Ultrasonography in the diagnosis of asymptomatic hyperuricemia and gout.

Sonography has detected urate deposits in 34%-42% of the patients with asymptomatic hyperuricemia. This may prompt reclassification of asymptomatic hyperuricemia into "asymptomatic gout" and consideration of urate lowering therapy (ULT) to resolve urate deposits. In patients with gout and no visible tophi, sonography has detected urate deposits in half of the patients. This may allow diagnosing "tophaceous gout" and influencing the serum urate target level, prophylaxis to avoid acute gout flares during ULT, and clinical follow-up. Current accessibility to sonography may better classify patients with hyperuricemia and gout and contribute to delineate therapeutic objectives and clinical guidance.

A review of the implication of hypoxanthine excess in the physiopathology of Lesch-Nyhan disease.

Lesch-Nyhan disease is caused by HGprt deficiency, however, the mechanism by which enzyme deficiency leads to the severe neurological manifestations is still unknown. We hypothesized that hypoxanthine excess leads, directly or indirectly, through its action in adenosine transport, to aberrations in neuronal development. We found that hypoxanthine diminishes adenosine transport and enhances stimulation of adenosine receptors. These effects cause an imbalance between adenosine, dopamine, and serotonin receptors in HGprt deficient cells, and cells differentiated with hypoxanthine showed an increase in dopamine, adenosine and serotonin receptors expression. Hypoxanthine deregulates early neuronal differentiation increasing WNT4 and EN1 gene expression.

The management of hyperuricemia with urate deposition.

Recent epidemiological data suggest a progressive increase of serum levels of uric acid worldwide. This rise in the prevalence of hyperuricemia may be related to the epidemic diffusion of overweight and obesity as well as the shifts in diet with increased consumption of foods rich in purines, alcoholic consumption, and soft drinks sweetened with fructose. The rise in serum uric acid levels worldwide may be regarded as leading an increased risk for gout and other systemic diseases, especially in the cardio-renal system. Therefore, careful management of hyperuricemia with urate deposition is crucial to prevent or even treat those systemic diseases. Despite this, hyperuricemia and gout often remain untreated. This paper reviews current evidence on the management of hyperuricemia with urate deposition, with a focus on its most controversial aspects. This review is based on a PubMed/Embase database search for articles on hyperuricemia and its impact on cardiovascular and renal function.

Hypoxanthine deregulates genes involved in early neuronal development. Implications in Lesch-Nyhan disease pathogenesis.

Neurological manifestations in Lesch-Nyhan disease (LND) are attributed to the effect of hypoxanthine-guanine phosphoribosyltransferase (HPRT) deficiency on the nervous system development. HPRT deficiency causes the excretion of increased amounts of hypoxanthine into the extracellular medium and we hypothesized that HPRT deficiency related to hypoxanthine excess may then lead, directly or indirectly, to transcriptional aberrations in a variety of genes essential for the function and development of striatal progenitor cells. We have examined the effect of hypoxanthine excess on the differentiation of neurons in the well-established human NTERA-2 cl.D1 (NT2/D1) embryonic carcinoma neurogenesis model. NT2/D1 cells differentiate along neuroectodermal lineages after exposure to retinoic acid (RA). Hypoxanthine effects on RA-differentiation were examined by the changes on the expression of various transcription factor genes essential to neuronal differentiation and by the changes in tyrosine hydroxylase (TH), dopamine, adenosine and serotonin receptors (DRD, ADORA, HTR). We report that hypoxanthine excess deregulate WNT4, from Wnt/ß-catenin pathway, and engrailed homeobox 1 gene and increased TH and dopamine DRD1, adenosine ADORA2A and serotonin HTR7 receptors, whose over expression characterize early neuro-developmental processes.

Fenofibrate increases serum creatinine in a patient with familial nephropathy associated to hyperuricemia.

