AssessmentsGout and pseudogout: Pathology review
USMLE® Step 1 style questions USMLE
A 64-year-old woman comes to the physician complaining of pain in the right knee for the past day. The patient reports associated joint swelling, warmth, and redness. She says this has happened before in her knees and hips, but those episodes lasted for only a few hours and resolved spontaneously. She also reports feeling fatigued during the past several months, but attributes this to frequently waking up at night to urinate. The patient has also had to strain more than usual when having a bowel movement and frequently takes laxatives to help. Vital signs are within normal limits. Physical examination reveals swelling, erythema, and warmth of the right knee joint. It is tender to palpation with decreased active and passive range of motion. Laboratory studies show the following:
Arthrocentesis of the right knee is performed. Gram stain is negative. Polarized light microscopy shows rhomboid-shaped, weakly positively birefringent crystals. Further evaluation of this patient is most likely to show which of the following?
Content Reviewers:Yifan Xiao, MD
On your rounds, you see Ashvir, a 50-year-old man who complains of severe pain and swelling in his first toe on the right foot.
This is the first time he has experienced this and the symptoms developed in the last 5 hours.
He described the pain as very severe and that it’s causing him to limp.
On examination, he is obese and the toe is swollen, red, warm, and painful to the touch.
Then you see Bianca, a 22-year old who also came in with a pain and swelling of the left big toe and left knee, which developed yesterday.
However, unlike Ashvir, she is not overweight and has a history of hemochromatosis.
Synovial fluid analysis was performed in both, detecting negatively bi-refringent crystals in Ashvir, and weakly positively birefringent crystals in Bianca.
Now, both seem to have some type of crystalline arthropathy.
But let’s talk about physiology first.
Purines, together with pyrimidines, are key components of nucleic acids like DNA and RNA.
Purines are first broken down into adenosine monophosphate or AMP and guanosine monophosphate or GMP.
AMP is converted to inosine via two different mechanisms; either by removing an amino group to form inosine monophosphate or IMP, which is quickly converted to inosine, or by removing a phosphate group to form adenosine, which is also converted to inosine.
These last two steps are catalyzed by the enzyme xanthine oxidase.
GMP is converted to guanosine, which is then converted to guanine.
Guanine is deaminated to form xanthine, which is oxidized by xanthine oxidase to form the final product, uric acid.
Now, under normal physiologic conditions, uric acid circulates in plasma and synovial fluid as urate an-ions.
However, human tissues have a limited ability to metabolize urate; thus, it is quickly eliminated by the kidney and the gut to maintain urate homeostasis.
Another way the body can avoid excess uric acid is by recycling purines via the purine salvage pathway.
This is when organs convert hypoxanthine back to IMP via hypoxanthine-guanine phospho-ribo-syl-transferase or HGPRT, which then gets converted to AMP to make new purines; conversely, we can take guanine and convert it to GMP by HGPRT to make new purines;
Now, gout is a monoarticular inflammatory disease where monosodium urate crystals cause joint damage.
First is underexcretion of uric acid by the kidney, which can be idiopathic, when the cause is not known; due to renal failure; or it can be exacerbated by medication, like thiazide diuretics and aspirin.
Second is overproduction of purines.
This can occur with increased consumption of purine-rich foods such as shellfish, anchovies, and red meat.
High-fructose corn syrup containing beverages can contribute to hyperuricemia too, usually by increasing purine synthesis.
Others might have a genetic predisposition to overproduction of uric acid, or it can develop as a result of chemotherapy or radiation treatment, where a lot of tumor cells die, causing what is known as tumor lysis syndrome.
The syndrome occurs because dead cells release their contents into the bloodstream, resulting in increased levels of potassium, causing hyperkalemia; phosphate, causing hyperphosphatemia, and uric acid, leading to hyperuricemia.
Finally, there are some rare causes of uric acid overproduction that are high yield.
For example, Lesch-Nyhan syndrome is an X-linked genetic disorder leading to HGPRT deficiency, which results in build-up of uric acid in all body fluids secondary to decreased purine recycling.
Then we have phosphoribosyl pyrophosphate synthetase excess, caused by an X-linked genetic defect in the enzyme.
Because it is involved in purine production and because it acts as a substrate used by HGPRT during purine salvage, the enzyme’s excess results in increased de novo synthesis and decreased recycling of purines.
This causes pyruvate, a noncarbohydrate precursor, to accumulate, preventing the conversion of lactate into pyruvate.
Although the mechanism is not fully known, it is thought that the crystals interact and activate monocytes and macrophages, which try to clear them by phagocytosis.
This leads to the release of proinflammatory cytokines like TNF-alpha, interleukin-8, and other chemokines into the surrounding area, triggering the inflammatory reaction and an influx of neutrophils into the joints, resulting in joint damage and symptoms of acute gout.
Chronic gout can eventually lead to permanent deposits of urate crystals, called tophi, which form along the bones just beneath the skin.
Microscopic tophi can be walled off by a ring of proteins, which blocks their interaction with immune cells and, therefore, don’t trigger an inflammatory response.
Sometimes, though, some of these crystals can get past the wall, and trigger new gout attacks, which brings further destruction to the joint. Individuals with chronic gout are also at an increased risk for developing kidney stones made of uric acid, as well as urate nephropathy, which is when urate crystals deposit in the interstitium of the kidney.
Now, symptoms of gout are high-yield and frequently tested, and they depend on which joint is affected and if the presentation is acute or chronic.
Ok, so the disease is usually symmetrical and affects the first metatarsal joint of the foot, or the base of the big toe, but the joints of the ankles, knees, wrists, and elbows can be involved too.
When it involves the big toe, this condition is called podagra.
Classically, in an acute gout attack, individuals feel sudden pain over the affected joint that’s so severe, it even wakes them up from sleep feeling like their big toe is on fire.
People describe this pain as the worst they ever had but, fortunately, the pain generally lessens over time.
And because it is an inflammatory process, the affected joint is also swollen, warm, and red.
Occasionally, a gout attack triggers a systemic inflammatory response manifesting with fevers, leukocytosis, elevated sedimentation rates, and elevated C-reactive protein, or CRP.
Something else to know is that the acute attacks tend to occur after a large meal (with foods rich in purines), trauma, surgery, dehydration, and diuresis.
They can also be triggered by alcohol consumption because alcohol metabolites compete for the same excretion sites in the kidney as uric acid, causing decreased uric acid excretion.
The clinical picture is dominated by the presence of tophi around the affected areas.
- "Robbins Basic Pathology" Elsevier (2017)
- "Harrison's Principles of Internal Medicine, Twentieth Edition (Vol.1 & Vol.2)" McGraw-Hill Education / Medical (2018)
- "The British Society for Rheumatology Guideline for the Management of Gout" Rheumatology (2017)
- "Diagnosing and Treating Gout: A Review to Aid Primary Care Physicians" Postgraduate Medicine (2010)
- "The British Society for Rheumatology Guideline for the Management of Gout" Rheumatology (Oxford) (2017)
- "Gout" The Lancet (2010)
- "Management of Gout: A Systematic Review in Support of an American College of Physicians Clinical Practice Guideline" Annals of Internal Medicine (2016)
- "Diagnosis of Acute Gout: A Clinical Practice Guideline From the American College of Physicians" Ann Intern Med (2017)
- "Genetics and Mechanisms of Crystal Deposition in Calcium Pyrophosphate Deposition Disease" Current Rheumatology Reports (2011)
- "European League Against Rheumatism recommendations for calcium pyrophosphate deposition. Part I: terminology and diagnosis" Annals of the Rheumatic Diseases (2011)