医学教学课件：Hyperuricemia and gout

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1、Hyperuricemia and gHyperuricemia and gout out HyperurisemiaHyperurisemiaHyperuricemia exits when blood uric acid 420mol/L (7.0mg/dl) in male or postmenopausal female 360mol/L (6.0mg/dl) in premenopausal female Metabolism of uric acid Uric acid Uric acid is the end product of purine purine metabolism

2、, wich is poorly soluble70% of total body urate is produced endogenously70% of the urate is excreted by the kidneysMechanism of hyperurisemiaUnderexcretion(90%) :Underexcretion(90%) : Decreased tubular secretion is the most causes of hyperuricemia: 1)metabolic syndrome 2)familial juvenile gouty neph

3、ropathy 3)renal insufficiency Overproduction(-10%):Overproduction(-10%): Endogenous increased purine nucleotide breakdown 1)Idiopathic (polygenic) 2) enzymatic defects(monogenic) 3) cells destruction - myeloprolfierative disease -rhabdomyolysis -cytotoxic therapy -tumor lysis syndrome E3 E1E2E6X-染色体

4、连锁遗传：染色体连锁遗传：E3:磷酸核糖焦磷酸合成酶,活性增加E1:磷酸核糖焦磷酸酰基转移酶，活性增加E2：次黄嘌呤-鸟嘌呤磷酸核糖转移酶，活性降低多基因遗传：多基因遗传：E6:黄嘌呤氧化酶，活性增加FeedbackGenetic enzyme defect in hyperuricemiaClasification of hyperuricemiaPrimary hyperuricemiaPrimary hyperuricemiacause unclearoften together metabolic syndromeIn most cases uric acid excretion is

5、 decreasedSeconary hyperuricemia Seconary hyperuricemia Renal dysfunctionMyeloprolfierative disease cells destructionDrugs inhibiting uric acid excretion (thiazide and loop diuretics) GoutGoutGout develops when supersaturated monosodium urate crystallize and precipitate around joints, under the skin

6、 and in the kidney. Gout is characterized by- recurrent attacks of acute arthritis, -tophi, -kidney stones,- urate nephropathy. Prevalence :0.34-2.84% in China, estimated at 3.9% of adults in the US.5%-15% patients with hyperuricemia develop gout.most present in male aged 40 yr ，or in posamenopausal

7、 femalePattern of clinical Pattern of clinical manifestations manifestations 1. Asymptomatic phase（无症状期）2.Acute gouty arthritis（急性痛风性关节炎）3. Chronic tophaceous gouty arthritis（,CTGA痛风石及慢性痛风性关节炎）4. Uric acid nephropathy and nephrolithiasis （尿酸肾病和肾结石） acute gouty arthritis acute gouty arthritis1) patho

8、geneis:pathogeneis: precipitated urate micocristals induce chemotactic movement of leukocytes，which release inflammatory factor(IL-1) and hydrolytic enzyme2) triggers :triggers :consumption of alcohol, fructose-sweetened drinks, meat, and sea food physical trauma and surgery the lower body temperatu

9、re (at night) . 3)Clinic:3)Clinic:a recurrent attack of acute inflammatory arthritis (a red, swollen，hot, tender). The metatarsal-phalangeal joint at the base of the big toe is affected most often(podagrapodagra)Joint pain usually begins over 24 hours and during the night.Other symptoms include fati

10、gue and fever .Natural course varies in days to one to two weeksDuring intercritical periods joints are free of symptomspodagra chronic chronic tophaceoustophaceous gouty gouty arthritis(CTGA)arthritis(CTGA) Tophi: Tophi: *deposit of sodium urate in the tissues, producing a chronic, foreign-body inf

11、lammatory response. *mainly found in perarticular, auricular, bursal, bone, kidney and cutaneous tissues , are a pathognomonic feature of goutMcGraw-Hill Concise Dictionary of Modern Medicine. 2002 by The McGraw-Hill Companies, Inc.Dorlands Medical Dictionary for Health Consumers. 2007 by Saunders,

