Crystal Deposition Disorders

BY: MUSTAFA ABBAS FADHIL AL-OBEIDEE LEVEL 4 GROUP A

UNDER SUPERVISION OF: DR.GHAZI ARIKI DR. SAEED AL-DUBAEE DR. ANWAR NAIF

Introduction
The crystal deposition disorders are a group of conditions characterized by the presence of crystals in and around joints, bursae and tendons. Although many different crystals are found, three clinical conditions in particular are associated with this phenomenon: gout calcium pyrophosphate dihydrate (CPPD) deposition disease calcium hydroxyapatite (HA) deposition disorders. Characteristically, in each of the three conditions, crystal deposition has three distinct consequences: (1) it may be totally inert and asymptomatic; (2) it may induce an acute inflammatory reaction; or (3) it may result in slow destruction of the affected tissues.

GOUT
Gout is a disorder of purine metabolism characterized by hyperuricaemia, deposition of monosodium urate monohydrate crystals in joints and peri-articular tissues and recurrent attacks of acute synovitis. Late changes include cartilage degeneration, renal dysfunction and uric acid urolithiasis. Although the risk of developing clinical features of gout increases with increasing levels of serum uric acid, only a fraction of those with hyperuricaemia develop symptoms. However, hyperuricaemia and gout are generally regarded as part and parcel of the same disorder.

GOUT: Epidemiology
The prevalence of symptomatic gout varies from 1 to over 10 per 1000, depending on the race, sex and age of the population studied: it is much commoner in Caucasian than in Negroid peoples; it is more widespread in men than in women (the ratio may be as high as 20:1); and it is rarely seen before the menopause in females. It also corresponds with serum creatinine /BUN levels, body weight, height, age,

blood pressure, and alcohol intake.

Body bulk (as estimated by body weight, surface area, or body mass index) has proved to be one of the most important predictors of hyperuricemia in people of widely differing races and cultures.
The prevalence of asymptomatic hyperuricemia is 5 to 8%. Peak incidence in men is in the fifth decade. 90% of patients with primary gout are men. Women rarely develop gout before the menopause, because estrogens are thought to be uricosuric.

GOUT :Pathology
Nucleic acid and purine metabolism normally proceeds, through complex pathways, to the production of hypoxanthine and xanthine; the final breakdown to uric acid is catalysed by the enzyme xanthine oxidase. Monosodium urate appears in ionic form in all the body fluids; about 70 per cent is derived from endogenous purine metabolism and 30 per cent from purine-rich foods in the diet. It is excreted (as uric acid) mainly by the kidneys and partly in the gut. Urate is poorly soluble, with a plasma saturation value of only 7 mg/dL (0.42 mmol/L). This concentration is commonly exceeded in normal individuals and epidemiological studies have identified entire populations (for example the Maoris of New Zealand) who have unusually high levels of serum uric acid. The term hyperuricaemia is therefore generally reserved for individuals with a serum urate concentrationbwhich is significantly higher than that of the population to which they belong (more than two standard deviations above the mean); this is about 0.42 mmol/L for men and 0.35 mmol/L for womenin western Caucasian peoples. By this definition, about 5 per cent of men and less than 1 per cent of women have hyperuricaemia; the majority suffer no pathological consequences and they remain asymptomatic throughout life.

Excretion of Uric Acid

Mechanisms of urate excretion
kidney (~66%) Gut (~33%)

Renal Excretion of Uric Acid

- Completely filtered by the glomerulus - Completely (essentially) reabsorbed in the proximal tubule - Approximately 50% is secreted back into the tubule in the descending loop - Approximately 80% (of the 50% now in the loop) is reabsorbed in the ascending loop - Net excretion = 10% of filtered load

GOUT : Pathophysiology
- Hyperuricemia is the common denominator in gout. - Two-thirds of uric acid are excreted by the kidney and the rest in the GI tract. - 90% of cases of gout are secondary to under-excretion. - Overproduction is secondary to defects in the HGPRT or PRPP. Urate crystals are deposited in minute clumps in connective tissue, including articular cartilage; the commonest sites are the small joints of the hands and feet. For months, perhaps years, they remain inert. Then, possibly as a result of local trauma, the needlelike crystals are dispersed into the joint and the surrounding tissues where they excite an acute inflammatory reaction. Individual crystals may be phagocytosed by synovial cells and polymorphs or may float free in the synovial fluid. With the passage of time, urate deposits may build up in joints, peri-articular tissues, tendons and bursae; common sites are around the metatarsophalangeal joints of the big toes, the Achilles tendons, the olecranon bursae and the pinnae of the ears. These clumps of chalky material, or tophi (L. tophus = porous stone), vary in size from less than 1 mm to several centimetres in diameter. They may ulcerate through the skin or destroy cartilage and peri-articular bone.

