Gout and pseudogout: Pathology review

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Case Study0:00–0:53

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.

Physiology0:53–2:48

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.
Inosine is then converted to hypoxanthine, and hypoxanthine to xanthine, which is finally metabolized to uric acid. 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.

Gout2:48–7:46

When plasma becomes saturated with urate acid molecules, these bind sodium to form monosodium urate crystals, especially in areas with slow blood flow, like the joints and the kidney tubules.
Ok, so the main risk factor for gout is excess uric acid, or hyperuricemia, and it can be caused by many things. 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.
Also these kinds of foods and drinks can lead to obesity and diabetes, both of which are risk-factors for gout, alongside male sex, hypertension, dyslipidemia, and alcohol use.
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.
A final one is von Gierke disease, a condition in which the body cannot break down glycogen due to Glucose-6-phosphatase deficiency.
As a result, glucose-6-phosphate can’t be converted to glucose, impairing gluconeogenesis, which is the process by which the body produces glucose from noncarbohydrate precursors.
This causes pyruvate, a noncarbohydrate precursor, to accumulate, preventing the conversion of lactate into pyruvate. This causes lactate to build-up causing lactic acidosis.
Since lactic acid competes with uric acid for transport in the renal tubules, uric acid excretion decreases so it also builds up in the body.
Now, moving on, the problem with these crystals accumulating in soft tissues and joints is that they cause tissue damage and a self-limited acute inflammatory episode called a gout attack.
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.
These episodes resolve spontaneously in around ten days, possibly mediated by anti-inflammatory cytokines. Over time, repeated acute gout episodes can develop into chronic gout, which is a type of arthritis with joint tissue destruction and permanent joint deformity.
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.

Gout Symptoms7:46–9:49

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.
Chronic gout, on the other hand, can be asymptomatic between gout attacks, which can occur quite frequently if the cause of hyperuricemia is not dealt with.
The clinical picture is dominated by the presence of tophi around the affected areas. Sometimes, these tophi can even develop in unexpected places, like the external ear, olecranon bursa, or Achilles tendon.
If, in time, people develop uric acid kidney stones, they might present with symptoms like lumbar pain that radiates to the lower abdomen and groin, pain on urination, and hematuria.

Gout Diagnosis9:49–11:08

If clinical symptoms suggest gout, diagnosis is based on elevated serum urate levels, and synovial fluid analysis. Synovial fluid analysis is when synovial fluid is extracted with a syringe from the affected joint, and then analyzed on a microscope for increased white blood cell count with a neutrophil dominance, and the presence of monosodium urate crystals.
A high yield fact is that on a microscope, under polarized light, monosodium urate crystals can be both inside and outside the cells, have a sharp, needle-like form, and are negatively birefringent.
Negative birefringence means they are yellow under parallel light, and blue under perpendicular light. In addition, the fluid should be examined by Gram stain and culture, especially if no crystals are found, to exclude infection as a possible cause for the symptoms.
Next, because serum uric acid levels can be normal during a gout attack and monosodium urate crystal can be absent on synovial fluid analysis, an x-ray or CT of the affected joint is needed.
Imaging can detect crystal deposits and well-defined erosions with sclerotic margins and overhanging edges, which usually occur in chronic gout.

Gout Treatment11:08–13:50

Treatment of gout is also high yield. First-line treatment in a gout attack is nonsteroidal anti-inflammatory medications, or NSAIDs, like ibuprofen or naproxen sodium.
NSAIDs work by inhibiting cyclo-oxygenase enzymes, thus decreasing prostaglandin production, resulting in decreased inflammation.
However, these drugs should be avoided in those with liver and renal dysfunction. Second-line medication include colchicine.
Colchicine binds to the protein subunit of the neutrophils' microtubules, which are part of the cellular cytoskeleton, and prevents microtubule assembly.
This, in turn, disrupts membrane dependent functions like leukocyte migration and phagocytosis. This means that neutrophils won’t be able to come at the site of injury and process monosodium urate crystal and, subsequently, cause gout attack symptoms.
Keep in mind that colchicine is not preferred over NSAIDs due to its side effects, which include nausea, abdominal pain, and diarrhea.
It should also be avoided in the eldery or those with renal dysfunction. Occasionally, corticosteroids can be used as an alternative to NSAIDs and colchicine.
It’s also important to treat the underlying cause of increased uric acid, though, individuals should modify their diet by eliminating soda, alcohol, red meat, and seafood.
It also helps to stay hydrated, and stay active to ward off obesity. There are also medications that help to decrease uric acid levels, which are indicated in chronic gout or as a preventive method, but they are not helpful during an attack.
These should be initiated if there are macroscopic tophi, more than 3 gout attacks per year, uric acid kidney stones, and significant hyperuricemia.
The most high yield medications include xanthine oxidase inhibitors like allopurinol and febuxostat, which decrease uric acid production by inhibiting xanthine oxidase.
Allopurinol can be used in the prevention of tumor lysis syndrome as well, and it can increase the toxicity of aza-thi-oprine if used together.
This is because xanthine oxidase catalyzes 1 of 2 major azathioprine-inactivating pathways. Allopurinol competitively inhibits xanthine oxidase, which results in increased conversion of azathioprine to its active metabolite.
The second most common option is uricosuric medications, like probenecid, which increases excretion of uric acid by the kidneys.
Low doses of colchicine can also be used to prevent a gout attack. Okay, let’s move onto the next disease which is calcium pyrophosphate deposition disease or CPPD, previously known as pseudogout.

