Gout Flashcards
What is the pathophysiology of gout?
The two main sources of purines are from the diet and cell turnover.
This is degraded to uric acid.
Humans lack the uricase enzyme which converts uric acid to allatoin (more soluble) so we have higher uric acid levels.
There is a delicate balance of uric acid in the body.
A sustained elevation will produce gout but hyperuricaemia does not always produce gout.
What is the prevalence of gout?
10% maori, 2.9% European
Predominantly male
Higher incidence in obese, alcohol drinkers, and people with high intake meat me fish diets
What are the two main types of disease states in gout?
Over producers of uric acid (90% of patients)
Underexcretors of uric acid (10% of patients)
What is gout?
The excess of uric acid accumulation due to overproduction of underexcretion
What causes an over production of uric acid?
Abnormalities in two main enzymes:
Increased Phosphoribosyl pyrophosphate synthetase activity leads to increased posphoribosyl pyrophosphate which is the key determinant of purine synthesis
Deficiency of hypoxanthine-guanine Phosphoribosyltramsferase results in more purines present in the bloodstream and an increased metabolism of guanine and hypoxanthine to uric acid.
What is the role of hypoxanthine-guanine Phosphoribosyltransferase normally?
Conversion of guanine to gunalyic acid
Conversion of hypoxanthine to inosinic acid
What causes underexcretion of uric acid?
Uric acid is mostly excreted renally (only 1/3 is excreted by gut bacteria)
Declined urinary excretion of uric acid below the rate of production leads to hyperuricaemia and increased miscible pool of sodium urate.
There is a close link between proximal tubular sodium reabsorption and uric acid reabsorption.
Dehydration is a common cause
Can also be caused by diuretics, nicotinic acid, low dose salicylate a, ethanol, pyrazinamide, levodopa, ethambutol, cyclosporine and cytotoxic drugs which decrees the renal clearance of uric cis
How are over producers of uric acid defined?
Individuals with gout who excrete >600mg on a Purine free diet for 3-5 days
How are underexcretors defined?
Individuals with gout who excrete <600mg of uric acid per 24 hours on a purine free diet
How does inflammation arise in gout?
Deposition of urate crystals in synovial fluid causes an inflammatory reaction involving chemical mediators which cause
Vasodilation
Increased vascular permeability
Complement activation
Chemotactic activity for polymorphonuclear leukocytes
What is the result of phagocytosis of urate crystals by leukocytes?
Rapid lysis of cells and a discharge of proteolytic enzymes into the cytoplasm.
What is inflammation in gout associated with?
Intense joint pain
Erythema
Warmth
Swelling
What are the main processes of the inflammatory response?
Inflammatory response occurs due to precipitation of uric acid crystals in joint
Release of cytokines and Chemokines: neutrophils and leukocytes migrate to the site of inflammation
Aggressive phagocytosis of uric acid crystals results in neutrophil death and enzyme/mediator release
Causing an acute gouty attack
What is uric acid nephrolothiasis?
Occurs in 10-25% of patients with gout
When urine is acidic, uric acid exists in the unionised form
When there is saturation of uric acid, spontaneous precipitation of stones can occur
What are the predisposing factors to uric acid nephrolothiasis ?
Excessive urinary excretion of uric acid
Acidic uirne
Highly concentrated urine
What are the foods that contain purines?
Beer and other alcoholic beverages
Anchovies, sardines in oil (fatty acids found in certain fish like sap,on may possess some anti inflam effects)
Yeast
Organ meat (liver, kidneys, gravies)
Meat extracts
Mushrooms, spinach, asparagus, cauliflower
What are the precipitating factors of gout?
Hypertension (thiazide diuretics decrease renal CL of uric acid)
Obesity (strong corr. With hyperuricaemia and gout)
High alcohol intake
Dietary factors
Hyperinsulineamia (occurs in 76-95% of gout sufferers)
Also associated with hyperlipidaemia, type II diabetes, coronary artery disease.
Higher risk of gout in maori and Pacifica, (1/8 men, 1/20 women)
What are the 6 principle contributing factors leading to increased gout?
Incidence of hypertension Obesity Incidence of diabetes Renal failure Cardiac failure Changing dietary trends and alcoholism
What are tophi?
Deposits of uric acid salts appearing around the affected joint due to frequent recurrent attacks of gout, or high levels of uric levels for a long period of time.
These appear as chalky coloured nodules and may also appear in other areas of the body e,g, ears.
What is the role of surgery in the treatment of gout?