Acute gout spasm: the inflammation is usually monoarticular, e.g., metatarsophalangeal joint (podagra), less frequently present on feet, ankles, and knees.

Tophaceous gout affecting the hands

This is the typical gouty type, with his rubicund face, large olecranon bursae and small subcutaneous tophi over the elbows.

Gouty Tophi in the Helix of the Ear

Factors predisposing to hyperuricaemia

- Older age, male gender - Genetic enzyme defects, hyperparathyroidism - Haemolytic disorders, myeloproliferative disorders - Obesity, diabetes, hypertension - High consumption of red meat, hyperlipidaemia - Chronic inflammatory diseases - Long-term use of aspirin or diuretics - Alcohol abuse

GOUT : Classification
Gout is often classified into primary and secondary forms. Primary gout (95 per cent) occurs in the absence of any obvious cause and may be due to constitutional under-excretion (the vast majority) or overproduction of urate. Secondary gout (5 per cent) results from prolonged hyperuricaemia due to acquired disorders such as myeloproliferative diseases, administration of diuretics or renal failure. This division is somewhat artificial; people with an initial tendency to primary hyperuricaemia may develop gout only when secondary factors are introduced for example obesity, alcohol abuse, or treatment with diuretics or salicylates which increase tubular reabsorption of uric acid.

Causes of decreased renal excretion of URATE

Primary
- Idiopathic - Familial juvenile gouty nephropathy

Secondary
- Hypertension - Hyperparathyroidism - Myxoedema - Downs syndrome - Increased level of organic level - Lead nephropathy - Sarcoidosis - Bartters syndrome - Beryllium poisoning - Drug: diuretics, B-blocker, ACEI, salicylates (low dose), PEA, EMB, cyclosporin, nicotinic acid - Chronic renal failure - Volume depletion

Causes of increased uric acid production

Primary
- Idiopathic - HPRT deficiency - PPRT overactivity - Ribose-5-phosphate overproduction - AMP-deaminase deficiency

Secondary
- Glycogen storage disease type II (G6PD), type III, V, VII - Hereditary fructose intolerance - Lymphoproliferative and myeloproliferative diseases ( leukemia, Hodgkins dz, lymphosarcoma, myeloma, PV, Waldenstroms macroglobulinemia ) - Cytotoxic drugs - Carcinomatosis - Gauchers disease - Chronic hemolytic anemia - Severe exfoliative psoriasis

GOUT : Clinical features

Patients are usually men over the age of 30 years; women are seldom affected until after the menopause. Often there is a family history of gout. The gouty stereotype is obese, rubicund, hypertensive and fond of alcohol. However, many patients have none of these attributes and some are nudged into an attack by the uncontrolled administration of diuretics or aspirin.

GOUT : THE ACUTE ATTACK

The sudden onset of severe joint pain which lasts for a week or two before resolving completely is typical of acute gout. The attack usually comes out of the blue but may be precipitated by minor local trauma, operation, intercurrent illness, unaccustomed exercise or alcohol consumption. The commonest sites are the metatarsophalangeal joint of the big toe, the ankle and finger joints, and the olecranon bursa. Occasionally, more than one site is involved.

The skin looks red and shiny and there is considerable swelling. The joint feels hot and extremely tender, suggesting a cellulitis or septic arthritis. Sometimes the only feature is acute pain and tenderness in the heel or the sole.
Hyperuricaemia is present at some stage, though not necessarily during an acute attack. However, while a low serum uric acid makes gout unlikely, hyperuricaemia is not diagnostic and is often seen in normal middle-aged men. The true diagnosis can be established beyond doubt by finding the characteristic negatively birefringent urate crystals in the synovial fluid. A drop of fluid on a glass slide is examined by polarizing microscopy. Crystals may be sparse but if the fluid specimen is centrifuged a concentrated pellet may be obtained for examination.

CHRONIC GOUT
Recurrent acute attacks may eventually merge into polyarticular gout. Joint erosion causes chronic pain, stiffness and deformity; if the finger joints are affected, this may be mistaken for rheumatoid arthritis. Tophi may appear around joints over the olecranon, in the pinna of the ear and less frequently in almost any other tissue. A large tophus can ulcerate through the skin and discharge its chalky material. Renal lesions include calculi, due to uric acid precipitation in the urine, and parenchymal disease due to deposition of monosodium urate from the blood.

