Disorders of Uric Acid Metabolism - Lesson 8 - DLP-2

1. Pakistan Society Of Chemical PathologistsDistance Learning Programme In Chemical Pathology(DLP-2)Lesson No 8Disorders of Uric Acid MetabolismBy Prof AsmaShoukatProf of Chemical Pathology, Quaid-e-Azam Medical College BahawalpurDrLubnaSarfrazQuaid-e-Azam Medical College Bahawalpur

2. Part IMCQs (One Best Type)

3. c. Hodgkin lymphoma Q.1: Which pathological process increases the production of uric acid?a. Acute renal failure b. Chronic renal failurec. Hodgkin lymphoma d. Hyperparathyroidism e. Hypothyroidism

4. Myeloproliferative Lymphoproliferative diseases   Hemolytic anemias Polycythemia vera Other malignancies     Psoriasis Glycogen storage disease Secondary Hyperuricemia with Urate Overproduction

5.   Renal insufficiency     Polycystic kidney disease Lead toxixity  Drugs Diuretics, Salicylates (low dose),  Pyrazinamide,  Ethambutol,  Cyclosporine Didanosine Secondary GOUTWith Uric acid under-secretion

6. Uric acid undersecretion (80%–90%) Idiopathic Urate overproduction (10%–20%) Phosphoribosylpyrophosphateamidotransferase(PRPP) synthetaseoveractivity HGPRT deficiency Idiopathic Primary Gout With no Associated Condition

7. c. Orange juice Q 2.Which of these beverages has been associated with an increased risk of incident gout in women?a. Flavoured waterb. Milkc. Orange juiced. Soda in diet e. Tea

8. Orange Juice and Uric AcidFructose-rich beverages such as sugar-sweetened soda and orange juice can increase serum uric acid levels and, thus, the risk of gout. The contribution of these beverages to the risk of gout in women is likely modest given the low incidence rate among women.

9. a. Allopurinol Q 3: A 63-year-old male presents with severe pain in his left big toe. The wrist is swollen, tender to touch and red. Aspiration reveals fine needle shaped yellow birenfringent crystals. Which treatment is unlikely to help this patient?a. Allopurinolb. Colchicinec. Corticosteroidsd. Ibuprofene. Indomethacin.

10. Treatment of Acute Gout1. The diagnosis is gout from uric acid deposition in the joint space. Allopurinol is a prophylactic agent, and is given to prevent attacks of gout. It acts by inhibiting xathine oxidase and prevents further breakdown of purines.2. All the other treatment are useful for acute gout. 3. Colchineis also effective for acute gout.

11. c. Decrease in leucocyte count Q 4: A seventy years old man with a history of hypertension, taking diuretics, presents with a two day history of acutely swollen left knee. Artherocentesis is performed and synovial fluid is stored in the refrigerator for analysis the next day.Which of the following problems can arise as a result of delayed analysis of synovial fluid? a. Appearance of pyrophosphate crystalsb. Appearance of cholesterol crystalsc. Decrease in leucocyte countd. Increase in number of urate crystalse. Production of tyrosine crystals

12. Delay in synovial fluid analysisIf synovial fluid analysis is delayed for more than 6 hours, results may be spuriously altered. Decrease in leucocyte count may occur due to cell disruption. Crystal artefacts may appear. Calcium pyrophosphate and urate crystals may dissolve.

13. b. Are a result of hyperuricemia Q 5 : All statements about uric acid stones are correct EXCEPT:a. Appear as filling defects on excretion urogramb. Are a result of hyperuricemiac. CT SCAN is required for confirmationd. Are radiolucent e. Visible on radiograph

14. Uric Acid Stones1. Most children with uric acid calculi do not have hyperuricemia. 2. Elevated serum uric acid levels are frequently due to dehydration and excessive purine intake. 3. Consistently low urine pH is a risk factor for stone formation. As the urine pH level increases above the pK (5.8), uric acid forms the more soluble urate ion.4. May be faintly visible on radiograph (due to some amount of calcium)

15. c. Allopurinol hypersensitivity syndrome Q 6 :A 65 years old man with a history of hypertension taking bendroflumethiazide and amlodipine was referred to the rheumatology department with recurrent episodes of acute gout affecting the 1st metatarsophalyngeal joint. The serum uric acid was 560 μmol/l and he had normal renal function. He was commenced on allopurinol 300 mg/day. Six weeks later he presented with a fever and maculopapular rash. On examination the temperature was 380C, pulse was 90 beats/min, BP was 140/90 mmHg. He had extensive maculopapular rash with target lesions. Systemic examination was normal. The results of blood tests were• Hb 12.5 g/dl• WBC 15.4 x103/ml• Neutrophills 62%• Eosinophils 16%• Lymphocytes 22%• Urea 15 mmol/l• Creatinine 300 μmol/l• ALT 328IU/L• ALP 600IU/L• Bilirubin 65 μmol/l• The urine dipstick, blood culture at 48 h , chest X-ray and ultrasound scan of the abdomen were normal.The most likely diagnosis is a. Acalculouscholecystitisb. Acute viral hepatitisc. Allopurinol hypersensitivity syndromed. ANCA associated vasculitise. Leptospirosis