12、an imprint of Elsevier, Inc. All rights reserveda tophus, with central urate deposition surrounded by mononuclear inflammatory cells , giant cells, fibroblasts and epithelioid histiocytesExtensive tophi may invade bone and induce arthritis with deformity of jionts.A 74-year-old woman with chronic re

13、nal failure was admitted for diarrhea and functional impairment. She was noted to have a tender, soft swelling of the medial and distal phalanx of the right index finger (Panel A). Plain radiography showed substantial osteolysis of the distal phalanx and partial osteolysis of the medial phalanx (Pan

14、el B). Needle aspiration yielded a white viscous liquid, with numerous urate crystals identified on polarized light microscopy (Panel C). Bone destruction was attributed to tophaceous goutN Engl J Med 2012; 366:e6January 19, 2012 A case of tophaceous gout uric acid nephropathy and uric acid nephropa

15、thy and nephrolithiasisnephrolithiasis Elevated levels of uric acid may lead to crystals precipitating in the kidneys, resulting in uric acid calculi in the renal pelvis renal pelvis (nephrolithiasis) or uric acid nephropathy,wich include two form: (1) Chronic hyperuricaemic nephropathy : gouty toph

16、i formation and fibrosis in the renal medullarenal medulla (2) Acute hyperuricaemic nephropathy: *due to the sudden oversaturation, uric acid precipitates as crystals or sludge in tubules and collecting ducts. *These precipitates cause obstruction and acute renal failure *It is most often (but not e

17、xclusively) found in children suffering from haematopoietic malignanciesChronic hyperuricaemic nephropathyNephrol Dial Transplant (1997) 12: 18321838Chalky white urate depositsin the articular cartilageyellowish areas in the pyramids (arrow) representing fibrosis and urate deposits.crystalloid mater

18、ial in the centre surrounded by a narrow rim of fibrosis and inflammationAcute hyperuricaemic nephropathyAcute hyperuricaemic nephropathyyellow/white streaks in the pyramids (=intratubular urate deposits without fibrosis).Nephrol Dial Transplant (1997) 12: 18321838Diagnostic workupDiagnostic workup

19、1)Blood uric acid concentration 2) urine uric acid excretion 24h urine uric acid excretion exceeds 3.57mmol(600mg) means overproduction of UA【 5 days after purine-poor diet 】3)X-ray: “punched out ” periarticular erosions normal mineralization joint space preservation 4）aspiration from synovial fluid

20、 or tophi : Monosodium urate (MSU)crystals, a needle-like morphology and strong birefringence（双折射） under polarized light microscopy . DiagnosisDiagnosis Gout can be diagnosed with classic podagra.A definitive diagnosis :Identification of MSU crystals in synovial fluid or a tophus X-rays, while usefu

21、l for identifying chronic gout1977 ACR Diagnosis criteria for acute gout 1. The presence of characteristic urate crystals in the 1. The presence of characteristic urate crystals in the joint fluidjoint fluid or or 2.a tophus proved to contain urate crystals by chemical 2.a tophus proved to contain u

22、rate crystals by chemical means or polarized light microscopy, ormeans or polarized light microscopy, or 3. the presence of 6 of the following 12 clinical, 3. the presence of 6 of the following 12 clinical, laboratory, and radiographic phenomena: laboratory, and radiographic phenomena: 1. More than

23、one attack of acute arthritis 2. Maximum inflammation developed within 1 day 3. Monoarthritis attack 4. Redness observed over joints 5. First metatarsophalangeal joint painful or swollen 6. Unilateral first metatarsophalangeal joint attack 7. Unilateral tarsal joint （跗骨关节）attack 8. Tophus (proven or

24、 suspected) 9. Hyperuricemia 10. Asymmetric swelling within a joint on x ray/exam 11. Subcortical cysts without erosions on x ray 12. Joint fluid culture negative for organisms during attackRome criteriaRome criteria Patients must meet 2 2 of the following 4 criteria: (1) an SU level 7 mg/dL in men

25、or 6 mg/dL in women(2) tophi(3) MSU crystals in synovial fluid（SF） or tissues (4) a history of painful joint swelling with abrupt onset and remission within 2 weeksNew York criteriaNew York criteria 2 2 of following 4 criteria are required for a clinical diagnosis at least 2 attacks of painful joint