Diagnosis
Clinical :
In men , initial attack monoarticular 1st MTP joint(50% of cases) Other jts involved instep/knees/wrists/ olecranon bursa. Often begins at night. Usually abrupt , severely painful. Later attacks polyarticular , associated with systemic signs., most often initial presenting complaint in women. (hands/tarsal jts/knees) Precipitants Minor trauma , ethanol, diuretics , Surgery, severe medical illness, hypouricemic drugs. Tophi Classically , helix/ antihelix ,but rare ; more common , hands, feet, olecranon bursa. Complications : ulceration/infection.

Laboratory:- GOLD STANDARD

Synovial Fluid Analysis WBC count 2000-100 000/ml MSU crystals- needle shaped , negatively birefringent. Serum Uric acid level important in monitoring treatment .(42% - normal levels) 24 hr uric acid collection useful in young patients with gout/ + family history

Diagnosis : CONT.
X-rays During the acute attack x-rays show only soft-tissue swelling. Chronic gout may result in joint space narrowing and secondary osteoarthritis. Tophi appear as characteristic punched-out cysts or deep erosions in the para-articular bone ends; these excavations are larger and slightly further from the joint margin than the typical rheumatoid erosions. Occasionally, bone destruction is more marked and may resemble neoplastic disease. Radiographic Hallmarks of Gout - Overhanging edges - Punched out lesions with sclerotic borders. - Preservation of joint space (till late) - Degenerative changes

American College of Rheumatology (ACR) Diagnostic Criteria Of Gout

Criteria for a definitive gout diagnosis from the American College of Rheumatology (ACR) are as follows: A. Presence of characteristic urate crystals in the joint fluid, or B. Presence of a tophus proven to contain urate crystals by chemical means or polarized light microscopy, or C. Presence of six of the following clinical, laboratory, and radiographic phenomena: 1- More than one attack of acute arthritis. 2- Development of maximal inflammation within 1 day. 3- Attack of monarticular arthritis. 4- Observation of joint redness. 5- Pain or swelling in first metatarsophalangeal joint. 6- Unilateral attack involving first metatarsophalangeal joint. 7- Unilateral attack involving tarsal joint. 8- Suspected tophus. 9- Hyperuricemia. 10- Asymmetric swelling within a joint on x-ray. 11- Subcortical cysts without erosions on x-ray. 12- Negative culture of joint fluid for microorganisms during attack of joint inflammation.

Exacerbation of a chronic gout process in the hand: the fingers are deformed, the joints of the phalanges are swollen, with tight, hot, and dark-red skin, frequently accompanied by some general symptoms (fever, higher sedimentation rate, increased number of white blood cells) (a). The radiograph of the same patient presents the characteristics of chronic gouty arthropathy, narrowed joint spaces, and typical punched-out periarticular lytic lesions (b)

Late stage of gout: numerous subcutaneous tophi are present in the palmar region (a). These tophaceus gouty deposits are also visible in the radiograph around the small joints of the hand (b)

Deposits of urate crystals may occur in the synovium (a) and in the cartilage of the knee joint (b) as visualized by arthroscopy

Bursitis olecrani due to the massive tophaceus deposit of urate crystals

Acute gout spasm of the left knee

The intraoperative picture demonstrates the encapsulated yellow chalky mass of gouty tophi (a). The cut surface of a gouty tophus (b)

Gout x-rays

The typical picture is of large periarticular excavations tophi consisting of uric acid deposits. Arthropathy of the left ankle joint in a patient suffering from gout for a long time. Note the narrowed joint space and the deposits around the joint, visible on the radiograph

Gout x-rays

Late stage of gout with extensive destruction of the elbow joint and tophaceus gouty deposits around it are demonstrated on the anteriorposterior(a) and lateral (b) radiographs

Sodium urate crystal image

Sodium urate crystal image on polarization The electron microscope image of sodium microscope: characteristic negative double urate crystals (magnifi cation: 6,600). refraction

Differential diagnosis
Acute
Infective arthritis Bursitis, cellulitis, tenosynovitis Other crystal arthropathy ( pseudogout, apatite or brushite arthritis or periarthritis ) Traumatic arthritis Hemoarthrosis RA with palindromic onset Reactive arthritis Spondarthritis with peripheral involvement Psoriatic arthritis Sarcoid arthritis Rheumatic fever

Chronic
Nodular rheumatoid arthritis Psoriatic arthritis Osteoarthritis with Heberdens and Bouchards nodes Sarcoid arthritis xanthomatosis

Treatment
The acute attack The acute attack should be treated by resting the joint, applying ice packs if pain is severe, and giving full doses of a non-steroidal anti-inflammatory drug (NSAID). Colchicine, one of the oldest of medications, is less effective and may cause diarrhoea, nausea and vomiting. A tense joint effusion may require aspiration and intra-articular injection of corticosteroids. Oral corticosteroids are sometimes used for patients who cannot tolerate NSAIDs or in whom NSAIDs are contraindicated. The sooner treatment is started the sooner is the attack likely to end.