BACKGROUND: Kidney function progressively deteriorates in patients with familial juvenile hyperuricemiac nephropathy (FJHN, OMIN 162000) and chronic renal disease is commonly associated to dyslipidemia. We report for the first time abrupt renal insufficiency in a patient with FJHN and hypertrygliceridemia following fenofibrate administration. CASE REPORT: A 53-year-old man was diagnosed clinically with FJHN at age 24 years which was subsequently confirmed by genotypic analysis of the UMOD gene at age 40 years. His mother and two brothers suffered the disease. At that time, renal size and function were normal, as was his blood pressure and serum lipids. At age 34 years, serum urate was 8.5 mg/dL and creatinine 1.7 mg/dL (GFR, 58 mL/min/1.73 m2). He was treated with allopurinol, losartan, and lovastatin. Serum TG levels ranged between 150 and 250 mg/dL. At age 52 years, serum urate was 4.1 mg/dL, creatinine 3.2 mg/dL, LDLc 99 mg/dL (atorvastatin 40 mg/d), and TG 275 mg/dL. Fenofibrate (160 mg/d) was added. One month later, serum creatinine increased to 4.2 mg/dL and TG decreased to 125 mg/dL. He did not complain of muscle pain, weakness, or changes in urinary frequency or color and rabdomyolysis was discarded. Fenofibrate was withheld and three months later serum creatinine decreased to baseline levels (3.2 mg/dL) and TG increased to 197 mg/dL. CONCLUSION: To our knowledge, this is the first patient with FJHN in whom fenofibrate administration was associated to a further impairment in renal function not attributable to rabdomyolysis.

HPRT deficiency in Spain: what have we learned in the past 30 years (1984-2013)?

Since 1984, we have diagnosed at the La Paz University Hospital, Madrid, Spain, 41 patients with hypoxanthine phosphoribosyltransferase (HPRT) activity deficiency. These patients belonged to 34 families. We have also performed molecular and enzymatic diagnosis in three patients from India, one from Belgium, and three from Colombia. About 1/3 of these patients were followed up at La Paz University Hospital at least every year. This fact has allowed us to examine the complete spectrum of HPRT deficiency as well as to perform a more accurate diagnosis and treatment. In the present review, we also summarized our studies on the basis of physiopathology of the neurological manifestation of Lesch Nyhan disease (LND).

Partial HPRT deficiency phenotype and incomplete splicing mutation.

Deficiency of hypoxanthine-guanine phosphoribosyltransferase (HPRT) activity is an inborn error of purine metabolism associated with uric acid overproduction and a continuum spectrum of neurological manifestations depending on the degree of enzyme deficiency. The complete deficiency causes Lesch-Nyhan syndrome (LNS). Partial HPRT-deficient patients can show a variable degree of neurological manifestations. Both diseases have been associated with mutations in the HPRT1 gene. Documented mutations in HPRT deficiency show a high degree of heterogeneity in type and location within the gene. In fact, more than 300 disease-associated mutations have been described. Splice mutations accounts for more that 16% of HPRT mutations and in most cases cause a complete LNS phenotype. A 16 year-old boy consulted to La Paz University Hospital because of hyperuricemia (9.4 mg/dL). At age one year he was given a diagnosis of dystonic cerebral palsy. Although he usually employs a wheelchair, under certain circumstances, he is able to stand up and walk by himself. He has never showed self injurious behavior. This patient presented a splice mutation (NM_000194.2: c.552 -2 A > G) causing exon 5 exclusion. An exon-5 specific PCR was designed, and a minor amount of normally spliced HPRT mRNA was found. Normally spliced HPRT mRNA was quantified by real-time PCR in this patient, in control subjects, and in two Lesch Nyhan patient with splice mutations excluding exon 4 (patient B) and exon 8 (patient C) who had clinically a Lesch Nyhan disease phenotype. A minor amount of normally spliced HPRT mRNA was found in all the patients. No correlation was found between the percentage of the normally spliced HPRT mRNA and the phenotype. We conclude that the partial HPRT deficient phenotype of this patient can not be explained by the finding of a minor amount of normally splice HPRT mRNA. It is possible that the amount of normally splice mRNA vary among different tissues.

