Uric acid extrarenal excretion: the gut microbiome as an evident yet understated factor in gout development.

Humans do not produce uricase, an enzyme responsible for degrading uric acid. However, some bacteria residing in the gut can degrade one-third of the dietary and endogenous uric acid generated daily. New insights based on metagenomic and metabolomic approaches provide a new interest in exploring the involvement of gut microbiota in gout. Nevertheless, the exact mechanisms underlying this association are complex and have not been widely discussed. In this study, we aimed to review the evidence that suggests uric acid extrarenal excretion and gut microbiome are potential risk factors for developing gout. A literature search was performed in PubMed, Web of Science, and Google Scholar using several keywords, including "gut microbiome AND gout". A remarkable intestinal dysbiosis and shifts in abundance of certain bacterial taxa in gout patients have been consistently reported among different studies. Under this condition, bacteria might have developed adaptive mechanisms for de novo biosynthesis and salvage of purines, and thus, a concomitant alteration in uric acid metabolism. Moreover, gut microbiota can produce substrates that might cross the portal vein so the liver can generate de novo purinogenic amino acids, as well as uric acid. Therefore, the extrarenal excretion of uric acid needs to be considered as a factor in gout development. Nevertheless, further studies are needed to fully understand the role of gut microbiome in uric acid production and its extrarenal excretion, and to point out possible bacteria or bacterial enzymes that could be used as probiotic coadjutant treatment in gout patients.

Taxonomic variations in the gut microbiome of gout patients with and without tophi might have a functional impact on urate metabolism.

OBJECTIVE: To evaluate the taxonomic composition of the gut microbiome in gout patients with and without tophi formation, and predict bacterial functions that might have an impact on urate metabolism. METHODS: Hypervariable V3-V4 regions of the bacterial 16S rRNA gene from fecal samples of gout patients with and without tophi (n = 33 and n = 25, respectively) were sequenced and compared to fecal samples from 53 healthy controls. We explored predictive functional profiles using bioinformatics in order to identify differences in taxonomy and metabolic pathways. RESULTS: We identified a microbiome characterized by the lowest richness and a higher abundance of Phascolarctobacterium, Bacteroides, Akkermansia, and Ruminococcus_gnavus_group genera in patients with gout without tophi when compared to controls. The Proteobacteria phylum and the Escherichia-Shigella genus were more abundant in patients with tophaceous gout than in controls. Fold change analysis detected nine genera enriched in healthy controls compared to gout groups (Bifidobacterium, Butyricicoccus, Oscillobacter, Ruminococcaceae_UCG_010, Lachnospiraceae_ND2007_group, Haemophilus, Ruminococcus_1, Clostridium_sensu_stricto_1, and Ruminococcaceae_UGC_013). We found that the core microbiota of both gout groups shared Bacteroides caccae, Bacteroides stercoris ATCC 43183, and Bacteroides coprocola DSM 17136. These bacteria might perform functions linked to one-carbon metabolism, nucleotide binding, amino acid biosynthesis, and purine biosynthesis. Finally, we observed differences in key bacterial enzymes involved in urate synthesis, degradation, and elimination. CONCLUSION: Our findings revealed that taxonomic variations in the gut microbiome of gout patients with and without tophi might have a functional impact on urate metabolism.

Investigating MIF in Mouse Model of Gout.

Mice are widely used to assess the pathogenesis of diseases. An experimental model of gout consists of the injection of uric acid crystals into joints of mice, which reproduce inflammation and functional changes of the human disease. Uric acid crystals activate synoviocytes culminating in the release of IL-1ß and neutrophil recruitment, key inflammatory elements in gouty arthritis. Since MIF plays an important role in orchestrating gout inflammation, we detail valuable procedures to investigate uric acid crystal-induced joint inflammation in mice and give options for further understanding the functions of MIF in gouty arthritis in vivo and in vitro.

Combined effects of MSU crystals injection and high fat-diet feeding on the establishment of a gout model in C57BL/6 mice