Pseudogout13:50–14:50

This is a crystal arthropathy associated with those over 50 years old. Although the pathogenesis of CPPD disease is not as well understood, similarly to gout, there is probably excessive pyrophosphate production, resulting in calcium pyrophosphate supersaturation and the formation of CPPD crystals.
These accumulate in the joints and soft tissue, where they cause inflammation and tissue damage. Now, the condition is usually idiopathic, meaning its cause is unknown, and it can be associated with certain underlying diseases like trauma to the joint, hyper-parathyroidism, hypo-magnesemia, hypo-thyroidism, hypo-phosphatasia, and hemochromatosis, which is an abnormal accumulation of iron in parenchymal organs.

Pseudogout Symptoms14:50–15:24

The clinical symptoms of CPPD during an acute attack can be indistinguishable from acute gout where the affected joint is painful, swollen, warm, and red.
Now, although CPPD disease and gout can affect the same joints, CPPD disease tends to affect more than one joint, usually larger joints like the knee.
Other joints that can be affected include the elbow, shoulder, and wrist joints. And just like gout, it can also lead to chronic degeneration with joint destruction and limited joint mobility.

Pseudogout Diagnosis15:24–16:39

Since the symptoms are similar to gout, the definitive diagnosis requires synovial fluid analysis. CPPD crystals might not be as evident as monosodium urate crystals, as they are weakly positively birefringent under polarized light, which means they have the opposite pattern seen in gout; they are blue under parallel light and yellow under perpendicular light.
They also have a rhomboid or rod-shaped appearance and can be seen either in or outside the cell. In addition, because CPPD disease and gout can coexist, monosodium crystals might be observed as well.
Next, imaging can help confirm the diagnosis if fluid analysis is inconclusive, and it typically shows chondro-calcinosis in the joint involved, which is cartilage calcification.
Chondrocalcinosis can occur even if the disease is not clinically active at the time of presentation. And because CPPD disease is associated with a variety of underlying conditions, screening for hyperparathyroidism, hypothyroidism, hypomagnesemia, hypophosphatasia, and hemochromatosis is also necessary.

Pseudogout Treatment16:39–17:03

Regarding treatment, acute attacks can be managed with NSAIDs, colchicine, and glucocorticoids. Prophylaxis is done with colchicine.
Unlike gout, however, there are no hypouricemic equivalents to improve the long-term control of acute attacks or to prevent or reverse CPPD disease.
All right, as a quick recap, gout is a type of inflammatory disease that typically affects the first metatarsal joint, which is the base of the big toe, where uric acid precipitates to form monosodium urate crystals, which deposit in the joint and lead to inflammation and pain, redness, warmth, and edema.

Review17:03–18:01

Over time, chronic gout can lead to bone erosion. Diagnosis is based on synovial fluid analysis, where monosodium urate crystals have a sharp, needle-like form, and are negatively birefringent.
CPPD is caused by calcium pyrophosphate crystal accumulation in the joint, which results to a similar clinical picture as gout.
This disorder is more likely to affect multiple joints and are more common in larger joints like the knees. Diagnosis is based on synovial fluid analysis as well, where CPPD crystals are weakly positively birefringent and they have a rhomboid or rod-shaped appearance.
Ok, now back to our cases. Ashvir comes in with the classic presentation of a gout attack; a severely painful right big toe with signs of inflammation like redness, swelling, and warmth.

Summary18:01–18:40

He is also obese, which is a risk factor for gout. Our suspicion was confirmed by synovial fluid analysis, which detected monosodium urate crystals.
Bianca’s symptoms painted a similar picture, however, her history of hemochromatosis makes us think of CPPD and not gout.
This suspicion was confirmed by the weakly positively birefringent crystals found on synovial fluid analysis, which are characteristic of this condition.
Gout and pseudogout: Video, Causes, and Symptoms | Osmosis