Methylation status of HPRT1 promoter in HPRT deficiency with normal coding region.

UNLABELLED: Lesch-Nyhan syndrome is an X-linked recessive inborn error of metabolism due to a complete deficiency of hypoxanthine-guanine phosphoribosyltransferase (HPRT) activity (OMIM 300322). Partial deficiency of HPRT (OMIM 300323) is characterized by the effects of excess uric acid synthesis and a continuum spectrum of neurological manifestations, without the manifestations of full-blown Lesch-Nyhan syndrome. Both diseases have been associated with mutations in the HPRT1 gene. We have described one Lesch-Nyhan patient and four partial HPRT deficient patients with a normal HPRT1 coding region. These patients showed markedly decreased HPRT mRNA expression, but no mutation in their genomic regulatory sequences from HPRT1 gene. In this study, we analyzed the promoter region methylation status of the HPRT1 gene in these five HPRT deficient patients. METHODS: DNA was bisulphite modified and a 620 bp fragment including 320 bp 5' to start codon was amplified and sequenced. The methylation status of 35 CpG island 5' to start codon and 28 CpG island 3' to start codon were investigated in male controls, female controls, patients, and the patient's mothers. Primer pairs were designed for methylated-specific and unmethylated-specific amplification and PCR was performed employing DNA bisulphite treated as template. RESULTS: No alterations in the methylation pattern of the HPRT1 promoter were found in the five HPRT deficient patients. CONCLUSIONS: The promoter region methylation status of these five HPRT deficient patients was similar to that of normal subjects. Thus, some other genetic alteration must explain a reduced enzyme activity with a normal gene coding region.

Metabolic syndrome characteristics in gout patients.

Gout is commonly associated with obesity, arterial hypertension, diabetes, and dyslipidemia. However, the prevalence of metabolic syndrome has not been widely recognized in patients with gout. We studied 41 patients (37 males) with primary gout to assess the prevalence and characteristics of the associated metabolic syndrome. Twenty-one patients with gout (51%) showed >or=3 criteria for the metabolic syndrome. Pathological conditions associated were obesity (21/41), high blood pressure (30/41), dyslipidemia (30/41), and fasting plasma glucose >or= 100 mg/dL (22/41). The most frequent triad was the presence of increased waist circumference, elevated fasting plasma glucose, and hypertension. Mean serum urate concentration did not differ significantly in gout patients with the metabolic syndrome (8.5 mg/dl) and without (8.1 mg/dl). Given the complications associated with metabolic syndrome, its diagnosis may determine the long-term treatment of patients with gout.

Uric acid metabolism in patients with primary gout and the metabolic syndrome.

Forty-four patients (40 males) with a mean age of 58 years were included in this pilot study. Mean serum urate concentration in patients with and without the metabolic syndrome (MS) was 8.8 mg/dL and 8.1 mg/dL, respectively. Urinary uric acid excretion was 543 mg/day/1.73 m(2) in the former and 609 mg/day/1.73 m(2) in the latter. Uric acid to creatinine ratio was 0.37 mg/mg in patients with the MS and 0.42 mg/mg in those without the MS. Mean serum urate increased from 8.6 mg/dL in subjects with three or more MS components to 10.3 mg/dL in those with five MS components. Serum urate was markedly lower in patients with mild MS (9 patients, 8.6 mg/dL) as compared to severe MS (10 patients, 9.2 mg/dL). In contrast, urinary uric acid to creatinine ratio was 0.42 mg/mg in patients with gout and mild MS and 0.33 mg/mg in gout patients with severe MS. Uric acid underexcretion appears to be more severe in gout patients with the MS. This disturbance appears to be related to the severity of the MS.

