Hyperuricemia Lecture Presented by Usama Ragab Youssif For 5th-year medical students - Zagazig University

1. Hyperuricemia
Usama Ragab Youssif, MD
Consultant Internal Medicine
Lecturer of Medicine
Zagazig University
Email: usamaragab@medicine.zu.edu.eg
Slideshare: https://www.slideshare.net/dr4spring/
Mobile: 00201000035863

2. Gout & hyperuricemia
• The term gout refers to a disorder characterized by
defect in purine metabolism, and manifested by:
1. Hyperuricemia, that leads to
2. Crystalline deposition of monosodium urate in
tissues (tophi), that leads to
3. Gouty arthritis, and
4. Uric acid stones and gouty nephropathy.

3. Why gout?
• Gout is now the most common cause of chronic
inflammatory arthritis

4. Introduction

5. Classification of hyperuricemia
Either renal (under execretion, 90%) and metabolic (over
production, 10%) (Each is primary or secondary…)
• Primary defect
Metabolic
Renal
• Secondary defect
Metabolic
Renal

7. Primary (genetic)
1- Metabolic overproduction
Predictors or risk factors are…
• Male gender
• Age <40 years
• Obesity
• Family history
• Alcohol use and purine rich foods
• Renal insufficiency
• Hypertension

8. Primary (genetic) (cont.)
1- Metabolic overproduction (cont.)
Enzymatic defect
• Complete or partial deficiency of HGPRT which is essential
for reconversion of guanine, hypoxanthine into their
mother substance so this enzymatic defect → accumulation
of uric acid
• Glucose 6 phosphatase deficiency (von Gierke’s disease):
autosomal recessive + other glycogenosis III, V, VII
• X-linked raised PRPP synthetase activity: gout in 2nd or 3rd
decade + uric acid stones

9. Primary (genetic) (cont.)
2- Renal underexecretion
• Idiopathic under excretion (Isolated tubular defect),
more than two thirds of individuals with primary gout
(with normal initial kidney functions) = familial
juvenile gouty nephropathy (AD).

10. Secondary
1- Metabolic overproduction
Increased nucleic acid turnover e.g.
• Haemolysis.
• Myeloproliferative diseases: CML, essential thrombocytosis, myelofibrosis, PV
• Lymphoproliferative diseases: CLL, Lymphoma, Prolymphocytic leukemia,
HCL.
• Tumor lysis syndrome
• Psoriasis, psoriatic arthropathy.
• Sarcoidosis.
Drugs:
• Alcohol, cytotoxic drugs, warfarin

11. Secondary (cont.)
2- Renal under-execretion
• Acute or chronic renal failure (as part of accumulated acid): in
CRF there is rare gouty attacks in spite of hyperuricemia due to
lazy neutrophil.
• Altered tubular handling by drugs. e.g. thiazides, low dose aspirin
and cyclosporine → decrease renal excretion of uric acid.
• Lactic acidosis, DKA, alcohol, starvation: accumulated acid
compete with urate for execretion.
• Lead nephropathy (saturnine gout)
• Other Drugs—levodopa, ethambutol, pyrazinamide.
• Hypothyroidism, hyperparathyroidism, triosmy 21

12. Hyperuricemia
• Hyperuricemia is defined as a serum uric acid
>7mg/dL in males and >6mg/dL in females

13. Clinical classification
Hyperuricemia may be
Asymptomatic
OR
Symptomatic

14. Asymptomatic hyperuricemia
1. It may progress to a clinically manifested gout
(uncommon)
2. Recognizing hyperuricemia in the asymptomatic
patient provides the physician with an opportunity to
modify or correct underlying acquired causes of
hyperuricemia
3. Uric acid can no longer be considered biologically
inert, but rather has numerous biologic functions

15. • Most patients with asymptomatic hyperuricemia do not
require treatment, but efforts should be made to lower
their urate levels by encouraging them to make changes
in diet or lifestyle

16. Acute gouty arthritis
• Urate crystals themselves are not irritating and urate
crystals can be found in asymptomatic joints.
• When urate crystals become phagocytosed by
leucocytes → ++ their lysosomal enzymes, cytokines
and chemotactins which can elicit an inflammatory
reaction → Acute arthritis.
• Colchicine leads to suppression of leucocytes migration
and modifies their phagocytic activity (in other words;
↓ chemotaxis & phagocytosis).

