Clinical History: A 48 year-old female presents with pain in the left shoulder with reduced range of motion. (1a) A coronal oblique T2-weighted fat-suppressed image and (1b) an axial T2-weighted image are provided. What are the findings? What is the diagnosis?
Hydroxyapatite deposition disease (HADD), with calcium hydroxyapatite crystal deposition along the bursal surface of the supraspinatus tendon.
Hydroxyapatite deposition disease (HADD) refers to a spectrum of abnormalities that includes calcific tendinitis, other periarticular hydroxyapatite deposition, and hydroxyapatite induced arthritis.1,2 Other names for HADD include calcific tendinosis, peritendinitis calcarea, calcific peritendinitis and bursitis, and hydroxyapatite rheumatism.3 Calcium hydroxyapatite (CHA) is the most common type of calcium in human bone and is also the most common pathologic calcification found in the body.4 CHA, as well as other basic calcium phosphate crystals, are considered the causal agents in some entities. In other situations, the basic calcium phosphates are considered secondary to underlying diseases. For example, the calcifications associated with severe renal disease, collagen vascular disease (dermatomyositis and scleroderma), chronic neurologic conditions, Vitamin D overload, tumoral calcinosis and dystrophic calcification are composed largely of CHA.4
CHA deposits occur in tendons, peritendinous tissues, bursae, and ligaments. The pathogenesis of periarticular CHA deposits is uncertain and several explanations have been offered. Possible etiologies for CHA deposition include local trauma, ischemia, and necrosis of tendons. CHA deposits in the supraspinatus tendon are typically located in the poorly vascularized critical zone, which is a few millimeters medial to the osseous insertion. CHA deposits in other tendons occur preferentially in hypovascular segments, supporting the hypothesis that local necrosis leads to crystal deposition.3 CHA deposition is a cell-mediated process where tissue changes result in transformation of tendinous tissues into chondrocytes. The CHA crystals are deposited in an extracellular matrix derived from the chondrocytes.5 Metabolic and genetic factors can predispose patients to CHA deposition.4
Laboratory tests are usually negative in patients with HADD. CHA crystals are 75-250 nm, and are not visible with light microscopy, except when the crystals form aggregates. The CHA crystals are non-birefringent in polarized light. Transmission electron microscopy or electron diffraction studies are needed to identify CHA crystals. Alizarin red S stain reportedly is a sensitive but non-specific tool for screening for CHA crystals.6
HADD typically presents in a monoarticular fashion. Most patients are between the ages of 40 and 70 years7 and HADD is rare in children.8 Approximately 50% of patients present with pain, erythema, swelling, and limitation of motion of the affected joint.9 The signs and symptoms of HADD are likely from rupture of a calcific deposit into an adjacent soft tissue space or bursa (4a), resulting in an acute inflammatory reaction. Phagocytosis of CHA crystals leads to the release of lysosomal enzymes and other inflammatory mediators.10,11 This presentation is called acute calcific periarthritis and most commonly involves the shoulder.12,13 HADD can be associated with a fever and can be confused with an infection. Unlike patients with infection, patients with HADD have normal erythrocyte sedimentation rates and leukocyte counts.9
The clinical course of HADD is variable. Although many patients have complete resolution of symptoms, other patients develop chronic pain syndromes. In the shoulder it is difficult to determine what contribution, if any, the CHA deposits themselves make to an individual patient. Some patients with HADD have a pattern of recurrent episodes of acute shoulder pain, followed by pain-free periods of months or years, and subsequently develop chronic pain. These patients seem to be predisposed to full thickness rotator cuff tendon tears.3
Mosely divided HADD into three phases and this classification is commonly referenced.14 According to Mosley, HADD begins with the silent phase where the CHA is completely contained within the tendon. Radiographs will show well defined CHA deposits which represent dry granular or “cheesy” material. In the silent phase, patients have minimal symptoms.
In the second or mechanical phase, enlargement of the deposit occurs followed by impingement-like symptoms which result from CHA deposit enlargement. The deposits liquefy and cause increased intratendinous pressure and bursitis. The CHA deposits become less defined radiographically. The CHA deposits rupture either into or around the adjacent bursa. This phase is characterized clinically by acute painful attacks. On radiographs the CHA deposits disperse into the adjacent bursa or peribursal soft tissues. The CHA deposits frequently disappear on the radiographs but this disappearance may or may not correlate with regression of clinical symptoms.