Abnormal adenosine and dopamine receptor expression in lymphocytes of Lesch-Nyhan patients.

Self-injurious behavior is the most outstanding feature of Lesch-Nyhan syndrome and has recently been ascribed to an obsessive-compulsive behavior. Lesch-Nyhan syndrome results from the complete enzyme deficiency of hypoxanthine-guanine phosphoribosyl transferase (HPRT) but the link between abnormal purine metabolism and its neurological and behavioral manifestations remains largely unknown. Previous studies led us to hypothesize that adenosine and dopamine receptor expression could be altered in HPRT-deficient cells. To test this hypothesis, we examined mRNA expressions of adenosine (ADORA2A and ADORA2B) and dopamine receptors (DRD1 and DRD2 like), and dopamine transporter (DAT1) in peripheral blood lymphocytes (PBLs) from Lesch-Nyhan patients. We also examined the influence of hypoxanthine in these expressions. As compared to normal PBLs, both ADORA2A and DRD5 expression were abnormal in PBLs from Lesch-Nyhan patients. In contrast, DAT1 expression was similar to control values in HPRT deficient PBLs. These results indicate an abnormal adenosine and dopamine receptor expression in HPRT-deficient cells and suggest disrupted adenosine and dopamine neurotransmission may have a significant role in the pathogenesis of the neurological manifestations of Lesch-Nyhan syndrome.

The diagnosis of HPRT deficiency in the 21st century.

We have studied 36 patients with HPRT deficiency, 25 with Lesch-Nyhan syndrome and 11 with partial HPRT deficiency (grades 1 to 3). Patients diagnosed with HPRT deficiency have increased 50% since 2000. The most relevant recent advances have been made in molecular diagnosis. Nevertheless, enzyme determinations are still essential for the diagnosis of HPRT deficiency. Therapy for the neurological manifestations of HPRT deficiency has not advanced. Allopurinol remains the drug of choice to diminish uric acid overproduction, but the optimal allopurinol dose must be established in each patient to prevent xanthine or uric acid urolithiasis, a process aided by sequential determination of urinary oxypurines and uric acid.

Urinary guanidinoacetate and creatine levels in patients with HPRT deficiency.

Neurobehavioral manifestations of complete HPRT deficiency include severe action dystonia, choreathetosis, alteration of executive functions, and self-injurious behavior. Dystonic manifestations are also present in patients with partial HPRT deficiency. Pathophysiology of these manifestations is unknown. Guanidinoacetate is a neurotoxin implicated in certain dystonic syndromes. We have examined guanidinoacetate and creatine levels in urine from 11 HPRT deficient patients (9 with Lesch-Nyhan syndrome and 2 with partial deficiency). Urinary guanidinoacetate and creatine levels in HPRT deficient patients were within the normal range. Guanidinoactetate alteration does not seem to be implicated in the pathogenesis of the neurological disease associated with HPRT deficiency.

Asymptomatic hyperuricemia: impact of ultrasonography.

Thirty-five patients (23 males) with asymptomatic hyperuricemia for at least two years underwent two-dimensional ultrasonography of knees and ankles. Urate deposits (tophi) in tendons, synovium, and other soft tissues were detected in 12 patients (34%). Increased vascularity (inflammation) was evident in 8 of these patients (23%). Tophi were more frequently found in knees than in ankles and were especially prevalent in the distal patellar tendon. The presence of tophi was unrelated to the known duration of hyperuricemia (mean, 5 years). Ultrasonography allows detection of tophi and inflammation in a third and in a fourth, respectively, of asymptomatic hyperuricemic patients.

An unusual patient with hypothyroidism, tophaceous gout, and marked joint destruction.