16. About 2% of patients develop a rash. And 0.4% , predominantly those on thiazides , may experience a severe idiosyncratic reaction known as allopurinol hypersensitivity syndrome. this is characterized by skin reactions, fever, eosinophilia, and multiorgan involvement with a mortality of upto 25%. • Acalculouscholecystitis is associated with gall bladder distention on USG • Acute viral hepatitis is unlikely to present with renal impairment • Leptospirosis is associated with a clear history of exposure to contaminated water • ANCA associated vasculitis is a resenabledifferential but it is unlikely as the urine dipstick is normal. Allopurinol hypersensitivity syndrome

17. a. Decreased uric acid secretion Q 7 :Effect of thiazide diuretics on uric acid : a. Decreased uric acid secretionb. Decreased uric acid reabsorption c. Increased uric acid reabsorptiond. Increased uric acid secretione. No effect on uric acid excretion

18. Diuretics reduce uric acid excretion by both directly and indirectly decreasing uric acid secretion and increasing uric acid reabsorption • Recent studies have shown that thiazide compete for the same secretory process by which uric acid is secreted into the proximal tubule, thus reducing the clearance of uric acid, and raise the levels of uric acid in the blood. • Human organic ion transporter 4 (hOAT4), located at the apical membrane of proximal tubule cells, is responsible for facilitation of hydrochlorothiazide-associated hyperuricemia Effect of Thiazide Diuretics on Uric Acid

19. c. It is oxidized to form Uric acid Q 8 : Which statement best describes Xanthine ?a. It is a direct precursor of Guanineb. It covalently binds to Allopurinolc. It is oxidized to form Uric acidd. It is oxidized to form Hypoxanthinee. It is a substrate rather than a product of the enzyme Xanthine oxidase

21. b. Decrease in renal functional mass Q 9 :Mechanisms which have the potential for purine overproduction include all EXCEPTa. Decrease in concentration of the nucleotide inhibitors of APT b. Decrease in renal functional mass c. Increase in the amount, or intrinsic activity of APTd. Increase in the substrate levels of glutaminee. Increase in the substrate levels of PP-ribose-P

22. a. Hereditary xanthinuria Q 10 :Which of the following conditions is associated with most pronounced hypouricemia?a. Hereditary xanthinuriab. High dietry intake of fructosec. Pre eclampciad. Vitamin C intakee. Von Gierke’s disease

23. Hereditary xanthinuria is caused by a defect of xanthine oxidase and inherited with an autosomal recessive manner. • Characterized by decrease of urate and increase of xanthine and hypoxanthine in blood and urine. • May start at any age. • Approximately 50 % of the patients with classical hereditary xanthinuria present with symptoms of urinary tract infection, hematuria, renal colic, acute renal failure, crystalluria or urolithiasis. Hereditary Xanthinuria

24. Diagnosis is based on estimation of uric acid in blood and urine • There is no curative treatmentbut low purine diet and high fluid intake is recommended. • Alkalization is of no value as the solubility of xanthine is not affected by urinary pH. • When calculi are present, a pyelolithotomy might be necessary. • The overall prognosis is favorable, even though, in some cases, the disease progresses to end-stage renal insufficiency. Hereditary Xanthinuria (Cont)

25. Part IIShort Answer Questions:

26. Q. 11: A 47 year male frequently develops swelling and pain in his ankle and big toe. His biochemical profile shows:Urea: 5.5 (3.3-6.7 mmol/l)Creatinine: 89 (55-100 μmol/l)Uric Acid: 520 (120-420 μmol/l)All his haematological and imaging investigations are normal.His physician has informed him that he has got Gout but there is no ‘secondary cause’ of his disease.What is the most common biochemical mechanism of hyperuricaemia which can lead to these features in this patient?

27. The most common biochemical mechanism of hyperuricaemiaHyperuricemiadue to Decreased elimination (underexcretion) (90%): kidney has increased threshold for uric acid so that excretion is diminished Impaired excretion is most often due to abnormalities in the kidney urate transporter called ( URAT1) or organic ion transporter (OAT), both of which control the movement of uric acid out of proximal kidney tubules and into urine.Overproduction (10%): cause of overproduction is often unknown,

28. Q. 12: A number of drugs commonly used in clinical practice can affect the serum concentration of uric acid. This information is vital for safe patient management. Please answer following queries in this regard:a. Name TWO drugs which cause increase in Uric Acid level due to its increased production.b. Name ONE drug which has a ‘biphasic action’ on uric acid level. c. Give mechanism of ‘biphasic action’ of this drug on uric acid level in TWO lines.d. A patient has hyperuricaemia, hypertriglyceridaemia and hypertension. Can you name ONE drug which is most helpful in all these conditions? 

