TBL 4: Hyperuricemia

allopurinol for gout treatment

-Allopurinol starting dose is no greater than 100 mg/day and gradually esclated by 100 mg daily every 2 to 5 weeks with serum urate monitoring until the target serum urate is achieved. -max dose is 800 mg daily. --kidney disease, starting dose should be 50 mg with incremental dose in 50.

clinical manifestations of LND

-hyperuricemia -intellectual disability -dystonic movement disorder that may be accompanied by choreoathetosis and spasticity -dysarthric speech -compulsive slef biting

prevalence and life expectancy of LND

-1 in 100,000 to 1 in 380,000 persons in the US. -rarely survive the 3rd decade due to renal or respiratory compromise. -life span may be normal for those patients with partial HPRT deficiency.

HPRT genetics

-HPRT located to the long arm of the X chromosome. -disorder appears in males, female occurrence is extremely rare and ascribed to nonrandom activation of the normal X chromosome.

conditions of urate crystals

-MSU crystals in joints, soft tissues, and organs cause pain and destruction -urate crystals will form only when physiologic conditions permit. -->urate becomes insoluble at concentrations of 6.8 mg/dL with a pH of 7.4 and normal body temperature. --> reduction in pH or temperature will lower solubility threshold further.

NSAIDs for gout

-NSAIDs may be inappropriate for pets with renal insufficiency or peptic ulcer disease.

Uric acid

-Uric acid is end product of purine metabolism in humans -purine catabolism stops at uric acid (humans do not have uricase) -accumulation of uric acid leads to supersaturation of urate ion in the blood and precipitation of MSU crystals in synovial fluid, soft tissue, and organs

crystal maturation

-after the first flare as a result of being phagocytize and partially digested, matured crystals appear to help terminate the gouty flare. -after acute attack, low grade inflation persists leading to bony erosion, cartilage destruction and synovial hypertrophy

age of onset of self injury

-as early as 1 year old and as late as teens -usually begins with self biting fingers, mouth, buccal mucosa -intensity of self injury generally requires that the patient be restrained. -self mutilation presents as a compulsive behavior that the child tries to control but frequently is unable to resist. -may show injury to others through pinching, grabbing, or hitting.

presumptive diagnosis of gout

based on a pattern of acute joint symptoms coupled with the patient's own medical history or a family history -->pt history may show frequent commodities or medication associated with urate retention.

before treatment with ULT

pt should be placed on maintenance of anti-inflammatory therapy. -prevent or minimize the anticipated increase in flare activity that is associated with starting ULT usually, anti-inflammatory prophylaxis is in the form of colchicine once or twice daily to low dose NSAIDs. -anti-inflammatory prophylaxis should be continued until the subject has been free of gout flares for 6 months or more.

characteristic clinical presentation

rapid onset (8-12 hours) of severe pain in one or several lower extremity joints. -presumptive diagnosis is given much greater credence if there has been similar previous attacks that resolved.

first flare of gout

-at the time of flare, the lattice crystal structures break apart and shed a massive number of crystal into the joints. -these non-opsonized crystals activate receptors on synovial macrophages and are then phagocytize by monocytes and macrophages leading to interaction with NALP3 inflammasome. -->results in rapid production of interleukin-1 which is responsible for the severe inflammation associated with acute gout.

differential diagnosis of gout

-bacterial infection -trauma -sarcoidosis -CPPD arthropathy (pseudogout) diseases usually occasionally confused with advanced gout rheumatoid arthritis, reactive arthritis, and CPPD arthropathy.

clinical manifestation

-birth: no apparent neurologic dysfunction -several months: developmental delay, intellectual disability, and neurologic signs become apparent. -4 mo: hypotonia, reccurent vomiting, and difficulty with secretions may be noted 8-12 mo: extrapyramidal signs appear, primarily dystonic movements. spasticity may become apparent

other forms of treatment

-bone marrow treatment based on the hypothesis that CNS damage is produced by circulating Toxins --several infants have died. No evidence of beneficial treatment -behavior therapy such as systematic desensitization, extinction, and differential reinforcement, self management -->do not respond to contingent shock or similar aversive, instead it increases self injury -restraints and dental procedures -deep brain stimulation to the anteroventral internal globus plaids is procedure that has successfully treated self injury and lessened dystonia in several case reports.

corticosteroids for gout

-can be administered orally, IM, or inta-articularly for acute gout. -valuable option in patients with poor renal function or intolerance to colchicine.

