifacts should not be classified as positive findings, and they are especially dependent on the postprocessing protocols used.
      • Mallinson P.I.
      • Coupal T.
      • Reisinger C.
      • et al.
      Artifacts in dual-energy CT gout protocol: a review of 50 suspected cases with an artifact identification guide.
      Park and colleagues concluded that setting the minimum attenuation to a higher value of 150 Hounsfield units in their study reduced the frequency of artifacts and that adding a tin filter to DECT greatly reduced their occurrence.
      • Park E.H.
      • Yoo W.H.
      • Song Y.S.
      • et al.
      Not all green is tophi: the importance of optimizing minimum attenuation and using a tin filter to minimize clumpy artifacts on foot and ankle dual-energy CT.
      A prospective blinded randomized study by Choi and colleagues
      • Choi H.K.
      • Burns L.C.
      • Shojania K.
      • et al.
      Dual energy CT in gout: a prospective validation study.
      showed 84% sensitivity and 93% specificity for detection of MSU deposits by DECT in the lower extremities, as well as wrists and hands. The role of DECT has also been shown by Hu and colleagues
      • Hu H.J.
      • Liao M.Y.
      • Xu L.Y.
      Clinical utility of dual-energy CT for gout diagnosis.
      reporting a high sensitivity and specificity of 75.2% and 92.7% of DECT for the detection of gouty arthritis in upper and lower extremities. In recent studies a modified postprocessing protocol with lowering of the threshold of attenuation from 150 HU to 120 HU and keeping the kilovoltage settings constant showed promising results.
      • Klauser A.S.
      • Halpern E.J.
      • Strobl S.
      • et al.
      Gout of hand and wrist: the value of US as compared with DECT.
      ,
      • Strobl S.
      • Halpern E.J.
      • Ellah M.A.
      • et al.
      Acute gouty knee arthritis: ultrasound findings compared with dual-energy CT findings.
      ,
      • Strobl S.
      • Kremser C.
      • Taljanovic M.
      • et al.
      Impact of Dual-Energy CT postprocessing protocol for the detection of gouty arthritis and quantification of tophi in patients presenting with podagra: comparison with ultrasound.
      DECT may also demonstrate cardiovascular MSU deposits, which might have implications for patients who are at risk of cardiovascular disease.
      • Klauser A.S.
      • Halpern E.J.
      • Strobl S.
      • et al.
      Dual-energy computed tomography detection of cardiovascular monosodium urate deposits in patients with gout.
      ,
      • Feuchtner G.M.
      • Plank F.
      • Beyer C.
      • et al.
      Monosodium urate crystal deposition in coronary artery plaque by 128-slice dual-energy computed tomography: an ex vivo phantom and in vivo study.
      Figure thumbnail gr15
      Fig. 15MSU deposits in a 3D reconstructed DECT of the knee, showing color-coded green MSU deposit in the lateral condyle.
      Figure thumbnail gr16
      Fig. 16Coronal DECT of the hand shows color-coded green MSU deposits in the second MCP joint, as well as in the lateral aspect of the os triquetrum.

      Summary

      Crystal arthropathies are a group of joint disorders due to deposition of crystals in and around joints, which lead to joint destruction and soft tissue masses. Clinical presentation is variable and diagnosis might be challenging. Therefore, first-line imaging of ultrasound in accessible joints is recommended to assess crystal arthropathies; however, DECT is a useful adjunct to differentiate gout from CPPD.

      Clinics care points

      • Aging is the main risk factor for CPPD crystal deposition disease.
      • CPP crystals almost exclusively deposit into articular fibrocartilage and hyaline cartilage, the most common cause of chondrocalcinosis.
      • Calcifications need to be part of the radiological report, as they may become symptomatic.
      • Absence of crystal deposit detection on radiographs does not exclude the diagnosis of CPPD, gout, or HADD.
      • Rapid joint destruction without visible calcifications should raise the diagnosis of CPPD.
      • Barbotage is an effective method to accelerate the natural course of HADD.

      Disclosure

      The authors have nothing to disclose.

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