17. Chronic tophaceous gout (Deposition of
urate)
Deposition of urate:
• In joint → chronic erosive arthropathy.
• In kidney → gouty nephropathy.
• Skin → tophi.

19. Natural History
There are 3 classic stages
= Natural history of gout

20. I- Asymptomatic hyperuricemia
• Refers to elevation of serum uric acid prior to the
development of arthritis.
• This is 10 times more common than gout: probably
95% of hyperuricemic subjects never develop gout.
• Hyperuricemia without symptoms may be found in
many conditions such as obesity, hypertension,
MAFLD…

21. II- Acute gouty arthritis
• There is a painful arthritis; acute, often at
night.
• 90 % of cases of the initial attacks are
monoarticular usually in the first
metatarsophalangeal joint (podagra): red,
hot, tender, and swollen, with limited
range of movement.
• Other initial sites: Ankles, wrist, heels,
finger, knee, ellbow. Shoulders & hips are
usually spared.
• It may be precipitated by:
 Trauma.
 Surgery
 Ingestion of alcohol
 High protein diet.
 Exercise
 Diuretics.
 Severe cold.
 Emotional stress.
• Intercritical periods are asymptomatic
periods between attacks; up to 2 years
and patient may not develop another
attack and if occur it's usually more
severe and tend to be polyarticular.

23. Pitfalls
• Minority of patients (10%) showing acute gout with
normal serum uric acid.
• Dramatic relief of pain with colchicine is suggestive
(but not pathognomonic).
• In severe attacks, overlying crystal cellulitis makes gout
difficult to distinguish clinically from cellulitis.
• Milder episodes for few days called petite attacks.
• There is elevated temperature, TLC, ESR and CRP.

24. III- Chronic tophaceous gout
A- Joints: chronic erosive arthropathy…
• Polyarthritis 20%.
• Asymmetrical joint affection.
• Exacerbation and remission.
• Late → joint destruction, erosions.
B- Tophi are deposits of solid monosodium
urate urate crystals that elicit a foreign
body reaction this occurs after
longstanding severe hyperuricemia.
• Tophi deposits occur usually in the skin,
around joints and ear lobule, extensor
surface of fingers, achilles tendon or in
elbows.
• Large deposition may cause overlying
skin to ulcerate and extrude urate
crystals; chalky material.
C- Chronic gouty nephropathy
• Uric acid nephropathy (acute
hyperuricemic nephropathy) due to
precipitation of uric acid in renal tubules
especially with myelo or Iympho
proliferative diseases during
chemotherapy (tumour lysis syndrome)
(uric acid > 25 mg/dl) → Acute kidney
injury.
• Chronic gouty nephropathy (chronic
urate nephropathy): urate precipitation in
renal interstitial tissue → chronic kidney
disease.
• Uric acid stones: uric acid precipitation
in acidic urine → obstructive uropathy.

27. However, hyperuricemia is not just gout
• It is a common association with metabolic
syndrome
Hypertension
Dysglycemia
Obesity
Dyslipidemia

29. A- Laboratory
• Serum uric acid > 7 mg/dl in males or > 6 mg/dl in females
(it may be normal)
• ESR, CRP and TLC are elevated.
• Under purine restricted diet, uric acid in urine > 1100 mg /
24 hours = overexcertion
By 24-hour urine collection
Spot urine uric acid to creatinine ratio > 0.8
Fractional execretion of urate FeUrate
Normal level of serum uric acid is:
•3.5 - 7 mg/dl in males
•2.5-6 mg/dl in females
•Normal serum uric acid does not exclude the diagnosis of gout (due
excessive cytokine release in acute phases and what initiate attack is the
change in uric acid levels).