Treatment : CONT.
Interval therapy Between attacks, attention should be given to simple measures such as losing weight, cutting out alcohol and eliminating diuretics. Urate-lowering drug therapy is indicated if acute attacks recur at frequent intervals, if there are tophi or if renal function is impaired. It should also be considered for asymptomatic hyperuricaemia if the plasma urate concentration is persistently above 6 mg/dL (0.36 mmol/L). However, one must remember that this starts a life-long commitment and many clinicians feel that people who have never had an attack of gout and are free of tophi or urinary calculi do not need treatment. Uricosuric drugs (probenecid or sulfinpyrazone) can be used if renal function is normal. However, allopurinol, a xanthine oxidase inhibitor, is usually preferred, and for patients with renal complications or chronic tophaceous gout allopurinol is definitely the drug of choice.

Treatment : CONT.
Urate-lowering drugs should never be started before the acute attack has completely subsided, and they should always be covered by an antiinflammatory preparation or colchicine, otherwise they may actually prolong or precipitate an acute attack. Patients who suffer an acute attack of gout while already on a constant dose of urate-lowering treatment should be advised to continue taking the drug at the usual dosage while the acute episode is being treated. Surgery With prolonged urate-lowering therapy, adjusted to maintain a normal serum uric acid level (less than 0.36 mmol/L), tophi may gradually dissolve. However, ulcerating tophi that fail to heal with conservative treatment can be evacuated by curettage; the wound is left open and dressings are applied until it heals.

Indications for Antihyperuricemic Therapy in Gout

1- Frequent and disabling attacks of acute gouty arthritis

2- Clinical or radiographic signs of chronic gouty joint disease 3-The presence of tophaceous deposits in soft tissues or subchondral bone
4- Gout with renal insufficiency

5- Recurrent nephrolithiasis 6- Serum urate levels persistently in excess of 13 mg/dL in men or 10 mg/dL in women
7- Urinary uric acid excretion exceeding 1100 mg/day 8- Impending cytotoxic chemotherapy or radiotherapy for lymphoma or leukemia

Therapy
- Patients taking uricosuric agents are at risk for urolithiasis. This can be decreased by ensuring high urinary output and by adding sodium bicarbonate 1 gram TID. - The available agents include: probenecid (1-2 g/day) and sulfinpyrazone (50-400 mg BID). - Dose should be increased to decrease uric acid < 6.0 mg/ml - Allopurinol decreases uric acid in overproducers and under- excreters; it is also indicated in patients with a history of urolithiasis, tophaceus gout, renal insufficiency and in prophylaxis of tumor lysis syndrome. - Allopurinol: usual dose is 300 mg/day. Maximal recommended dose is 800 mg/day. - In renal insufficiency dose should be decreased to 200 mg/day for creatinine clearance < 60ml/min and to 100 mg/day if clearance < 30 ml/min).

Therapy
- Start with small doses of allopurinol to reduce the risk of precipitating an acute gout attack. - Most common side effects are rash (2% of patients) but rarely patients can develop exfoliative dermatitis that can be lethal. -Chronic use of colchicine (0.6-1.2 mg/day) is used as prophylaxis for acute attacks. 1.2 mg followed by 0.6 mg 2 hrs later. -Loading dose same in renal insufficiency. - Maintenance (preventive) dose 0.6 mg qd or bid. - 0.3 mg 2-3 times per week in dialysis patients (preventive).

Therapy :Febuxostat
- Non-xanthine inhibitor of XO and XD. - Better tolerated than allopurinol. - Lower uric acid levels than allopurinol (53% vs. 21% met target of 6.0 mg/dl). -Better dissolution of tophi.

