Crystal Deposition Diseases

Clinical Presentation

Patient Profile – males over 30 mostly affected

Gout Attack – sudden onset of joint pain and swelling, reaching maximum intensity quickly (within 24 hours)

non-symmetrical monoarticular (80%) or polyarticular (20%) joint pain – MTP (90%) > foot > ankle > hand > elbow

can move from one joint to another – often first manifestation is MTP and assumed to be stubbed toe

often incited by precipitating event (surgery or binge drinking)
resolves within 3 days to 3 weeks if untreated; days to years between attacks, during which joint is totally normal

Diagnosis

Diagnosis is dependent upon joint fluid examination; Colchicine response is non-diagnostic

presence of negatively birefringent synovial crystals diagnostic – needle-shaped crystals, although rapidly digested
type II fluid (3,000-50,000 WBC/ml) – mostly PMNs – worse earlier in disease pathogenesis

Laboratory findings – elevated serum uric acid (lower with polyarticular), elevated WBC and sedimentation rate (worse with polyarticular)

X-rays are abnormal only in late disease – uric acid deposition in soft tissues, calcification of joints, erosion of bone

Classification of Gout

Primary Gout – inborn error of metabolism – probably genetic (but <30% has family history) – two mechanisms:

(1) overproduction (10-15%) – defined by increased 24 hour excretion of uric acid, even with purine-free diet

normal urate metabolism: ribose-5-phosphate Þ PRPP Þ inosinic acid Þ hypoxanthine Þ xanthine Þ uric acid

gout is caused by increase in rate limiting step (aminotransferase, PRPP Þ inosinic acid) due to Ý PRPP

increased PRPP synthetase activity – Ý PRPP

absent or reduced activity of HGPRTase – Ý PRPP (also ß negative feedback on aminotransferase)

Lesch-Nyham Syndrome – no HGPRTase – uric acid gravel in stool, kidney stones, mental defect

glucose-6-phosphatase deficiency – all G6P must go through pentose pathway, so Ý PRPP

what about diet? – purines in diet do contribute, but purine-free diet results in only 1% reduction in serum uric acid

(2) underexcretion (85-90%) – all gout patients probably undersecrete to some extent; two mechanisms of excretion

intestinal uricolysis – bacterial digestion of uric acid – but this process is increased in gout patients
renal excretion – uric acid is the only substance both reabsorbed and secreted, both at multiple sites
92-95% filtered, 98-100% reabsorbed, 5-8% secreted – pathology is usually undersecretion (unknown defect)

Secondary Gout – due to another disorder

(1) drug-induced – diuretics or low-dose aspirin (>12 aspirin/day has the opposite effect) – causes gout 10% of the time

(2) other diseases – either elevated cell turnover (blood dyscrasias, lymphoma, psoriasis) or renal disease

(3) metabolic–acidosis (ß renal excretion), starvation, EtOH (produces purines from ATPÞ AMP; causes acidosis as well)

Mechanism of Gouty Attack – vicious circle: precip. Þ inflammation Þ acidÞ precip.

Precipitation of crystals following hyperuricemia – unknown why this occurs

hyperuricemia localized to joint – possibly released from proteoglycans, also pooling (uric acid stays when water leaves)
change in uric acid levels (up or down) is more important than level itself – binge drinking, surgery, even gout treatment

Phagocytosis with inflammation – uric acid directly activates complement, hageman factor, bradykinin pathway

phagocytosis causes release of lysosomal enzymes and acid – lower pH causes crystals to precipitate – vicious circle
unknown countermeasures turn it off

Stages and Treatment of Gout

Stage I – asymptomatic hyperuricemia – usually not treated (only 12% proceed to gout) – but see below

Stage II – periodic arthritis – treat by immobilizing joint (patients usually do this anyway)