29. Q. 12: a. Name TWO drugs which cause increase in Uric Acid level due to its increased production.1. Fructose2. Xylitol3. Theoophyline4. Cytotoxic Drugs

30. Q. 12: b. Name ONE drug which has a ‘biphasic action’ on uric acid level. Salicylate e.g. Aspirinc. Give mechanism of ‘biphasic action’ of this drug on uric acid level in TWO lines.At low doses (≤2.5 g/day) salicylates cause the retention of uric acid by blocking the OAT1/OAT3 tubular uric acid secretors resulting in hyperuricemia.At high doses (>3 g/day) they cause increased urinary excretion of uric acid by competitively inhibiting reabsorption through URAT 1 in proximal tubule resulting in uricosuria

31. d. A patient has hyperuricaemia, hypertriglyceridaemia and hypertension. Can you name ONE drug which is most helpful in all these conditions?Losartan (Angiotensin Receptor Blocker)Fenofibrate

32. Q. 13: Sumo wrestling is a common sport in Japan. A Sumo wrestler takes about 5000 calories per day (not different from our pehlwans)!!!! Studies have shown higher incidence of hyperuricaemia and gout in these wrestlers. Please answer following questions in this regard:a. What are TWO possible causes of hyperuricaemia in these wrestlers?b. Write biochemical mechanism of hyperuricaemia related to their diet in THREE lines.

33. Q. 13: a. What are TWO possible causes of hyperuricaemia in these wrestlers?1. Mainly by high calorie diet (5000 kcal/day)with more than 80% of calories from carbohydrates2. Partly by the infrequent meal intake usually twice a day

34. Q. 13: b. Write biochemical mechanism of hyperuricaemia related to their diet in THREE lines.1. When excessive carbohydrates are consumed the excess acetyl co-enzyme A produced is not catabolized but is diverted for fatty acid and triglyceride synthesis. 2. This requires NADPH, which is derived from the pentose phosphate pathway. Under normal conditions the first committed step of the pentose phosphate pathway is under tight negative feedback control by NADPH, but as the latter is utilized in fat synthesis the pathway becomes derepressed and the additional pentose phosphate produced will be available for synthesis of more PP-ribose-P and more uric acid3. These wrestlers have higher fasting free fatty acid levels leading to more ketone formation. Infrequent meal intake also results in more ketone formation. Ketones interfere with tubular excretion of urates leading to hyperuricemia. .

35. Metabolic Pathway of hyperuricaemia related to High Carbohydrate Diet.

36. Q. 14: A 45 years male is a known patient of Chronic Kidney Disease (CKD). He has following biochemical findings:Urea: 27.8 (3.3-6.7 mmol/l)Creatinine: 874 (55-100 μmol/l)Uric Acid: 512 (120-420 μmol/l)Why his uric acid level is not very high in spite of the fact that kidneys are important source of uric acid excretion. Please write TWO lines.

37. Why his uric acid level is not very high in spite of the fact that kidneys are important source of uric acid excretion. Please write TWO lines.1.Failure of the tubular reabsorption of urate in patients with CKD results in clearance of greater proportion of filtered urate. 2. Extrarenaldegradation of urate by the action of microbial flora of gut increases markedly from 22-25% as in health to as much as 65% in CKD.

38. Q. 15: It is said that ‘only man and a few other mammals can develop gout’. What is the biochemical background of this statement?Two factors are responsible for high UA levels near to its solubility limit (6.8 mg/dl or 408 umol/l) in man and few other mammals and only they can develop gout.Absence of uricase enzyme: Main difference is that the majority of mammals and low primates have very low serum urate levels because UA is converted by uricase to more soluble and non toxic allantoin which is freely eliminated by the kidneys. However absence of uricase enzyme in man and few mammals due to modification of uricase enzyme gene to pseudogene status results in high UA levels. Renal reabsorption: Another less important factor is that man and some higher primates also have efficient renal mechanism for reabsorbing filtered urate.

39. Q. 16: A 54 years male has moderately severe pain in his right knee with swelling and redness. He has following laboratory findings:• Urea: 6.9 (3.3-6.7 mmol/l)• Creatinine: 91 (55-100 μmol/l)• Uric Acid: 288 (120-420 μmol/l)• Synovial Fluid Analysis: Rectangular shape crystals seen with positive bisfringence on polarized microscopy.What is the most probable diagnosis? How will you defend it?

40. Q. 16: A 54 years male has moderately severe pain in his right knee with swelling and redness. He has following laboratory findings:• Urea: 6.9 (3.3-6.7 mmol/l)• Creatinine: 91 (55-100 μmol/l)• Uric Acid: 288 (120-420 μmol/l)• Synovial Fluid Analysis: Rectangular shape crystals seen with positive bisfringence on polarized microscopy.What is the most probable diagnosis? How will you defend it?Diagnosis: PseudogoutPoints that favour Pseudogout:Rectangular crystals with positive bisfringence on polarized microscopy are calcium pyrophosphate dihydrate crystals (CPPD).Large joint (knee) InvolvmentModerate painswollen jointserum uric acid usually normalage greater than 50 years These all features are suggestive of pseudogout.

41. Thank You and Best Of Luck