Abstract Objective: Gout is characterized by inflammatory arthritis with hyperuricaemia and deposition of monosodium urate (MSU) crystals in the joints. Several animal models have been proposed based on MSU crystals injection or high-fat diet feeding; however, neither hyperuricaemia model nor acute gout model can effectively reflect clinical features of gout. This study aimed to assess the effectiveness of a compound gout model induced by the combination of MSU crystals injection and high-fat diet feeding. Methods: The compound gout model was induced by high-fat diet feeding per day and the intraplantar injection of MSU crystals (1 mg) into the footpad of each mouse every 10 days. Serum uric acid, foot swelling and pain analyses were performed at days 22, 32 and 42. Gout inflammation, serum proinflammatory cytokines and gut microbiota analyses were performed only at day 42. Results: Compared to hyperuricaemia model or acute gout model, the compound gout model showed little advantages of elevating serum uric acid, causing foot swelling and gout inflammation, while it caused more severe serum inflammation and gut microbiota dysbiosis. Severe serum inflammation in the compound gout model could be reflected by the increased levels of IL-1 α, IL-4, IL-6, IL-10, IL-12p40, IL-12p70, IFN-γ, KC, MCP-1 and MIP-1β. In addition, the compound gout model induced more alterations in the gut microbiota, including increasing levels of Desulfovibrio and Parasutterella. Conclusion: The injection of MSU and feed of high-fat diet have a combined effect on elevating serum inflammation and causing gut microbiota disorders in the process of establishing a gout model.(AU)

Clinical characteristics and risk factors for gout flare during the postsurgical period

Abstract Objectives: To evaluate the clinical features and risk factors for gout flare during postsurgical period in patients who were previously diagnosed with gout. Methods: Seventy patients who had histories of gout and had been consulted in the rheumatologic clinic before surgery under general anesthesia were included. Clinical characteristics of patients who developed a postsurgical gout flare were compared with those of patients who did not develop gout flare. Results: Among 70 patients, 31 (44.3%) developed gout flare during the postsurgical period. Mean intervals from surgery to gout flare was 3.7 days. Flares tended to involve monoarticular joints (61.3%) and affect lower extremity joints (83.9%). Knee joints (26%) and foot joints except the first metatarsophalangeal (MTP) joint (26%) were more frequently involved than the first MTP joint (13%). Presurgical uric acid level ≥ 9 mg/dL (OR 3.77, 95% CI 1.28-11.10, p = 0.016) and amount of uric acid changes between before and after surgery (OR 1.62, 95% CI 1.21-2.18, p = 0.001) were risk factors for postsurgical gout flare. Taking allopurinol reduced the risk of postsurgical gout flare (OR 0.15, 95% CI 0.05-0.45, p = 0.001). Operation time, amount of blood loss during surgery, and surgery site were not significantly associated with postsurgical gout flare. Conclusions: Adequate uric acid control before surgery could prevent the postsurgical gout flare.

Levels of Cytokines and MicroRNAs in Individuals With Asymptomatic Hyperuricemia and Ultrasonographic Findings of Gout: A Bench-to-Bedside Approach.

OBJECTIVE: To assess potential associations among serum cytokines and microRNA (miR) levels with ultrasound (US) findings suggestive of urate deposits in chronic asymptomatic hyperuricemia and gout. METHODS: All participants underwent musculoskeletal US and measurements of serum interleukin-1ß (IL-1ß), IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12, IL-13, interferon-γ, tumor necrosis factor, monocyte chemoattractant protein 1, and epithelial neutrophil-activating peptide 78, as well as miR-146a, miR-155, and miR-223 levels. RESULTS: Thirty individuals with asymptomatic hyperuricemia, 31 normouricemic controls, and 30 patients with gout were included. The frequency of synovitis and double contour sign using US was similar between asymptomatic hyperuricemia (67% and 27%, respectively) and patients with gout (77% and 27%, respectively), and each had a higher frequency than controls (45% and 0%, respectively). Serum IL-6 and IL-8 levels were similar between patients with asymptomatic hyperuricemia (mean ± SD 69.7 ± 73.4 and 18.5 ± 25.6 pg/ml, respectively) and gout (mean ± SD 75.8 ± 47.6 and 24.4 ± 31.7 pg/ml, respectively), and higher than controls (mean ± SD 28.2 ± 17.6 and 7.4 ± 6.0 pg/ml, respectively). A similar distribution was observed for miR-155 levels in asymptomatic hyperuricemia, patients with gout, and controls (mean ± SD 0.22 ± 0.18, 0.20 ± 0.14, and 0.08 ± 0.04, respectively). Associations between morphostructural abnormalities suggestive of urate deposits (regardless of clinical diagnosis) and serum markers were assessed. Subjects with urate deposits had higher IL-6 (257.2 versus 47.0 pg/ml; P = 0.005), IL-8 (73.2 versus 12.0 pg/ml; P = 0.026), and miR-155 (0.21 versus 0.16; P = 0.015) levels than those without deposition findings. CONCLUSION: In individuals with chronic asymptomatic hyperuricemia, the presence of synovitis and double contour sign by US may represent a subclinical manifestation of monosodium urate crystal nucleation, capable of triggering inflammatory pathways (IL-6 and IL-8) and mechanisms of intercellular communication (miR-155), similar to what is observed in patients with gout.