Adverse Reactions
Nausea Gout flare (must be on prophylaxis!) Elevated ALT, AST (3% > 3xULN) Elevated CRP Rash Elevated CK

USES:

- Allopurinol failures - Renal insufficiency - Tophaceous gout

Table III. Main medications used in the treatment and prophyaxis of gout.1-8,13,81
Agent
Acute therapy/ prophylaxis NSAIDs

Adverse Events
Dose-dependent gastropathy, nephropathy, liver dysfunction, central nervous system dysfunction. May cause fluid overload in patients with congestive heart failure. Less GI toxicity than conventional NASIDs renal effecect similar to conventional NSAIDs

Contraindications
Peptic ulcer disease or bleeding ASA- Or NSAID-induced asthma, urticaria, or allergic-type reactions.

Regimen
Indomethaction 50mg TID for 2 to 3 days, then tapered over 5 to 7 days; naproxen 750 mg, followed by 250mg TID, then tapered over 5 to 7 days, sulindac 200mg BID, then tapered over 5 to 7 days. Prophylaxis low daily doses. Etoricoxise 120 mg/d (available outside the United States)

Cox-2 selective inhibitors (etoricoxib)

Cautious use in patients with advanced renal disease, history of ischemic heart disease, or history of NSAID-induced asthma. Use cautiously in renal or hepatic dysfunction.

Colchicine

Dose-dependent GI symptoms, neuromyopathy; improve IV dosing can cause bone narrow suppression, renal failure, paralysis, and death. Fluid detention, impaired Wound healing, psychosis Hyperglycemia hypothalamus Pituitary axis suppression Osteoporosis, potential for Rebound inflammation.

1.2mg initially then 0.6mg every 1 to 2 hours until pain relief or abdominal discomfort/diarrhea develops (do not exceed 4 mg/d). Prophylaxis 0.6 to 1.2 mg/d. Intra-articular; methylprednisolone 10 to 20mg for a small joint; 20 to 10 mg for large joint. IM: triamcinolone acetonide 60mg repeat after 24 hours if necessary. PO: prednisone 30 to 60mg QD, then tapered over 7 to 10 days.

Corticosteroids

Table III. (Continued)

Agent
ACTH

Adverse Events
Fluid retention, hypokalemia relapse of gout, worse diabetes control

Contraindications

Regimen
40 to 80 IU IM, repeat every 12 hours as necessary.

Orate-lowering therapy Allopuriol Rash, GI symptoms, headache, urticaria, and intestinal nephritis; rare potentially fatal hypersensitivity syndrome, reduces orate levels in over producers and underexcretors. Rash, headache, and GI symptoms; rare nephritic syndrome, hepatic necrosis, aplastic anemia and hemolytic anemia. Reduced orate levels in underexcretors.Potential for numerous drug interactions because of interference with excretion of many medications. Rash, headache, and GI symptoms, bone narrow suppression, minor hypersensitive. Possesses inherent antiplatelet activity. Renal dysfunction (CrCI <50mL/min) or renal calculi 250mg BID for 1 to 2 weeks ny500mg increments every 1 to 2 weeks until satisfactory control is achieved or maximal dose 3 g.

Probenecid

Sulfinpyrazone

Renal dysfunction (CrCI <50mL/min) or renal calculi

50mg BID; to 300 to 400 mg/d in 2 to 3 divided doses maximum dose 800 mg/d.

Low Purine Diet

On a strict low purine diet, protein is derived principally from eggs and cheese. Grains, most vegetables, fruits and nuts are acceptable. The following should be AVOIDED Animal-based proteins Meats, poultry, seafood, Liver, kidney, heart, gizzard, sweetbreads, Meat extracts, yeast extract. Vegetables Beverages Peas, beans, spinach, lentils. Alcohol, beer, and beer products.

CALCIUM PYROPHOSPHATE DIHYDRATE ARTHROPATHY (PSEUDOGOUT)

CPPD deposition encompasses three overlapping conditions: (1) chondrocalcinosis the appearance of calcific material in articular cartilage and menisci; (2) pseudogout a crystal-induced synovitis; and (3) chronic pyrophosphate arthropathy a type of degenerative joint disease. Any one of these conditions may occur on its own or in any combination with the others. In contrast to classic gout, serum biochemistry shows no consistent abnormality. CPPD crystal deposition is known to occur in certain metabolic disorders (e.g. hyperparathyroidism and haemochromatosis) that cause a critical change in ionic calcium and pyrophosphate equilibrium in cartilage. The rare familial forms of chondrocalcinosis are probably due to a similar biochemical defect. However, in the vast majority of cases chondrocalcinosis follows some local change in the cartilage due to ageing, degeneration, enzymatic degradation or trauma.