This report describes a 75-year-old Caucasian man with extensive urate deposits and severe gouty arthropathy that confined him to a wheelchair. Since age 50, he suffered multiple acute gout flares and progressive deformities in his hands, feet, knees, and elbows (tophi). Serum creatinine was 1.4 mg/dL and serum urate 9.4 mg/dL. Conditions known to increase uric acid production (psoriasis, chronic bronchitis) and to decrease uric acid excretion (hypothyroidism, metabolic syndrome, and nephroangiosclerosis) may operate in a single patient, illustrating the dramatic clinical course of untreated gout.

Serum urate, metabolic syndrome, and cardiovascular risk factors. A population-based study.

We studied the associations between serum urate levels (determined in 503 subjects from a population of 1,344 subjects living in northern Madrid) and both the metabolic syndrome (MS) (defined by the Adult Treatment Panel III criteria) and C-reactive protein (CRP, determined in 382 subjects). MS was diagnosed in 25% (95%CI, 21-28%) and was associated with hyperuricemia (p<0.001). There was a graded increase in serum urate levels with increasing number of MS components. Urate concentrations significantly correlated with waist circumference (r=0,455, p<0.01). Serum urate was not independently associated with CRP levels. This study shows that serum urate levels are associated with the presence of MS and each of its features.

Hypoxanthine decreases equilibrative type of adenosine transport in lymphocytes from Lesch-Nyhan patients.

BACKGROUND: Lesch-Nyhan (LN) syndrome is associated with deficient hypoxanthine-guanine phosphoribosyltransferase (HPRT) activity, but the connection between the aberrant purine metabolism and the neurological symptoms remains largely unknown. The aim of this study was to determine adenosine transporter subtypes affected by HPRT deficiency and by the associated hypoxanthine excess. MATERIALS AND METHODS: Nucleoside transporter types (depending on their sodium dependence and 10 microm nitrobenzylthioinosine, NBTI, sensitivity) involved in adenosine transport were compared between peripheral blood lymphocytes (PBL) obtained from nine LN patients, PBL(LN) (2-21 years) and from nine controls, PBL(C) (2-23 years) under basal conditions and after 25 microm hypoxanthine incubation. RESULTS: We found four types of adenosine transporters in PBL: equilibrative and concentrative transporters that are either sensitive (ENT1 or cs) or insensitive (ENT2 or ci) to NBTI. Adenosine ENT1 uptake was the predominant transporter in both PBL(C) (55%) and PBL(LN) (46%). Under basal conditions no significant differences were found in adenosine transport between PBL(C) and PBL(LN). Incubation of PBL with 25 microm hypoxanthine markedly decreased total adenosine transport in both cell types. Hypoxanthine affected equilibrative transport (mainly ENT2 type) in PBL(LN) and PBL(C). Only in PBL(C) was concentrative transport affected by hypoxanthine. Expressions of human (h) ENT1 and hENT2 mRNA were not significantly modified by hypoxanthine incubation in PBL(C). CONCLUSIONS: This study contributes to further knowledge of the defective adenosine transport found in PBL(LN). Increased hypoxanthine levels, similar to those reported in HPRT deficient patients, reduced adenosine uptake by 32% in PBL(LN) as compared to normal transport.

A comparison of the tolerability of the direct renin inhibitor aliskiren and lisinopril in patients with severe hypertension.