30. B- Synovial fluid analysis (gold standard)
• Synovial fluid analysis remains the single
most important diagnostic study.
• cells: 25,000-100,000 leucocytes/ mm3
• Polarized microscopy: typical needle
shaped crystals, –ve birefrinent
sodium urate crystals.
• The crystals may be extra- or intracellular
(i.e. free or phagocytosed).
• The absence of crystals does not rule out
the diagnosis.

31. C- Joint xray
• Soft tissue shadow (tophi).
• Calcification of tophi.

32. D- Other investigations
• Dual-Energy Computed
Tomography (DECT) can
differentiate urate from
calcium, and may be useful
to confirm a diagnosis of
gout when arthrocentesis is
not practical.
• MRI and muscloskeletal
US may be also utilized

33. D- Other investigations (cont.)
• Diagnosis of the cause of hyperuricemia: e.g.
myeloproliferative diseases:
Routine checkup lab i.e. CBC, KFT, LFT, plasma glucose
ESR, CRP, LDH
Calcium, phosphorus
TSH
• Diagnosis of co-morbid conditions especially CKD and CVD
profile as hyperuricemia is considered as CVD risk factor.

34. 2018 Updated EULAR Evidence-based Recommendations for the
Diagnosis of Gout

35. Recommendation *
Every person suspected of having gout should be tested for crystals. Finding MSU crystals allows a
definitive diagnosis of gout
***
Gout should be suspected in any adult with acute arthritis. As well as testing for crystals, gout may be
diagnosed by questioning the patients and examining the joints, particularly the foot and ankle for pain,
swelling or redness
***
Any person with undiagnosed inflammatory arthritis should have their
synovial fluid checked for crystals
**
The diagnosis of gout should not be made based solely on high levels of uric acid in the blood ***
Summary of recommendations in lay format (1 of 2)
35 26/12/2020
1 star (*) means it is a weak recommendation with limited scientific evidence; 2 stars (**) means it is a weak recommendation with some scientific evidence; 3 stars (***) means it is a strong
recommendation with quite a lot of scientific evidence; 4 stars (****) means it is a strong recommendation supported with a lot of scientific evidence.
Recommendations with just 1 or 2 stars are based mainly on expert opinion and not backed up by appropriate clinical studies, but may be as important as those with 3 and 4 stars.

36. Recommendation *
When a clinical diagnosis of gout is uncertain and crystal identification is not possible, imaging should
be used to look for urate deposits and features of any alternative diagnosis
****
X-rays can be used to look for urate arthropathy but cannot always diagnose acute gouty arthritis.
Ultrasound scanning or Dual Energy Computed Tomography (DECT) can aid diagnosis by detecting
tophi or urate deposits
****
People with gout should be checked for risk factors for high uric acid levels, including chronic kidney
disease, being overweight, certain medications, drinking excess alcohol or non-diet sodas, or eating meat
and shellfish
****
People with gout should be checked for linked diseases, including obesity, kidney impairment, heart
disease or failure, diabetes, high blood pressure or high lipid levels in the blood
****
Summary of recommendations in lay format (2 of 2)
36 26/12/2020
1 star (*) means it is a weak recommendation with limited scientific evidence; 2 stars (**) means it is a weak recommendation with some scientific evidence; 3 stars (***) means it is a strong
recommendation with quite a lot of scientific evidence; 4 stars (****) means it is a strong recommendation supported with a lot of scientific evidence.
Recommendations with just 1 or 2 stars are based mainly on expert opinion and not backed up by appropriate clinical studies, but may be as important as those with 3 and 4 stars.

39. Managment
• 2012 American College of Rheumatology (ACR)
• 2016 European League Against Rheumatism (EULAR)
• 2017 American College of Physician (ACP)

41. General advice
• Weight loss
• Regular physical activity might decrease the
excess mortality associated with chronic
hyperuricaemia.
• The association between excessive intake of
meat and alcohol with an increased risk of
developing gout has been confirmed.
• Consumption of coffee and cherries is
negatively associated with gout.
• There is inverse association between dairy
intake and urate levels, particularly with
skimmed milk and low-calorie yoghurt.