CPPD deposition
Demographics: - It is predominantly a disease of the elderly, peak age 65 to 75 years old. It has female predominance (F:M, 2-7:1). - Prevalence of chondrocalcinosis is 5 to 8% in the general population. Disease Associations: hyperthyroidsm, hypocalciuria, hypercalcemia, hemochromatosis, hemosiderosis, hypophosphatasia, hypomagnesemia, hypothyroidsm, gout, neuropathic joints, amyloidosis, trauma and OA.

CPPD deposition : Pathology

The incidence of CPPD arthropathy rises with increasing age; women are more affected and in some cases the disease runs in families . Pyrophosphate is probably generated in abnormal cartilage by enzyme activity at chondrocyte surfaces; it combines with calcium ions in the matrix where crystal nucleation occurs on collagen fibres. The crystals grow into microscopic tophi, which appear as nests of amorphous material in the cartilage matrix. Chondrocalcinosis is most pronounced in fibrocartilaginous structures (e.g. the menisci of the knee, triangular ligament of the wrist, pubic symphysis and intervertebral discs) but may also occur in hyaline articular cartilage, tendons and periarticular soft tissues. From time to time CPPD crystals are extruded into the joint where they excite an inflammatory reaction similar to gout. The longstanding presence of CPPD crystals also appears to influence the development of osteoarthritis in joints not usually prone to this condition (e.g. shoulders, elbows and ankles). Characteristically, there is a hypertrophic reaction with marked osteophyte formation. Synovitis is more obvious than in ordinary osteoarthritis.

CPPD deposition : Clinical features

The clinical disorder takes several forms, all of them appearing with increasing frequency in relation to age. Asymptomatic chondrocalcinosis Calcification of the menisci is common in elderly people and is usually asymptomatic. When it is seen in association with osteoarthritis, this does not necessarily imply cause and effect. Both are common in elderly people and they are bound to be seen together in some patients; x-rays may reveal chondrocalcinosis in other, asymptomatic, joints.

Chondrocalcinosis in patients under 50 years of age should suggest the possibility of an underlying metabolic disease or a familial disorder.

CPPD deposition : Clinical features

Acute synovitis (pseudogout) The patient, typically a middle-aged woman, complains of acute pain and swelling in one of the larger joints usually the knee. Sometimes the attack is precipitated by a minor illness or operation. The joint is tense and inflamed, though usually not as acutely as in gout. Untreated the condition lasts for a few weeks and then subsides spontaneously. X-rays may show signs of chondrocalcinosis, and the diagnosis can be confirmed by finding positively birefringent crystals in the synovial fluid. Chronic pyrophosphate arthropathy The patient, usually an elderly woman, presents with polyarticular osteoarthritis affecting the larger joints (hips, knees) and more helpfully unusual joints, such as the ankles, shoulders, elbows and wrists where osteoarthritis is seldom seen. There are the usual features of pain, stiffness, swelling, joint crepitus and loss of movement. It is often diagnosed, simply, as generalized osteoarthritis, but the x-ray features are distinctive. Sometimes alternating bouts of acute synovitis and chronic arthritis may mimic rheumatoid disease.

CPPD deposition : Clinical features

X-rays The characteristic x-ray features arise from a combination of (1) intra-articular and peri-articular calcification, and (2) degenerative arthritis in distinctive sites. Calcification is usually seen in and around the knees, wrists, shoulders, hips, pubic symphysis and intervertebral discs; it is often bilateral and symmetrical. In articular cartilage it appears as a thin line parallel to the joint. In the fibrocartilaginous menisci and discs it produces cloudy, irregular opacities. Less common sites are the joint synovium, capsule, ligaments, tendons and bursae. Degenerative changes are similar to those of straightforward osteoarthritis but notably involving unusual sites such as the non-weightbearing joints, the isolated patellofemoral compartment in the knee and the talonavicular joint in the foot. In advanced cases joint destruction may be marked, with the formation of loose bodies.

CPPD deposition : Clinical features

GOUT AND PSEUDOGOUT

CPPD deposition : Diagnosis

Synovial fluid examination CPPD crystals (Compensated polarised microscopy) In pseudogout, CPP crystals appear shorter and often rhomboidal. Positive birefringent In gout, crystals of MSU appear as needle-shaped intracellular and extracellular crystals. When examined with a polarizing filter, they are yellow when aligned parallel to the axis of the red compensator, but they turn blue when aligned across the direction of polarization (ie, they exhibit negative birefringence) Turbid fluid Blood stained Radiographs Chondrocalcinosis in hyaline and fibrocartilage (Occasionally capsule or ligament) with/ without structural changes of osteoarthritis