Management of Gout and Hyperuricemia in CKD.

Hyperuricemia and gout, the clinical manifestation of monosodium urate crystal deposition, are common in patients with chronic kidney disease (CKD). Although the presence of CKD poses additional challenges in gout management, effective urate lowering is possible for most patients with CKD. Initial doses of urate-lowering therapy are lower than in the non-CKD population, whereas incremental dose escalation is guided by regular monitoring of serum urate levels to reach the target level of <6mg/dL (or <5mg/dL for patients with tophi). Management of gout flares with presently available agents can be more challenging due to potential nephrotoxicity and/or contraindications in the setting of other common comorbid conditions. At present, asymptomatic hyperuricemia is not an indication for urate-lowering therapy, though emerging data may support a potential renoprotective effect.

Chronic tophaceous gout in patients with psoriasis.

Psoriasis is a chronic inflammatory disease of multifactorial etiology influenced by genetic, immunological, and environmental factors. We report the case of a patient with psoriasis for more than 25 years who developed hyperuricemia and chronic tophaceous gout with unusual appearance. In psoriasis, hyperuricemia may occur by increased epidermal cell turnover, which accelerates purine metabolism and has uric acid as the product of its catabolism. The association of psoriasis with hyperuricemia can trigger the onset of gouty arthritis, and pose a greater risk of developing other inflammatory comorbidities. Therefore, it is important to periodically investigate uric acid levels in order to treat changes triggered by hyperuricemia.

Chronic tophaceous gout in patients with psoriasis

Abstract: Psoriasis is a chronic inflammatory disease of multifactorial etiology influenced by genetic, immunological, and environmental factors. We report the case of a patient with psoriasis for more than 25 years who developed hyperuricemia and chronic tophaceous gout with unusual appearance. In psoriasis, hyperuricemia may occur by increased epidermal cell turnover, which accelerates purine metabolism and has uric acid as the product of its catabolism. The association of psoriasis with hyperuricemia can trigger the onset of gouty arthritis, and pose a greater risk of developing other inflammatory comorbidities. Therefore, it is important to periodically investigate uric acid levels in order to treat changes triggered by hyperuricemia.

Gout in renal allograft recipients according to the pretransplant hyperuricemic status.

BACKGROUND: Studies to date regarding hyperuricemia and gout in the postrenal transplant (RT) setting do not distinguish neither if patients with gout after the allograft had or did not have hyperuricemia before been transplanted nor if data concerning to hyperuricemia correspond to prevalent or incident cases. Among RT patients, we assessed (1) the incidence of gout in recipients with and without hyperuricemia pre-RT and (2) the incidence of hyperuricemia during the follow-up. METHODS: We selected from our RT registry (1989-2003) 236 subjects who were transplanted in our institution, with at least 1 year follow-up, without gout pre-RT, with at least one measurement of serum uric acid pre-RT and two post-RT. Immunosuppressants, demographic, and clinical features were registered. Survival curves for hyperuricemia and gout were derived using the Kaplan-Meier method and were statistically tested by log rank test. RESULTS: The median follow-up was 4.8 years (1.0-14.9), 43% were women, with a mean body mass index of 22.7+/-3.7 kg/m2 and a mean age at the moment of transplant of 32.4+/-11 years. The incidence of hyperuricemia was 315.2 x 1000 patient-years. Hyperuricemia was diagnosed in half of the subjects during the first year of follow-up. The incidence of gout was 19.7 x 1000 and 2.67 x 1000 patient-years in the groups with and without hyperuricemia pretransplant, respectively (Log rank 9.44, P<0.002). The group with hyperuricemia pre-RT also had earlier and more aggressive gout. CONCLUSIONS: Hyperuricemia was a common complication among RT recipients. However, gout incidence varied according to the pretransplant hyperuricemic status.

Gota familiar y nefropatía en una mujer joven: caso clínico / Familial gout and nephropathy in a young woman: clinical case

We report a 29 years old woman with a chronic tophaceous gout, whose disease started at the age of 18. On clinical examination, the blood pressure was elevated. The laboratory assessment showed a serum uric acid of 15 mg/dl, a urinary uric acid of 155 mg/24 h, a creatinine clearance of 59 ml/min/1.73 m2 and a uric acid excretion fraction off 1.3 per cent (normal 7 to 12 per cent). The clinical and laboratory features of this patient suggest the diagnosis of a familial juvenile gouty nephropathy

Gota e hiperuricemia / Gout and hyperuricemia

La lesión articular por microcristales de urato monosódico es la artritis mas frecuente en el sexo masculino entre los 40 y 60 años. Su presentación clínica clásica esta precedida por un estado morbido de hiperuricemia que debe ser adecuadamente reconocido y manejado. Una vez la gota se presenta clínicamente el papel del médico consiste no solo en tratar el episodio agudo sino en realizar un enfoque diagnóstico y terapéutico acorde con los parámetros internacionales, buscando un control sintomático rápido y seguro. Esta revisiàn incluye conceptos sobre la etiopatogenia, presentación clínica, criterios de diagnóstico y las diferentes opciones terapéuticas disponibles hoy en dia.