43. It is not just gout
• According to Framingham study: uric acid is considered as CVD risk.
• Both hyperuricaemia and gout are associated with chronic kidney
disease (CKD).
• CKD appears to be a major risk factor for gout and, conversely, gout
might cause renal dysfunction.
• Estimated glomerular filtration rate (eGFR) should be calculated at
the time of diagnosis for CKD classification and monitored regularly in
parallel with SUA measurement.

44. When to treat asymptomatic hyperuricemia
Pharmacological treatment of asymptomaic hyperuricemia SUA >8
mg/dL
1. High serum uric acid
2. At risk of complications e.g. those with a personal history or
strong family history of gout, stone or uric acid nephropathy
3. Before institution of chemotherapy or radiotherapy in certain
tumors to prevent acute gouty nephropathy
4. Hyperuricemia associated with metabolic syndrome

45. Acute gouty attack treatment
• Colchicine 1 mg then after 1 hour 0.5
mg od or bid.
• Prednisolone (35 mg/day for 5 days)
has analgesic effect equivalent to
NSAIDs or give IM triamcinolone 60
mg od (Kenacort-A 40 mg vial) was
equivalent to
• Naproxen (500 mg twice a day for 5
days) for treating flare + PPI if
appropriate.
• NOT ASPIRIN: because it can alter
uric acid levels and potentially
prolong and intensfy an acute attack.
• Intra-articular steroids are useful if
only one or two joints are affected.
Colchicine NSAID
Action: Reduce leucocyte
migration and release of
cytokines and other inflammatory
mediators
Action: Reduce release of Pgs
and other inflammatory mediators
Side-effects:
 Nausea, vomiting & diarrhea.
 Hepatotoxicity.
 Renal failure.
 BM suppression.
 Colchicine induced
neuromyopathy
 Mixed peripheral neuropathy.

46. IL-1 antagonist
• IL-1β was found to play a crucial role in
monosodium urate (MSU) crystal-
induced inflammation.
• Anti-IL-1β monoclonal antibody
canakinumab 150 mg subcutaneously,
one dose (not FDA approved i.e. not used
in US for this indication).
• IL-1 receptor antagonist (anakinra),
administered subcutaneously at 100 mg
for 3 days, could be effective in reducing
pain in patients with acute attacks (not
FDA approved for this indication).
• Current infection is a contraindication to
the use of anti-IL-1 biologics, which
implies screening for occult infections.

47. Treatment of acute gouty attack
Colchicine NSAIDs Steroids
IL1β
inhibition

48. Flare prophylaxis
• Flare prophylaxis with low-dose colchicine (colchicine,
0.6 mg/day) or low-dose NSAID (naproxen, 250 mg
twice daily) for up to 6 months appeared to provide
greater benefit than flare prophylaxis for 8 weeks, with
no increase in adverse events.
• IL-1 blockers may be effective but not approved for
prophylaxis

49. What target to choose
• The task force recommends a treat-to-target strategy for every patient
with gout, to maintain the SUA level <6 mg/dL, which is below the
saturation point for MSU.
• The task force also recommends reducing the SUA level to <5 mg/dL
for severe gout reflecting high crystal load until total crystal
dissolution has occurred.
• The task force also agreed that once dissolution of crystals is achieved,
SUA level could be maintained <6 mg/dL by a reduction in the dose of
ULT to avoid new formation of urate crystals.

50. Is lower is better?
• Uric acid might protect against various neurodegenerative
diseases such as Parkinson’s disease, Alzheimer’s disease
or amyotrophic lateral sclerosis.
• Given these data and the availability of ULT that has the
potency to greatly decrease SUA levels, the task force does
not recommend lowering continuously the SUA level to <3
mg/dL in the long term that is, for several years.