CPPD deposition : Diagnosis

Metabolic screening For patients with Early-onset CPPD deposition; <55yrs Florid polyarticular chondrocalcinosis Recurrent acute attacks without chronic arthropathy Additional clinical/ radiographic features of predisposing disease Tests to send: Calcium, Alkaline phosphatase, Magnesium, Ferritin LFTs

CPPD deposition : Diagnosis

THE ACUTE ATTACK Pseudogout must be distinguished from other acute inflammatory disorders. Acute gout usually occurs in men, and typically in smaller joints or in the olecranon bursa. The final word often lies with joint aspiration and identification of the characteristic crystals. Post-traumatic haemarthrosis can be misleading; pseudogout is often precipitated by trauma. A clear history and aspiration of blood-stained fluid will solve the problem. Septic arthritis must not be missed; a delay of 24 hours can mean the difference between successful and unsuccessful treatment. Systemic features are more evident, but blood tests and joint aspiration are essential to clinch the diagnosis; joint fluid should be submitted with a request for both crystal analysis and bacteriological culture. Reiters disease can start in a single large joint; always enquire about (and look for) signs of conjunctivitis, urethritis and colitis.

CPPD deposition : Diagnosis

CHRONIC CPPD ARTHROPATHY Chronic pyrophosphate arthropathy usually affects multiple joints and it has to be distinguished from other types of polyarticular arthritis. Osteoarthritis and joint calcification are both common in older people; the two together do not necessarily make it a CPPD arthropathy. The distinctive x-ray features, and especially the involvement of unusual joints (the elbow, wrist and ankle), point to a CPPD disorder rather than a simple concurrence of two common conditions. Inflammatory polyarthritis usually involves the smaller joints as well, and systemic features of inflammation are more marked. Metabolic disorders such as hyperparathyroidism, haemochromatosis and alkaptonuria may be associated with calcification of articular cartilage and fibro cartilage as well as joint symptoms. It is important to exclude such generalized disorders before labelling a patient as just another case of chondrocalcinosis

CPPD deposition : Treatment

The treatment of pseudogout is the same as that of acute gout: rest and high-dosage anti-inflammatory therapy. In elderly patients, joint aspiration and intra-articular corticosteroid injection is the treatment of choice as these patients are more vulnerable to the side effects of nonsteroidal anti-inflammatory drugs. Chronic chondrocalcinosis appears to be irreversible. Fortunately it usually causes few symptoms and little disability. When it is associated with progressive joint degeneration the treatment is essentially that of advanced osteoarthritis.

BASIC CALCIUM PHOSPHATE CRYSTAL DEPOSITION DISEASE

Basic calcium phosphate (BCP) is a normal component of bone mineral, in the form of calcium hydroxyapatite crystals. It also occurs abnormally in dead or damaged tissue. Minute deposits in joints and periarticular tissues can give rise to either an acute reaction (synovitis or tendinitis) or a chronic, destructive arthropathy.

Prolonged hypercalcaemia or hyperphosphataemia, of whatever cause, may result in widespread metastatic calcification.
However, by far the most common cause of BCP crystal deposition in and around joints is local tissue damage strained or torn ligaments, tendon attrition and cartilage damage or degeneration.

Basic calcium phosphate crystals

Types of crytals
- Hydroxyapatite - Tricalcium phosphate - Octacalcium phosphate

Identification of crystals
- Very difficult to detect secondary to small size - Non-birefringent chunks - Stain positive with Alizarin red stain

BCP DEPOSITION DISEASE: Pathology

The minute (less than 1 mm) BCP crystals are deposited around chondrocytes in articular cartilage and in relatively avascular or damaged parts of tendons and ligaments most notably around the shoulder and knee. The deposits grow by crystal accretion and eventually may be detectable by x-ray in the periarticular tendons or ligaments. Calcification of the posterior longitudinal ligament of the cervical spine may also be associated with BCP crystal deposition. Sometimes the calcific deposit has a creamy consistency but in longstanding cases it is more like chalk. The mini-tophus may be completely inert, but in symptomatic cases it is surrounded by an acute vascular reaction and inflammation. Crystal shedding into joints may give rise to synovitis. More rarely this is complicated by the development of a rapidly destructive, erosive arthritis. Bits of articular cartilage and bone or fragments of a meniscus may be found in the synovial cavity.