microtophi

-crystals form in joints and tissues long before any symptoms occur. -deposit in small lattice structures called microtophi on the surface of cartilage and synovial lining. -microtophi slowly grow, but ares stable as long as the environment surrounding does not change in regard to pH, urate concentration, or temperature

colchicine

-drug used frequently to treat gout -prevents phagocytic activity by binding to dimers of the alpha and beta subunit of tubular. -->When the tubular dimer-colchicine complexes bind to microtubules, further polymerization of the microtubules is inhibited, depolymerization predominates, and the microtubules disassemble. -Microtubules are necessary for vesicular movement of urate crystals during phagocytosis and release of mediators that activate the inflammatory response *Colchicine diminishes the inflammatory response, swelling, and pain caused by formation of urate crystals. -has a narrow therapeutic index (amount of drug that produces the desirable therapeutic effect is not much lower than the amount that produces an adverse effect). -inhibits tubulin synthesis in neutrophils, but it can also prevent tubulin synthesis in other cells. (cell division and other cellular processes) -Neutrophils concentrate colchicine so they are affected at lower intakes than other cell types because neutrophils lack P-glycoprotein that removes colchicine.

allopurinol

-drug used to treat gout -decreases production by inhibiting xanthine oxidase -commits suicide by converting a drug to a transition-state analog. -contains a molybdenum-sulfide complex that binds the substrate and transfers electrons required for oxidation reactions. -->Xanthine oxidase oxidizes the drug allopurinol to oxypurinol, a compound that binds very tightly to a molybdenum-sulfide complex in the active site -->the enzyme has committed suicide and is unable to carry out its normal function- the generation of uric acid.

atypical gout

-early onset gout who generally have a genetic component with a more accelerated clinical course. -occurs in 15% of heart transplant recipients who take cyclosporine -->lower frequency seen in kidney and liver transplant recounts. -->cyclosporine induced has a marked shortening of asymptomatic and actor intermediate stages. -most women with gout are postmenopasal. -->usually have renal insufficiencies and hypertension. -saturine gout-term used to describe gout caused by chronic lead exposure.

febuxostat for gout treatment

-febuxostat is an alternative ULT and should be used in patients who have failed allopurinol treatment or have demonstrated sensitivity or intolerance to allopurinol. --initial febuxostat dose is 40 mg daily can be increased to 80 mg daily after 2 weeks of therapy if the serum urate target is not achieved.

treatment

-focuses on prevention of renal failure by pharmacologic treatment of hyperuricemia with high fluid intake along with alkalization and allopurinol. -low purine diet and reduced fructose intake are desirable -allopurinol treatment -behavior management/use of restraints/removal of teeth -drugs can be given for symptomatic management of anticipatory anxiety, mood stabilization and reduction of self injurious behavior. -->diazepam (anxiety), Risperdal (aggression), carbamazepine/gabapentin (mood stabilization) -->S-adenosylmethionine (SAMe)- reduces self injury -despite treatment from birth for uric acid elevation, behavioral and neurologic symptoms are unaffected. -most significant complication of LND are renal failure and self mutilation

recurrent and advanced gout treatments

-goal is to lower the serum uric acid below its saturation point so that the process of crystallization will cease and the accumulated urate burden will be gradually diminished. -target serum urate is less than 6 mg/dL. -urate lowering therapy is recommended for all patients with two or more gouty flares per year, patients with advanced disease, and those with kidney stones -allopurinol and febuxostat are both xanthine oxidase inhibitors and are considered first line ULT.

treatment and prevention

-heavy emphasis on patient education in order to obtain an optimal treatment outcome. treatment goals: relieve pain and terminate the flare as quickly as possible -resting the painful joint, applying ice help, but pharmacologic intervention is ally necessary. -->nonsteroidal anti-inflammatory drugs, oral colchicine, and corticosteroids. -those already taking urate lowering therapy should continue the drug whereas those not receiving this therapy should not be started.

diagnosis of gout

-hyperuricemia is a critical risk factor for developing gout, but it is not a reliable diagnostic test because many people with elevated serum urate levels will never develop gout. -serum urate levels during acute flare is unreliable because they may be suppressed by as much as 1.5 to 2 mg/dL. -definitive diagnosis: polarized compensated microscopy of a synovial fluid aspirate from the affected joint. -->presence of intracellular needle shaped crystals with strong negative birefringence is diagnostic gold standard.