51. Urate lowering therapy (ULT)
Allopurinol (Zyloric 100 – 300 mg tab) Febuxostat (Feburic 80 – 120 mg tab)
• Start low go slow approach;
allopurinol should be started at a
low dose (100 mg/day) to reduce
early gout flare and because high
starting doses might increase the
risk of serious cutaneous adverse
reactions (SCARs)
• It needs high doses to be effective
but the skin reaction risk are high
e.g. TEN and SJS
• Daily doses of 80 and 120 mg in
Europe.
• In US, initial dose is 40 mg may
increase to 80 mg PO qday if SUA
< 6 mg/dL not achieved after 2
weeks.
• It is metabolised in the liver and
renal excretion is not a major route
of elimination, which allows for its
use in patients with mild-to-
moderate kidney failure.

52. Starting regime of allopurinol according to
glomerular filtration rate
Arthritis Rheumatol 2012;64:2529–36.
Estimated GFR
ml/min/1.73 m2 Allopurinol starting dose
< 5 50 mg/week
5-15 50 mg twice weekly
16-30 50 mg every 2 days
31-45 50 mg/day
46-60 50 mg and 100 mg on alternate days
61-90 100 mg/day
91-130 150 mg/day
>130 200 mg/day

53. Uricosuric drugs

54. Uricosuric drugs (cont.)
• Urine execretion < 800 mg per 24 hour is considered
under execretion.
• ACR, 2012: probenecid is of choice, consider fenofibrate
or losartan.
Alone or in combination with allopurinol in patients
without proper control with allopurinol alone.
• UK → benzbromarone
Benzbromarone (50–200 mg/day) is a more potent
uricosuric as compared with probenecid (1–2 g/day),
not used in US → fulminant hepatotoxicity.

55. Uric acid oxidase
• Pegloticase is a pegylated uricase, produced by a
genetically modified strain of Escherichia coli that
catalyses the oxidation of uric acid into allantoin, a
more soluble end product.

56. Achieve & maintain low SUA
XOi
Uricosuric
drugs
Uric acid
oxidase

60. Other drugs to be considered
• The uricosuric property of fenofibrate and statins has
been further documented.
• Fenofibrate is an established treatment for many lipid
disorders. It also has the ability to decrease serum urate
by increasing renal uric acid clearance. It may have a
role (off label) in patients resistant or intolerant to
other agents.
• Vitamin C may be tried (ACR).

62. Definition
• Group of metabolic disturbances results from significant tumor breakdown with
release of intracellular products to circulation.
• It occurs in tumors that grows rapidly and are sensitive to chemotherapy.
• Risk is high with acute leukemia, high grade lymphomas, bulky tumors,
elevated pretreatment levels of LDH, uric acid and renal dysfunction.
• TLS usually occurs at initiation of treatment (chemo- or radiotherapy, or even
corticosteroids) of lymphoproliferative (and, less commonly, solid)
malignancies but may occur spontaneously, with a large tumour burden, or at
later stages of treatment.

63. Cairo-Bishop definition
Laboratory TLS Clinical TLS
Two or more of the following
• uric acid ≥ 8 mg/dL or 25% increase
• potassium ≥ 6 meq/L or 25% increase
• phosphate ≥ 4.5 mg/dL or 25%
increase (or ≥ 6.5 mg/dL in children)
• calcium ≤ 7 mg/dL or 25% decrease
(or ionized Ca ≤ 1.12 mg/dL)
• increased serum creatinine (1.5
times upper limit of normal)
• cardiac arrhythmia or sudden
death
• seizure

64. Clinical features of TLS
1. Clinical picture of ↑↑ K
2. Clinical picture of ↑↑ P
3. Clinical picture of ↓↓ Ca

65. Prevention
According to national comprehensive cancer network
(NCCN)
• Fluid: 2 – 3 L daily
• XOi: allopurinol, febuxostat
• Rasburicase: uric acid oxidase
• Alkalization of the urine: using NaHCO3 with
plenty of fluid or utilizing carbonic anhydrase
enzyme inhibitor.

66. Treatment
1. Treatment is first targeted at the specific metabolic
disorder i.e. treat hyperkalemia and hypocalcemia
2. Preventive measures are utilized rigorously
3. If the patient does not respond, hemodialysis may be
instituted
4. Acute kidney injury after chemotherapy. The major cause
of acute kidney failure in this setting is
hyperphosphatemia, and the main therapeutic means is
hemodialysis.