BCP DEPOSITION DISEASE: Clinical features

Two clinical syndromes are associated with BCP crystal deposition: (1) an acute or subacute peri-arthritis; and (2) a chronic rapidly destructive arthritis. ACUTE OR SUBACUTE PERI-ARTHRITIS This is by far the commonest form of BCP crystal deposition disorder affecting joints. The patient, usually an adult between 30 and 50 years, complains of pain close to one of the larger joints most commonly the shoulder or the knee. Symptoms may start suddenly, perhaps after minor trauma, and rise to a crescendo during which the tissues around the joint are swollen, warm and exquisitely tender but tender near the joint in relation to a tendon or ligament, rather than in the joint. At other times the onset is more gradual and it is easier to localize the area of tenderness to one of the periarticular structures. Both forms of the condition are seen most commonly in rotator cuff lesions of the shoulder. Symptoms usually subside after a few weeks or months; sometimes they are aborted only when the calcific deposit is removed or the surrounding tissues are decompressed.

BCP DEPOSITION DISEASE: Clinical features

CHRONIC DESTRUCTIVE ARTHRITIS BCP crystals are sometimes found in association with a chronic erosive arthritis; whether they cause the arthritis or modify a preexisting disorder remains uncertain. A more dramatic type of rapidly destructive arthritis of the shoulder is occasionally seen in elderly patients with rotator cuff lesions. This was described in 1981 by McCarty and his colleagues from Milwaukee and acquired the sobriquet Milwaukee shoulder. Similar conditions affect the hip and knee. They have been attributed to BCP crystal (or mixed BCP and CPPD crystal) shedding into the joint.

Syndromes Associated with Hydroxyapatite

- Acute monoarthritis (pseudopseudogout) - Acute calcific tendinitis, bursitis - Scleroderma, dermatomyositis - Heterotopic calcification - Milwaukee shoulder - Crowned Dens Syndrome.

Acute Apatite Monoarthritis (Pseudopseudogout)

- Is usually a peri-arthritis. - Intense inflammation (looks septic) - Synovial fluid often non-inflammatory. - Often causes podagra (especially in younger women). - Look for the tell-tale calcifications on radiographs.

Crowned Dens Syndrome

- Headache - Pain with head rotation - Shoulder myalgias -Very elevated sedimentation rate

Milwaukee Shoulder
- Severe, destructive shoulder arthropathy. - Seen in elderly females with DJD of shoulder. - High-riding humeral head on radiographs (large rotator cuff tear). - Non-inflammatory fluid with BCP crystals.
- May effect other joints knees, hips and elbows

BCP DEPOSITION DISEASE: X-rays

With peri-arthritis, calcification may be seen in tendons or ligaments close to the joint, most commonly in the rotator cuff around the shoulder. Articular cartilage and fibrocartilaginous menisci and discs never show the type of calcification seen in CPPD deposition disease, but loose bodies may be seen in synovial joints. Erosive arthritis causes loss of the articular space, with little or no sclerosis or osteophyte formation. The typical picture of rapidly destructive arthritis is one of severe erosion and destruction of subchondral bone. In advanced cases the joint may become unstable and, eventually, dislocated.

BCP DEPOSITION DISEASE: Investigations

There is little help from special investigations. Serum biochemistry is usually normal, except in those patients with hypercalcaemia or hyperphosphataemia. Synovial fluid examination may reveal high counts of polymorphonuclear leucocytes, but this hardly serves to distinguish the condition from other types of subacute synovitis.

BCP crystals are too small to be seen by light microscopy but can be identified by electron probe or transmission electron microscopy.

BCP DEPOSITION DISEASE: Treatment

Acute peri-arthritis should be treated by rest and nonsteroidal antiinflammatory drugs. Resistant cases may respond to local injection of corticosteroids; this treatment should be used only to weather the acute storm repeated injections for lesser pain may dampen the repair process in damaged tendons or ligaments and thus predispose to recurrent attacks.

Persistent pain and tenderness may call for operative removal of the calcific deposit or decompression of the affected tendon or ligament.
Erosive arthritis is treated like osteoarthritis. However, rapidly progressive bone destruction calls for early operation: in the case of the shoulder, synovectomy and soft-tissue repair; for the hip, usually total joint replacement.

Steroid Crystal Arthritis

- Iatrogenic crystal arthritis. - Starts several hours after intra-articular steroid injection. - Septic arthritis usually takes longer. - Usually short-lived. - Ice it; may drain it, but dont operate on it.

References
Apleys System of Orthopaedics and Fractures 9th Edition Color Atlas of Clinical Orthopedics by Mikls Szendri & Franklin H. Sim Moritz and Dave Dycks Rounds Web Sites: American College of Rheumatology http://www.thegoutacademy.com Google Images Wikipedia