Acute Therapy:

cholchicine – ancient treatment – inhibits microtubule assembly – no PMN migration into joint (blocks diapedesis)

must be given early–IV form can block attack, oral form no longer used (cell division inhibitionÞ vomiting/diarrhea)

large dose NSAIDs – can abort attack, but must take large dose (800 mg ibuprofen)

local corticosteroid injection – useful if patient cannot tolerate NSAIDs (GI bleeding) or cholchicine (renal failure)

Interval Therapy – between attacks (must also give colchicine so that uric acid reduction does not produce attack):

uricosuric drug (probenecid, sulfinpyrazone, Ý dose salycylates) – increase uric acid secretion (block renal reabsorption)

not for patients who overproduce and overexcrete uric acid – causes kidney stones (urate = seed for Ca oxalate)

xanthine oxidase inhibitor (allopurinol) – stops terminal reaction, reacts with PRPP, provides neg. feedback

excellent for patients who overexcrete uric acid or who have renal disease
some long-term effects (liver problems, potentially fatal allergic skin rashes)

Stage III – chronic tophaceous gout – only 50% of stage II progress to this; can use NSAIDs or cholchicine

Hyperuricemia and Vascular Disease

Blood pressure reduced by diuretics does not reduce risk of CAD/MI/stroke, possibly because of resulting hyperuricemia

Also, allopurinol improves recovery from coronary artery bypass surgery

Pseudogout – caused by calcium pyrophosphate dihydrate deposition

Etiology – can be idiopathic (spontaneous), hereditary (primary), or disease-associated (secondary)

associated diseases:

primary or tertiary hyperparathyroidism, hypophosphatasia, hypomagnesemia – increased Ca⁺⁺ in blood

hemochromatosis/hemosiderosis – heavy metals inhibit calcium pyrophosphate dihydrate Þ hydroxyapetite

hyperthyroidism – unknown link

Clinical Presentation – elderly (>70 years), slightly more prevalent in men

subacute – asymptomatic chondrocalcinosis (calcification of hyaline or fibrous cartilage)
acute – arthritis (like osteoarthritis but more inflammation) – takes longer to develop than gout, but still within 24 hours
joints affected: knee (majority)>wrist>MCP>foot (not as often foot) – can be mono or pauciarticular – like gout
lasts 1-28 days

Diagnosis – requires joint fluid examination –presence of positively refringent crystals (rhomboid) in PMNs

also type II synovial fluid (like gout)
chondrocalcinosis on X-ray is NOT diagnostic, since most chondrocalcinosis is not pseudogout
also see elevated WBCs, depending upon size and number of joints involved (just like gout)

Etiology – crystals are stripped off superficial layers of cartilage by collagenase ("enzymatic strip mining")

resulting phagocytosis/inflammation causes synovial proliferation, neutral protease, and collagenase (vicious circle)

Treatment – more difficult to treat than gout – no "designer drugs" like allopurinol

IV cholchicine, NSAIDs; intraarticular corticosteroid injection and joint fluid aspiration can alleviate symptoms

Hydroxyapatite Crystal Disease – a.k.a. Milwaukee Shoulder Syndrome

Presentation – severe degenerative shoulder arthritis, rotator cuff ligaments torn, subchondral sclerosis

Etiology – endocytosis of hydroxyapetite by synoviocytes, like pseudogout

cause unknown – probably secondary arthritis due to aging and degeneration of the rotator cuff ("wear and tear")

Diagnosis – joint aspiration yields hydroxyapetite and hemarthrosis (similar to subchondral fractures)

Treatment is notoriously poor, since NSAIDs do not work well

repetitive aspiration and glucocorticoid injections work to treat outbreaks
shoulder replacement is not generally successful due to ligament damage

Arthropathy of Dialysis – particularly a problem with peritoneal dialysis

Presentation – chondrocalcinosis, similar symptoms to pseudogout

Etiology – elevated Ca⁺⁺ causes deposition of mixture of calcium salts in joints

calcium oxalate, calcium monohydrate, calcium phosphate, and calcium hydroxyapetite predominate
secondary hyperparathyroidism is also observed due to hypercalcemia

Treatment – same as pseudogout