Uric acid production
PATHOPHYSIOLOGY OF GouT
These lecture notes accompany my lectures on pathophysiology in the study module "Musculoskeletal system" at Innsbruck Medical University. The English version serves two purposes: as a learning aid for international students and to encourage German-speaking students to familiarize themselves with medical English; the lectures are delivered in German. The translation from the original German version is my own; I am afraid it will occasionally sound appalling to native English speakers, but it should at least be intelligible.
There is also a printable pdf-version.
Gout is an inflammatory reaction to monosodium urate crystals. In the human body, urate is constantly near its limit of solubility, in a flux balance between production and elimination.
URIC ACID PRODUCTION
Uric acid is formed by breakdown of purines from nucleic acids. By two hydroxylation reactions, xanthine oxidase transforms hypoxanthine via xanthine to uric acid. In animals, uric acid is further metabolized to highly water-soluble allantoin by opening the larger of the two rings with the help of the enzyme uricase. While the human genome still contains the gene for uricase, it has been inactivated by mutation in a hominid ancestor. Gout is therefore an exclusively human (or rather, primate) problem.
It has been known since a long time that fasting strongly elevates serum urate levels. As we will see in a minute, the ketoacidotic state typical of fasting causes increased renal reabsorption. But production of uric acid is increased, too, via a mechanism resembling the one seen in fructose consumption. In fasting, more ATP is broken down, causing AMP to be metabolized to uric acid. In addition, the normal equilibrium between cell death and proliferation in our organism is skewed towards cell death, causing breakdown of more DNA. A typical situation where involuntary fasting may result in a gout flare is surgery, where a certain period of fasting is required by anesthesia.
In patients with leukemia or lymphoma receiving their first rounds of chemotherapy, breakdown of cells may cause marked hyperuricemia and acute gouty arthritis.
URIC ACID ELIMINATION
As its name implies, uric acid is eliminated mainly via the kidneys. A smaller part is excreted via the intestines.
In the kidney, about 10% of filtered load is excreted, but this percentage is highly variable. The excreted amount is the net result of simultaneous reabsorption and secretion processes. In the proximal tubule, cells use SLC22A12 (synonym: URAT1, urate transporter 1) to reabsorb filtrated urate anions in exchange for intracellular organic anions such as lactate or ketone bodies. In a metabolic state of lactic acidosis (alcohol) or ketoacidosis, in which lactate or ketone bodies are actively secreted, urate reabsorption is thus increased: both feasting and fasting raise urate levels and abet gout flares. Working in the opposite direction, purine nucleoside transporter ABCG2 and voltage-driven transporter SLC17A3 pump urate back into the lumen. At the basolateral membrane, voltage-dependent SLC2A9 transfers urate from the cell into the blood.
Solute carrier SLC2A9 is expressed by all cells of our body. While in the proximal tubule cell, relative concentrations cause it to export urate, it is very well able to import urate into other cells. SLC2A9 is a target gene of p53, the guardian of our genome. Via p53, DNA damage by reactive oxygen species leads to induction of SLC2A9 and thereby to increased import of radical-scavenging urate. There are indications that the loss of uricase gene function may have enabled primates to live longer lives by better shielding cells from oxidative damage.
Renal excretion of urate is heavily influenced by genetic factors. Logically, polymorphisms making SLC22A12 less efficient increase renal excretion of uric acid, while problems with outward transporters result in hyperuricemia. A SNP (single nucleotide polymorphism) in ABCG2 results in amino acid exchange Gln141Lys. This substitution changes a conserved position in the intracellular ATP-binding domain and cuts the protein's urate transport rate by about 50%. This SNP is quite frequent, with about 10-20% of Europeans and 30- 50% of Asians carrying the allele. Presence of the allele roughly doubles the risks of hyperuricemia and gout. Missense mutations in SLC17A3, too, were reported to cause hyperuricemia and gout.
Urate excretion via the intestines is mediated by ABCG2, too. Thus, SNPs reducing the efficiency of this transporter negatively impact elimination via both kidneys and intestines.
Estrogen has a uricosuric effect by modulating expression of renal urate transporters, substantially decreasing serum urate levels in premenopausal women.
One key problem for our understanding of gout is the fact that only a minority of individuals with hyperuricemia develop gout. More than 10% of the population in affluent countries has hyperuricemia (21% of males but only 3% of premenopausal females), however, only about 0.5% develop gout. Hyperuricemia is defined as serum levels of 6.8 mg/dl or more, the limit of uric acid solubility under physiologic conditions. Above this level, monosodium urate (MSU) crystals are forming somewhere in the body. The higher the serum levels over time, the higher the probability of an eventual attack of gout. Hyperuricemia is in 90% caused by inadequate renal elimination.
Do we have to worry about asymptomatic hyperuricemia? We don't yet know for sure, but there are indications that hyperuricemia may promote hypertension and vascular disease.
The "crystal-clear" way to diagnose gout is to aspirate some synovial fluid from the affected joint and look for the birefringent needle-like crystals in the polarizing microscope. However, for the danger of infections and other potential complications, it is not terribly popular to puncture a joint. Therefore, in most cases diagnosis is based on clinical presentation, which is quite characteristic: severe pain developing within hours, tenderness, warmth, swelling and erythema, e. g. in the first metatarsophalangeal or metacarpophalangeal joint. Frequently, gout flares up following rich meals and alcohol consumption, in the middle of the night.