Patients with severe hypertension (>180/110 mm Hg) require large blood pressure (BP) reductions to reach recommended treatment goals (<140/90 mm Hg) and usually require combination therapy to do so. This 8-week, multicenter, randomized, double-blind, parallel-group study compared the tolerability and antihypertensive efficacy of the novel direct renin inhibitor aliskiren with the angiotensin converting enzyme inhibitor lisinopril in patients with severe hypertension (mean sitting diastolic blood pressure (msDBP)>or=105 mm Hg and <120 mm Hg). In all, 183 patients were randomized (2:1) to aliskiren 150 mg (n=125) or lisinopril 20 mg (n=58) with dose titration (to aliskiren 300 mg or lisinopril 40 mg) and subsequent addition of hydrochlorothiazide (HCTZ) if additional BP control was required. Aliskiren-based treatment (ALI) was similar to lisinopril-based treatment (LIS) with respect to the proportion of patients reporting an adverse event (AE; ALI 32.8%; LIS 29.3%) or discontinuing treatment due to AEs (ALI 3.2%; LIS 3.4%). The most frequently reported AEs in both groups were headache, nasopharyngitis and dizziness. At end point, ALI showed similar mean reductions from baseline to LIS in msDBP (ALI -18.5 mm Hg vs LIS -20.1 mm Hg; mean treatment difference 1.7 mm Hg (95% confidence interval (CI) -1.0, 4.4)) and mean sitting systolic blood pressure (ALI -20.0 mm Hg vs LIS -22.3 mm Hg; mean treatment difference 2.8 mm Hg (95% CI -1.7, 7.4)). Responder rates (msDBP<90 mm Hg and/or reduction from baseline>or=10 mm Hg) were 81.5% with ALI and 87.9% with LIS. Approximately half of patients required the addition of HCTZ to achieve BP control (ALI 53.6%; LIS 44.8%). In conclusion, ALI alone, or in combination with HCTZ, exhibits similar tolerability and antihypertensive efficacy to LIS alone, or in combination with HCTZ, in patients with severe hypertension.

Lercanidipine, enalapril and their combination in the treatment of elderly hypertensive patients: placebo-controlled, randomized, crossover study with four ABPM.

This double-blind, placebo-controlled, four-way balanced design crossover study included hypertensive patients aged 60-85 years with mean office-measured sitting systolic blood pressure (SBP) 160-179 mm Hg and daytime SBP > or =135 mm Hg. After a 2-week run-in period, during which previous medications were discontinued, each patient received the following four treatments in randomized order for 4 weeks each: lercanidipine 10 mg (L), enalapril 20 mg (E), lercanidipine 10 mg plus enalapril 20 mg (L/E) and placebo (P). At the end of each treatment period, office trough blood pressure (BP) was measured and a 24-h Ambulatory Blood Pressure Monitoring (ABPM) was performed. Seventy-five patients (mean age 66 years, office BP 168/92 mm Hg, daytime SBP 151 mm Hg) were randomized and 62 completed the study with four valid post-baseline ABPMs. The administration of P, L, E and L/E was associated with a mean 24-h SBP of 144, 137, 133 and 127 mm Hg, respectively. All active treatments significantly reduced the mean 24-h SBP in comparison with placebo, but L/E was significantly more effective than L and E alone. Similarly, office SBP was significantly more reduced with L/E (-16.9 mm Hg) than with L (-5.0 mm Hg) or E (-5.9 mm Hg). A BP <140/90 mm Hg was recorded in 18% of patients with L, 19% with E and 45% with L/E. Two patients on P and two on L/E were withdrawn from the study due to adverse events. In conclusion, combination therapy with L/E has additive antihypertensive effects on both ambulatory and office BP in elderly patients and is well tolerated.

Hypoxanthine effect on equilibrative and concentrative adenosine transport in human lymphocytes: implications in the phatogenesis of Lesch-Nyhan syndrome.

We postulated that increased levels of hypoxanthine, a main characteristic of hypoxanthine phosphoribosyltransferase (HPRT) deficiency, may influence adenosine function which could be related to some of the neurological features of the Lesch-Nyhan syndrome. We have examined the effect of hypoxanthine on different adenosine transporters in peripheral blood lymphocytes from control subjects. Increased hypoxanthine concentrations (25 microM) significantly decreased adenosine transport. The equilibrative adenosine transporters (79.6% of the adenosine transport), both NBTI sensitive and NBTI insensitive, were affected significantly. In contrast, the concentrative adenosine transporters were not influenced by hypoxanthine. These results supports the hypothesis that increased hypoxanthine levels influence equilibrative (predominantly NBTI-insensitive type) adenosine transporters.