The third and last phase is called adhesive periarthritis. This is a late stage that presents with general debility, pain, and limited range of motion. In the adhesive periarthritis phase, patients have adhesive bursitis, CHA deposits within the rotator cuff and intraosseous and dumbbell-like CHA deposits.14
Anatomic Sites of Involvement
The shoulder is the most common site of HADD. In one study that examined the prevalence of calcific tendinitis in the general population, 2.7% of study participants had calcified deposits (presumed CHA deposits) in the rotator cuff complex.15 Of these patients, only 34% to 45% had problems that could be associated with the CHA deposits. In this study, women were more often symptomatic than men and disease occurred most commonly between the ages of 31 and 40. The shoulder is said to account for 60% of cases of acute calcific periarthritis.16 HADD can involve any of the components of the rotator cuff complex (5a) and the supraspinatus tendon is most commonly involved. HADD can also involve adjacent tendon structures including the long and short heads of the biceps tendon, the coracobrachialis tendon, the triceps tendon and pectoralis tendon. Subacromial and subdeltoid bursal calcifications appear as a teardrop-shaped radiodense areas below the acromion and deltoid muscle.7
After the shoulder, the hip is the next most common location for HADD. CHA deposits at the hip are most common in the gluteus medius tendon either at the greater trochanter or the acetabulum.17 HADD not uncommonly involves the posterolateral femoral attachment of the gluteus maximus as well.18 Other areas of HADD involvement include the iliopsoas tendon insertion at the lesser trochanter, and the ischial origins of the common hamstring tendons.7
At the elbow, HADD can affect the flexor and extensor tendon complexes at the epicondylar origins. HADD can also occur in the medial and lateral collateral ligamentous complexes. As would be expected, HADD may involve the regional tendon groups of the elbow, including the triceps, brachialis, and biceps tendons.19 The bursa around the elbow can also be involved with HADD.20
HADD can involve the tendons and ligaments of the wrist and hand. The wrist is more commonly affected than the hand.21 The pisiform insertion site of the flexor carpi ulnaris tendon is reportedly the most common site of involvement in the wrist.22 In the hand, HADD involvement of the metacarpophalangeal and interphalangeal regions is not uncommon.
In the knee, HADD tends to occur near tendon attachments rather than other periarticular structures. The CHA deposits are usually next to the femoral condyles (6a), fibular head, and prepatellar region.23 HADD can also involve other sites around the knee including the popliteus tendon and lateral collateral ligament.24,25
In the ankle and foot, HADD can involve multiple structures.26 Sites of involvement include the flexor hallucis longus and brevis and the peroneus muscles. Fam described a presentation of HADD that involves the metatarsophalangeal joints. This has been coined ?hydroxyapatite pseudopodagra?, and occurs predominantly in young women.12
No discussion of HADD would be complete without mentioning involvement of the longus coli muscle and tendon. In this location patients present with severe pain in the neck and throat that increases with swallowing and movement. Typically the CHA deposition is anterior to C2 and is associated with soft tissue swelling.27
HADD presenting with intra-articular deposition
Uncommonly, HADD can present with intra-articular deposition of crystals, producing an acute and sometimes destructive arthritis. This arthropathy has been given various names including chronic apatite arthropathy, apatite-associated destructive arthropathy, idiopathic destructive arthropathy and Milwaukee Shoulder Syndrome (MSS).7 It is not known whether MSS is caused by HADD, but some authorities believe that there is an association.28 MSS is usually seen in female patients in their seventies.7 It has a predilection for large joints, and although shoulder involvement is most common, other joints including the elbows, hips, and knees can be involved.28 Patients typically present with joint swelling, reduced range of movement, instability and loss of function. Characteristically, patients with MSS have mild pain and little or no evidence of inflammation.7 MSS is associated with rotator cuff tears.29 Joint effusions are common and may be large, extending into the subdeltoid and subacromial regions. The synovial fluid is typically blood tinged and has a low, predominantly mononuclear, cell count. The effusions can rupture leading to a massive extravasation of blood and synovial fluid into the surrounding tissues.30 The natural history has not been carefully studied, but in some patients MSS stabilizes after 1-2 years. In most patients no cause for the MSS has been found but a familial pattern of MSS has been described in a small group of patients.31 With imaging there is accelerated osteoarthritis, osseous destruction, and intra-articular osteochondral bodies. A milky white effusion may be seen on radiographs.7