Hiperuricemia y gota postrasplante

Evaluamos la frecuencia y probable potegénesis de la hiperuricemia (HU) y la gota que se presentan en pacientes con trasplante renal: 163 recibieron ciclosporina (CS), azatioprina (AZA) y prednisolona (grupo CS), y 147 azotioprina y prednisolona (grupo AZA). La HU se presentó en 76 por ciento del grupos CS, frente a 25 por ciento de AZA (P<0.00001). Catorce pacientes presentaron uno a más episodios de gora, 12 de grupo CS y dos del AZA (P<0.00001); en estos pacientes predominó el sexo masculino (92 por ciento), la edad fue 36ñ8 y 36ñ4 años respectivamente (NS), y la función renal (expresada como creatinina sérica) fue igual en los dos grupos (1.6ñmg/dL). Los niveles séricos de ácido úrico mostraron correlación directa con el uso de diuréticos (r=0.48,P=0.001). La incidencia de HU fue de 15 veces más frecuente en el grupo CS, sugiriendo una interferencia de la CS en la depuración renal de los uratos. A los 24 meses de seguimiento, 70 por ciento de las HUs había desaparecido concomitantemente con la disminución de las dosis de CS. En conclusiónlla HU secundaria al empleo de la CS es un fenómeno transitorio y dependiente de la dosis, y su posible explicación es un defecto tubular en la depuración del ácido úrico

Compromiso osteoarticular asociado a Falciformismo / Osteoarticular involvement associated to sickle cell syndromes

Se reportan 6 pacientes con anemia falciforme (4 con Hb SS, 1 con Hb SC y 1 con Hb SB-talasemia), atendidos en el Hospital Nacional Cayetano Heredia entre 1983 y 1990, que presentaron diversas manifestaciones musculoesqueléticas en el curso de su evolución, resaltando dos casos de necrosis aséptica y un paciente con osteomielitis del fémur por Salmonella tiphy. se discuten los casos en relación a la literatura

Hyperuricemia, gout, and autosomal dominant polycystic kidney disease.

The relationship between hyperuricemia, gout, and autosomal dominant polycystic kidney disease (ADPKD) is not widely recognized. In an attempt to further clarify this relationship, the authors have studied 17 patients with ADPKD, 9 controls, 9 patients with proven gout and chronic renal failure, 11 patients with gout and normal renal function, and 11 patients with chronic renal failure. The mean serum uric acid concentration was higher in patients with ADPKD as a group than in controls (8.0 +/- 1.7 mg/dl vs. 6.4 +/- 1.6 mg/dl, p less than .02). Clinical gout was identified in 24% of patients with ADPKD; none of the patients with chronic renal failure of other etiologies had gout. Fractional excretion of uric acid and the activity of the enzyme hypoxanthine guanine phosphoribosyl transferase (HGPRT) were not different among the groups studied. From this study the authors conclude that ADPKD should be included among those diseases associated with hyperuricemia and gout. A partial deficiency in HGPRT or abnormal renal handling of uric acid do not appear to be responsible for the increased incidence of gout in patients with ADPKD.

Gota / Gout

Luego de hacer referencia al trastorno metabólico, en el curso del cual aparece la gota, el autor comienza por definir las cifras normales de uricemia y analiza el rol que sobre la misma juega la alimentación y otros factores. Recuerda la doble transferencia tubular del ácido úrico para explicar la acción a veces paradojal de muchas sustancias sobre la uraturia y la uricemia. Enumera y analiza los riesgos a que están sometidos los hiperuricémicos y termina con la clínica, los criterios diagnósticos y el tratamiento actualizado de la gota (AU)

Gota / Gout

Luego de hacer referencia al trastorno metabólico, en el curso del cual aparece la gota, el autor comienza por definir las cifras normales de uricemia y analiza el rol que sobre la misma juega la alimentación y otros factores. Recuerda la doble transferencia tubular del ácido úrico para explicar la acción a veces paradojal de muchas sustancias sobre la uraturia y la uricemia. Enumera y analiza los riesgos a que están sometidos los hiperuricémicos y termina con la clínica, los criterios diagnósticos y el tratamiento actualizado de la gota