Epidemiology of gout

-hyperuricemia is very common in western cultures (15-20%) -->twice the rate as observed 3 decades ago. -->factors that explain the increase include increased hypertension, metabolic syndrome and obesity; increase in longevity; ubiquitous use of thiazide diuretics and low dose aspirin; changes in dietary trends including greater use of high fructose corn syrup; increase in surveil of patients with end renal disease and organ transplantation -direct correlation between degree of serum urate elevation and likelihood of developing gout -3.9% of US adults see health care provider for gout -men make up majority of gout population (73%) -prevalence in women is increasing at disproportionately higher rate

urate overproduction

-in 10% of gouty subjects, hyperuricemia is caused by uric acid overproduction -most subjects reflects accelerated cell turnover or other cases of enhanced purine nucleotide breakdown as seen with alcohol abuse or fructose ingestion -primary disease processes that are also responsible for urate overproduction such as inborn errors of purine metabolism. -->PRPP synthetase overactivity, decreased purine salvage, complete and partial HPRT deficiencies. -overproduction is showing greater than 1000 mg of uric acid by a 24 hour urine collection.

brain and LND

-no specific brain abnormality is documented. -MRI has documented reduced volumes of basal ganglia nuclei. -Brain areas involved: caudate nucleus, putamen, nucleus accumbens. -neurochemical changes may be linked to functional abnormalities resulting from diminution of arborization or branching of dendrites rather than cell loss. -neurotransmitter abnormality is demonstrated by changes in CSF neurotransmitters and theyr metabolites.

oral colchicine for gout

-oral colchicine administered as 1.2 mg at a time of flare onset followed by 1 hour by a third 0.6 mg tablet is recommended for the first 24 hours. this is followed by 7-20 days of once daily or twice daily depending on renal function.

differential diagnosis of LND

-other cases of infantile hypotonia and dystonia -normally incorrectly diagnosed as having athetoid cerebral palsy -->when a dx of CP is suspected in an infant with a normal prenatal, perinatal, and postnatal course, then LND should be considered. -partial HPRT deficiency can be associated with acute renal failure in infancy, should be clinically aware. -simplest test: urinary uric acid: creatinine ratio.

diagnosis of LND

-presence of dystonia along with self mutilation of the mouth and fingers suggests LND -partial HPRT deficiency recognition is linked to either hyperuricemia alone or hyperuricemia and dystonic movement disorder -->serum levels of uric acid: exceed 4-5 mg uric acid/dLand a urine uric acid:creatine ratio of 3-4:1 definitive diagnosis: requires analysis of HPRT enzyme. -assayed in the erythrocyte lysate. -LND: near 0% enzyme activity. -partial deficiency: 1.5-60%

natural course of gout

-progresses from intermediate monoarthritis or oligoarthritis in the lower extremities to a chronic, destructive, and debilitating polyarthritis involving almost any peripheral joint in the body. -can result in deposition of MSU crystals in subcutaneous tissues and kidney manifesting as tophaceous deposits, inflammatory cellulitis, urate nephropathy, and kidney stones.

imaging for gout

-radiographic evaluation is not helpful except to r/of fracture. -ultrasound can detect MSU crystals layer over articular cartilage in early disease -MRI is not part of standard evaluation but will reveal soft tissue and intra-articular tophi long before they become clinical.

Lesch-Nyhan Disease (LND)

-rare X linked disorder of purine metabolism that results from HPRT deficiency. -absence of HPRT activity prevents the normal metabolism of hypoxanthine resulting in excess uric acid production and manifestation of gout.

factors provoking episodes of acute gout

-those that cause fluctuations in serum urate levels -trauma, surgery, starvation, overindulgence in certain high purine foods, and ingestion of medication that raises or lower serum urate.

neurologic/behavior disorders and LND

-unknown however hypoxanthine and guanine metabolism are affected and GTpP and adenosine have substantial effects on neural tissues -functional link between purine nucleotides and dopamine system: salvage of guanine by HPRT to form GTP -->this is essential for GTP cyclohydrolase activity which is the first step in the synthesis of pretense and dopamine. -dopamine binding to its receptor for activation or inhibition is mediate by G proteins dependent on guanine diphosphate. -dopamine and adenosine systems are also linked through the role of adenosine as the neuroprotective agent preventing neurotoxicity. -LND arises from nucleotide depletion in the brain, which relies upon the HPRT salvage pathway leading to dopamine and adenosine depletions.

How does hyperuricemia occur?

