Dr. Nortin Hadler, Emeritus Professor of Medicine and Microbiology/Immunology at the University of North Carolina at Chapel Hill, answers four questions from Orthopaedia on gout, among other things. [Related information can be found in the Orthopaedia chapter on Gout and Pseudogout.]

 

ORTHOPAEDIA: In your books including The Last Well Person, Worried Sick, and Rethinking Aging (available here), you have decried the excessive use of screening-tests, a practice that leads to not only too much treatment but too much disease-labeling. With that in mind, what is the proper role of screening asymptomatic people for gout with blood tests or other means? And if you are not a fan, is it because the tests are just too weak, or because the cost/benefit ratios of treatment (of true and false positives) is just unfavorable?

NORTIN M HADLER: The routine biochemical test most relevant to this discussion is the concentration of sodium urate in serum and urine.  Sodium urate is a product of purine catabolism. It is a small molecule that is highly soluble and biologically inert. However, extracellular fluids can become supersaturated, predisposing to uric acid crystal formation. These crystals have a structure such that renders them visible on polarized microscopy.  These crystals also have anionic surfaces that render them “phlogisitic”, that is, prone to cause inflammation.

The monosodium urate in solution is not the direct cause of gout and its concentration correlates very poorly with the likelihood of crystallization. That’s because the body fluids have a multitude of inhibitors of nucleation that can stop the initiation of the crystal formation. Gout, in that sense, may be the result of inadequate inhibition. Assessing for this inadequacy is a test we need but don’t have. Measuring serum urate is a very poor surrogate.

As such, there is no role for screening asymptomatic people for gout with serological or urinary assays. There is no biochemical assay in any body fluid that has the sensitivity, specificity, or predictive value to yield a clinically actionable result. Interestingly, tissue and tissue fluids from sites that are often targeted in gout may harbor monosodium urate crystals before symptoms appear. Needling these sites and withdrawing tissue fluid (usually traumatically and painfully) may prove diagnostic. MRI imaging may also serve the same purpose.

ORTHOPAEDIA: Gout was once known as the rich man’s disease, owing to its higher incidence among people who could afford to overeat and drink, back in the day. Does this type of terminology have any place in modern medicine– or might we be better served with a more biologically descriptive term for gout?  Moreover, the term gout not only fails to inform about true biology, it teaches wrong ideas: suggesting that the disease is caused by a gutta, (Latin for drop)  of black bile “dropped” into the affected joint.  After all, modern medicine has tended to jettison some old-fashioned names for diseases, like lumbago, even when they don’t convey wrong ideas.

NORTIN M HADLER: “Lumbago” is an assertion of the limitations of pathophysiologic insight. I prefer “regional low back pain” but am not sanguine about that. I would look askance if one still applied the “consumption” label to patients with tuberculosis. TB is TB.  “Gout” has a comparably long and colorful history and a unifying pathophysiology. We could substitute a label such as “urate crystallopathy” and feel smugly modern. Somehow that is not as satisfying as substituting pulmonary tuberculosis for consumption.

As to the old saw that gout is a rich man’s disease, I’m not sure that wasn’t a spurious observation. Before the 20^th century, average life expectancy hovered around 40 for all but the wealthy. Maybe most men didn’t live long enough to suffer gout? I raise that possibility since the relationship between dietary intake and gout is far from linear.  Most of the urate in body fluids is the result of the metabolism of intrinsic purines involved in cell turnover. Diet is a secondary source and a “low purine” diet is a rather inane therapy for gout. The relationship between gout and alcohol consumption (even alcohol contaminated by lead as in “Saturnine gout”) is also far from linear. Moonshine distilled in radiators relates to compromised renal function far better than to gout. Like the term “gout” itself, the notion of gout as an affliction of obese, profligate noblemen should be accepted somewhat tongue-in-cheek.

ORTHOPAEDIA: You have written a lot about the futility of disease prevention, at least insofar that we must recognize, as you put it, that no matter what we do, the death rate is going to remain unchanged: one per person. What, then, is the proper role of prevention in a disease like gout? Please note that the CDC website– your charges of inanity, above, notwithstanding– writes “Making changes to your diet and lifestyle, such as losing weight, limiting alcohol, eating less purine-rich food (like red meat or organ meat), may help prevent future attacks.”

NORTIN M HADLER: Alexander Gutman demonstrated years ago that weight loss would decrease the incidence in patients who suffer recurrent gouty arthritis. It is not clear that decreased intake of purines is responsible for this effect. As mentioned, a low purine diet barely touches either the concentration of urate or the incidence of gouty attacks. In fact, lowering the serum levels with agents such as allopurinol might decrease the incidence somewhat but not completely. It will decrease the likelihood damaging deposits of uric acid crystals (tophi) and even facilitate the dissolution of existing deposits. The story for urate nephrolithiasis is somewhat different since the likelihood of uric acid stones correlates with urinary urate excretion. Decreasing urate clearance is therapeutic, whether by dietary restriction of purines or pharmacologic interference with biosynthesis. The story in urate nephrolithiasis mirrors that in gouty arthritis. The pathogenesis is more a function of inhibition of nucleation than of decreasing the concentration of uric acid. Unlike the case with tophaceous disease, uricosurics are contraindicated then.

There is a critical role for prevention of recurrence and of persistence in any patient who has already suffered any of the musculoskeletal or renal manifestations of gout.  Prevention aimed at urate accretion and at the phlogistic properties of urate crystals is available and effective. Low dose colchicine is usually a match for the latter; agents that interfere with urate biosynthesis or promote excretion have a role in the former.  With rare exceptions, these interventions are hardly justified as a primary modality, i.e., before clinical manifestations. One exception is in some settings where cancer chemotherapy can result in a predictable flood of urate that can interfere with renal function.

ORTHOPAEDIA:  At times, it may be hard to distinguish a gout flare from an infection. How do you make this distinction? Also, is it possible that both conditions are present simultaneously, or does the presence of gout make the diagnosis of concurrent infection less likely?

NORTIN M HADLER:  The clinical presentations of gouty and infected arthritides have much in common: usually only one joint is affected, there is accumulation within the joint of highly inflammatory fluid (so much so that no pain-free arc of motion remains), and there is prominent erythema often beyond the confines of the joint space.  Also, both conditions can present with systemic biomarkers such as elevation in body temperature, elevated inflammatory markers (such as the ESR), and diaphoresis, though more frequently in the setting of an infected joint than in crystal-induced monoarthitis.

As a result, the ability to undertake synovialysis, a diagnostic analysis of synovial fluid, is a necessary skill for any physician who might see a patient with inflamed joints, especially to detect and recognize urate crystals.

Interestingly, the demonstration of urate crystals in the joint fluid not only establishes the diagnosis of gout, it tends to render the diagnosis of coincident bacterial infection highly unlikely. Occasionally, tophi can provide a welcoming substrate for a surrounding bacterial infection but as a rule, the demonstration of urate crystals in the inflammatory milieu essentially excludes the diagnosis of coincident infection.

Many rheumatologists think that the inflammatory milieu in joints afflicted with rheumatoid arthritis prohibits urate crystallization. There isn’t a better explanation for the fact that the two diseases almost never coincide in any joint.  As a corollary, an inflamed joint in which one demonstrates urate crystals on synovialysis makes the diagnosis of gout and excludes the other non-infected inflammatory arthritides including rheumatoid arthritis, psoriatic arthritis, and others.