In the early phases of HADD, calcifications typically present as a thin, poorly defined deposits in tendons, ligaments, bursae, or synovium.7 Rarely, the CHA crystals can deposit within the joint.1 The calcifications subsequently become denser and more homogeneous, with sharper edges. The course of the calcifications is variable. The calcifications may be stable for years or may enlarge, change shape, or disappear.7 Sharply demarcated CHA deposits may be associated with fewer symptoms than ill defined deposits. HADD calcifications are homogenous and amorphous, lacking boney trabeculae seen with heterotopic ossifications or accessory ossifications.4 CHA deposits vary from a few millimeters to several centimeters in size.32 Most HADD calcifications are ovoid but they can be linear or triangular. Tendinous HADD is usually close to the tendon insertion site but infrequently the deposits are well away from the insertion.4 HADD can cause osseous erosions and in some cases the CHA deposits are within the erosions (7a).33
HADD calcifications of the supraspinatus tendon are within 1 cm from the greater tuberosity insertion4 and are best seen with an anteroposterior external rotation view of the shoulder. HADD calcifications of the infraspinatus and teres minor tendons are best seen on internal rotation anteroposterior views. HADD calcifications of the pectoralis major tendon occur along the anterior aspect of the humeral shaft (8a).7
HADD deposits typically present on MR imaging as rounded areas of low signal intensity on all imaging sequences. The deposits are particularly conspicuous on gradient echo imaging. In the acute symptomatic phase of HADD (acute calcific periarthritis), the process has an aggressive appearance with marrow and soft tissue edema that may mimic infection, trauma, or neoplasm.34
Treatment of HADD is symptomatic and most symptoms resolve within 2-3 weeks. Nonsteroidal anti-inflammatory drugs (NSAIDs) are considered the treatment of choice for HADD. Local corticosteroid injections and oral or parenteral steroids have been used for patients who do not respond to or cannot tolerate NSAIDs. Recalcitrant CHA deposits can be removed surgically or with image-guided aspiration.35
The CHA depositions of HADD have a characteristic appearance. Rounded deposits in the anatomic sites favored by HADD without an underlying disorder helps narrow the differential diagnosis. The calcifications of calcium pyrophosphate deposition disease (CPPD) are more linear and diffuse than the calcifications of HADD. Gouty tophi are more faintly calcified and are associated with elevated urate levels, though the MRI appearance of a tophus can be indistinguishable from a deposit of CHA crystals (9a). Heterotopic bone and myositis ossificans have a trabecular pattern, marrow signal, and a cortical rim, findings that are not seen with HADD. As would be expected, smaller CHA deposits of tumoral calcinosis, either primary, idiopathic, or secondary to renal disease (10a,10b), are indistinguishable from HADD. In clinical practice, most patients with tumoral calcinosis have a known diagnosis prior to imaging. Collagen vascular disease such as scleroderma or dermatomyositis can also produce calcifications but the calcifications are widespread, often involve the subcutaneous tissues, and are associated with a known underlying disease. Periarticular calcifications may be seen in association with sarcoidosis, hypervitaminosis D, hypoparathyroidism, and milk-alkali syndrome, but these calcifications typically do not resemble CHA deposits and affected patients typically have known underlying diseases.7 In the acute phase of HADD (acute calcific periarthritis), the soft tissue and marrow edema seen on MR imaging can mimic infection, trauma and tumor. Detection of CHA deposits differentiates HADD from the other diagnoses in such cases.
HADD is a common disorder hallmarked by peri-articular deposition of CHA crystals and an accompanying inflammatory process. Although any joint can be involved, the shoulder is the most commonly affected site. With MR imaging, CHA deposits present as small, oval foci of decreased signal intensity. In the acute symptomatic phase of HADD, called acute calcific periarthritis, soft tissue and osseous edema can be present and needs to be distinguished from infection, tumor and trauma.
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