IL‑1β is just the leading ingredient of a macrophage-released cocktail that also includes TNFα, IL-6, CXCL8 (IL‑8) and other inflammatory mediators. CXCL8 attracts neutrophils. These are activated and contribute to acute arthritis with production of reactive oxygen species, lysosomal enzymes, prostaglandins and leukotrienes.
MSU crystals may form not only in the synovial fluid, but also in synovial membranes, peri-articular tissues like tendons, ligaments and bursae and elsewhere in the body, e. g. in the skin. Around these urate aggregates forms inflammatory reactive tissue that basically constitutes a foreign-body granuloma, altogether called a tophus. The reactive tissue consists of macrophages, multinuclear giant cells, lymphocytes and proliferating fibroblasts.
At the plasma pH of 7.4, 98% of uric acid is in the ionized form of urate. In the renal medulla, where pH may go down below uric acid's pKa of 5.75, uric acid formation is favored. Uric acid is less soluble than urate, so the renal medulla is especially conducive to uric acid crystallization which may lead to intratubular precipitations and interstitial tophi. Low volume and low pH of urine favor further development of urate stones.
Regarding kidney stones, about 10% consist primarily of uric acid.
Gout attack as part of the tumor lysis syndrome
Initial therapy of leukemia, lymphoma or a malignant tumor can result in massive simultaneous cell death. In this condition, one of the problems is large-scale breakdown of DNA in the presence of impaired renal function, resulting in a spike of hyperuricemia and gout attacks. In this case, short-term prevention is possible by injecting uricase from another organism.
PHARMACOLOGY CROSS REFERENCE: THERAPEUTIC STRATEGIES
Patients need treatment in two different situations: during an acute flare of gout to alleviate symptoms and, in case of repeated acute attacks, during the interval to reduce the likelihood of another attack. A constraint to be kept in mind is renal function: some of the drugs below are contraindicated if creatinine clearance is reduced.
Options to alleviate acute attacks:
Colchicine has been used to treat gout since antiquity. It is a toxin from autumn crocus (Colchicum autumnale) that binds to tubulin and inhibits its polymerization. Microtubules are required for vesicle transport and for the mitotic spindle. Colchicine works well to alleviate the excruciating pain of an acute flare, but its use is a balancing act against its toxic side effects. Obviously, the oral drug reaches its highest concentrations in the gastrointestinal tract, causing nausea and other gastrointestinal symptoms. It is contraindicated at reduced creatinine clearance. Colchicine is most useful if patients have it at home, so that they are able to take it quickly in response to a flare.
Options to bring down serum urate levels:
As we have seen, levels of urate depend on production as well as elimination. Urate-lowering therapy may be initiated on either end, with pharmaceuticals available to either inhibit urate-producing xanthine oxidase or to enhance renal elimination. During the first weeks or months of urate-lowering therapy patients are at increased risk of a flare of disease, possibly by mobilization of urate from tissue deposits. Prophylaxis with NSAIDS or colchicine is attempted to prevent these flares.
Xanthine oxidase inhibitors:
Allopurinol is a purine analog structurally resembling hypoxanthine: just a single nitrogen is shifted within the smaller of the two rings. It competes with hypoxanthine for the xanthine oxidase binding site. With inhibition of xanthine oxidase, less uric acid is produced and more hypoxanthine and xanthine are eliminated via the kidney. To minimize the risk of acute flares during therapy initiation, it has to be started in increments of 100 mg. It has to be dosed individually: at the typical dose of 300 mg per day, many patients remain underdosed and still demonstrate hyperuricemia. Patients with HLA allele HLA-B*58.01 are at increased risk for a hypersensitivity syndrome, which might be caused by allopurinol-modification of the MHC binding pocket, paralleling the hypersensitivity mechanism shown for HIV-medication Abacavir. The hypersensitivity syndrome may manifest as Stevens-Johnson or Lyell syndromes with high lethality. Should this risk be taken to prevent attacks of a painful, but usually self-limiting disease?
Febuxostat is a non-purine inhibitor of xanthine oxidase. It is hoped to avoid the grave but rare complications of allopurinol; whether that holds true will take years to establish. Flare prophylaxis seems even more important than with allopurinol and cardiovascular side effects may be more frequent.
Uricosuric agents enhance uric acid elimination, primarily by inhibiting urate anion reabsorption in the proximal tubule. Of the three potential candidates, in most countries, only one is licensed; which one, varies according to country. This is an indication that all three have their problems. Obviously, they all rely on adequate renal function and become useless below a certain level of creatinine clearance. More excretion means higher urine concentrations and therefore, increased risk of urolithiasis, especially in acidic urine.
Injecting uricase to break down uric acid
Reintroducing uricase, the enzyme lost in evolution, at first glance seems like a brilliant idea, but the problem is that our immune system never learned to tolerate it. Over time, we are bound to raise antibodies against it, in the best case making it ineffective, in the worst case producing more problems than we had before. So, it's either for desperate situations or for short-term indications. Two forms are used:
TEXTBOOK SOURCES AND FURTHER READING:
Kumar V. et al. (eds.): Robbins and Cotran Pathologic Basis of Disease, 10th Edition, Saunders, Philadelphia, 2020
Terkeltaub, Nature Rev. Rheumatol. 6: 30-38 (2010)
Neogi, New Engl. J. Med. 364: 443-452 (2011)
Schwarz et al. (eds.): Pathophysiologie, Maudrich, Wien, 2007