-uric acid accumulates from de novo synthesis, nucleotide degradation, and dietary consumption between 800-1200 mg/day. -increase in uric acid can be due overproduction or under excretion by kidneys. -90% of all gout cases is due to renal under excretion.

renal urate underexcretion

-uric acid is small and not protein bound, it is completely filtered by the glomerulus. -normal person, 8-10% of the filtered load is ultimately cleared in the urine. -transportasome: various renal tubular transporters located at the proximal convoluted tubules are responsible for determining how much of the filters uric acid is excreted -->reabsoprtion and secretion occur in this segment through organic acid transports (OATs). -->90% of uric acid filtered at the glomerulus is reabsorbed. -OATs eliminate organic acids and other medications. -URAT1 is the most important tubular transporter of uric acid. -->swaps urate ion for other monocarboylate organic ions across the luminal membrane of the proximal tubular cells. -->can reabsorb more uric acid from tubular lumen by raising concentration of lactic, pyruvate, or the ketoacids acetoacetate and beta hydroxybutrate. -->drugs can cause uric acid to be lost in urine.

failed target serum on ULT

-uricosuric agent probenecid can be added to the xanthine oxidase inhibitor. -pegloticase is an IV administered monomethoxypoly conguated recombinant uricase that dramatically lowers serum urate levels. --approved for treatment of gout in patients for whom conventional treatment is ineffective.

cognitive function in LND

-usually reported to be in the mild to moderate range of intellectual disability -some individuals may test in the low normal range. -overall intelligence may be underestimated due to physical difficulties in testing

classic gout

3 stages 1. asymptomatic hyperuricemia- state in which serum urate exceeds the level of solubility but symptoms of crystalline deposit have not occurred. --men: begins at puberty --women: delayed until menopause 2. Acute gout: innate episode usually follows decades of asymptomatic hyperuricemia. -men: occurs between 4th and 6th decade of life -women: onset is older, depends on age of menopause. 3. Chronic polyarticular gout -develops after 10 or more years and is evident when the pain free inter critical periods have disappeared. -subcutaneous tophus is the most characteristic lesion of advanced gout. -most commonly between fingers, wrists, ears, and knees, and olecranon bursa.

severity spectrum of HPRT deficiency

HPRT levels are related to the extent of motor symptoms, to the presence or absence of self injury, and possibly to the level of cognitive function. -classic LND has low or undetectable levels of HPRT enzyme -partial deficiency in HPRT (Kelley-Seegmiller syndrome) with more than 1.5-2% enzyme is associated with purine overproduction and variable neurologic dysfunction. -HPRT deficiency with more than 8% of normal level still exhibit purine overproduction but apparently normal cerebral functioning.

nongenetic causes of hyperuricemia

Impaired Uric acid Excretion clinical conditions: -reduced glomerular filtration rate, hypertension, obesity, systemic sclerosis, lead nephrophaty Drugs: -diuretics, ethanol, low dose silicates, cyclosporine, tacrolimus, levodopa Excessive uric acid production clinical conditions -myeloproliferative and lymphoproliferative neoplasms, obesity, psoriasis drugs/diet: -alcoholic (especially beer), red meat, organ meat, shellfish, high fructose corn syrup, cytotoxic drugs, nicotinic acid, pancreatic extract

Does uric acid and excess hypoxanthine enter the CSF and brain?

No. These do not cause the behavior disorder.

how is uric acid produced?

Urate is produced by the conversion of a very soluble molecule hypoxanthine to less soluble xanthine to very insoluble uric acid by the enzyme xanthine oxidase -xanthine oxidase is present in several organs, but most active in liver and intestine.

hyperuricemia

any serum urate level grater than 6.8 mg/dL in both men and women. -only 20% of all hyperuricemic subjects will develop gout.

uric acid excretion in normal males verses gouty males.

gout males- 70% as much uric acid as normal individuals. -->gout males required a serum urate concentration to be 1.7 mg/dL higher to obtain the same level of excretion -polymorphisms in glucose transporter GLUT-9 most significant determinants of serum urate. ABCG2 gene (transporter to ATP binding; found in the proximal tubule of kidney and in small intestine and liver) have a larger effect on urate levels in men that in women. -URAT1 may lead to hypouricemia or hyperuricemia.

classic acute gout attack

hallmarked by the rapid development of warmth, swelling, erythema, and exquisite pain in one or occasionally two joints -usually monoarticular and involve lower extremity joints. --most common is the first metatarsal phalangeal joint, then ankle, midget, and knee. -after years of intermediate attacks, upper extremity joints can become involved. -systemic symptoms: fever, chills, malaise, erythema of the joint. -first several attacks are 5-8 days.

gout

inflammatory arthritis of metabolic origins that is caused by crystallization of monosodium urate monohydrate crystals in the joints. -most common inflammatory joint disease in men and in older women. -due to supersaturation of blood and body fluids with the urate ion to the point that crystal formation is possible. -->supersaturated at >/= 6.8 mg/dL.