26、 swelling with complete resolution within 2 weekspodagratophus a rapid response to colchicine within 48 hours of starting treatment But a definitive diagnosis can be made if MSU crystals are seen in SF or in the tissues Differential dignosisDifferential dignosis1.rheumatiod arthritis2.septic arthrit

27、is(synovial fluid gram stain, culture)3.pseudogoutTratmentTratment1. Lifestyle intervention:1. Lifestyle intervention: avoid purine-rich foodgradual weight reductionWater drinking 2000ml 2.Medication2.Medication3.Orthopedic surgery3.Orthopedic surgeryPurine nucleotides hypoxanthinexanthineUric acidX

28、anthine oxidaseIntestinalexcretionUrinary excretionTissue deposition in excessUrate crystalmicrotophiPhagocytosis with acute inflammation and arthritisuricosuricscolchicineNSAID/SAIDAllopurinolXOXOuricosuricsMedication for acut gouty Medication for acut gouty athritisathritisNSAIDsNSAIDs:indometacin

29、,diclofenac sodium, etoricoxib(依托考昔) *contraindication: active peptic ulcer *caution:renal dysfunctionColchicine:Colchicine: special effect medicine of acute gouty arthrtis attack *disappear or regression of pain in 48h in 90 patients *Side effects:gastrointestinal reaction,myelosuppresion,hepatotox

30、icity *caution:renal dysfunctionSAIDsSAIDs:corticosteroids, for intolerance for NAIDs or colchine or renal dysfuction.Medication for hyperuricemia in phases Medication for hyperuricemia in phases of chronic gouty or interval between of chronic gouty or interval between acute attcks acute attcks （1 1

31、）U Uricosuricsricosuricsurate-lowering therapy urate-lowering therapy (ULT)(ULT) : : benzbromarone probenecid *inhibite urate resorption from proximal renal tubuli. *ineffective when Ccr30ml/min * not indicated by: acute gouty arthritis urate nephrolithiasis and urate nephropathy urine urate excreti

32、on rate3.57mmol（600mg） （2 2）Xanthine oxidaseXanthine oxidase inhibitor inhibitor： allopurinolindicated by: *urate overproduction; * urate nephrolithiasis and urate nephropathy *side effect: exanthem 、fever、gastrointestinal irritation; hepatic dysfunction、bone marrowk inhibition. *dosis reduction by

33、renal insufficiency Significance & Innovations Significance & Innovations Patient education on diet, lifestyle, treatment objectives,and management of comorbidities is a recommended core therapeutic measure in gout. Xanthine oxidase inhibitor (XOI) therapy with either allopurinol or febuxostat is re

34、commended as the first-line pharmacologic urate-lowering therapy (ULT) approach in gout. Serum urate level should be lowered sufficiently to durably improve signs and symptoms of gout, with the target 6 mg/dl at a minimum, and often 5 mg/dl. The starting dosage of allopurinol should be no greater th

35、an 100 mg/day and less than that in moderate to severe chronic kidney disease (CKD), followed by gradual upward titration of the maintenance dose, which can exceed 300 mg daily even in patients with CKD.HLA BHLA B* *5801 allele frequency and severe 5801 allele frequency and severe allopurinol hypers

36、ensitivity reaction allopurinol hypersensitivity reaction Prior to initiation of allopurinol, rapid polymerase chain reactionbased HLAB*5801 screening should be considered as a risk management component in subpopulations where both the HLA B*5801 allele frequency is elevated and the HLAB*5801positiv

37、e subjects have a very high hazard ratio (“high risk”) for severe allopurinol hypersensitivity reaction (e.g., Koreans with stage 3 or worse CKD and all those of Han Chinese and Thai descent)Arthritis Care & ResearchVol. 64, No. 10, October 2012, pp 14311446 Combination oral ULT with 1 XOI agent and 1uricosuric agent is appropriate when the serum urate target has not been met by appropriate dosing of an XOI. Pegloticase is appropriate for patients with severe gout disease burden and refractoriness to, or intolerance of, appropriately dosed oral ULT options. Thanks!