It may be required to restore joint function as recurrent severe attacks of gout and development of tophi can cause permanent damage to the joints.
May involve a joint replacement surgery.
How can gout impair kidney function?
Damage to the delicate filters within the kidneys and development of kidney stones.
This is a escort of high uric acid levels for a long period of time
What are the main riggers of gout?
Trauma
Alcohol
Dehydration
acidic pH (causes uric acid crystallisation)
Anything that compete is with uric acid transport systems like aspirin
Dietary excess
Irritation of uricosuric or allopurinol therapy
What are the symptoms of gout?
Fever and intense pain
Erythema
Warm, inflammation and swelling of involved joints
Observation of mono sodium urate crystals in synovial fluid or tophus
Max inflammation developed within a day
How do acute attacks of gouty arthritis begin?
At night, characterised by a rapid onset of excruciating pain, swelling and inflammation
How long do gout attacks last?
If untreated, may last from 3-14 days before spontaneous recovery
What is the pattern of gout attacks?
Typically mono articular.
Most often affecting the great toe
Then ankles, heels, knees, wrists, fingers and elbows.
Can atypical gout occur?
Yes, in the elderly
How is gout diagnoses?
Elevated serum uric acid levels and elevated WBC
Increased ESR and CrP (markers of inflammation)
Definitive diagnosis by aspiration of synovial fluid from affected joint and identification of intracellular crystals of monosodium urate monohydate in synovial fluid leukocytes
What is the differential diagnosis in gout?
Septic arthritis,
You would need to confirm this by checking for infection and if there is improvement if infection is treated
What are the symptoms of chronic gout?
Elevated serum urate
Recurrent attacks of acute gouty arthritis + monosodium urate crystals in synovial fluid leukocytes
Deposits of monosodium urate crystals in tissues and around joints (tophi)
Interstitial renal disease
Uric acid nephrolithiasis (crystallisation in renal tubules)
What is used to treat acute gout?
NSAIDs
Colchicine
Corticosteroids
How are NSAIDs used in acute gout?
As a first line short term treatment to reduce pain and inflammation.
Given in high doses for a short course
What are the NSAIDs commonly used in acute gout?
Indomethacin
Diclofenac
What is indomethacin ?
A non selective inhibitor of cox I and II enzymes that participate in prostaglandin synthesis from archi sonic acids
What is diclofenac?
NSAID which achieves analgesic action by cox inhibition
Why is aspirin not used in acute gout?
It inhibits the kidneys ability to eliminate uric acid and may exacerbate these conditions
What are the adverse reactions with NSAID use?
GI: gastritis, bleeding, perforation
Kidneys: reduced CrCl,
Cardiovascular: sodium and fluid retention, increased BP
CNS: impaired cognitive function, headache, dizziness
When should NSAIDs be used with caution?
In patients with peptic ulcer disease, congestive heart failure and renal insufficiency
How does colchicine work?
It affects the mitosis of WBC by inhibiting spindle fibre separation, thus stopping the proliferation and inflammation of inflammatory cells
When should colchicine be used in acute gout?
Should be reserved for patients with contraindications to NSAID use or whom have ineffective relief with NSAIDs
How is colchicine given in acute gout attacks?
Give until relief, nausea, vomiting, diarrhoea or until maximum dose is reached. (Need to wait 3 days between courses)
Selling and pain usually resolves in 24-48 hours
What should be avoided if a patient is on colchicine?
Macrolide antibiotics such as clarithromycin due to reduced biliary excretion which can lead to increased plasma colchicine levels and agranulocytosis (lower WBC), also avoid if patient is on prophylactic colchicine especially if CrCl <80ml/min
Avoid grapefruit juice as this increases blood levels of colchicine, putting patient at risk of toxicity
Why is IV colchicine avoided?
Can cause serious side effects like bone marrow suppression
Why is colchicine treatment stopped if patient displays vomiting/diarrhoea?
Patient needs to avoid being dehydrated
Elderly with reduced renal/hepatic clearance may suffer toxicity
What are the adverse effects of oral colchicine?
Dose dependent GI effects such as vomiting and diarrhoea
Can colchicine be used for prophylactic treatment of gout?
Yes, 12 hours after the symptoms have dissipated.
Give 0.5mg twice daily, max 1.2mg
When is colchicine for the short term prophylactic treatment of gout given until?
Urate levels are <0.36mmol/L and there are no acute attacks for 3-6 months
When are corticosteroids used to treat acute attacks of gouty arthritis?
Reserved primarily for patients with a Contraindication or who are unresponsive to colchicine or NSAID therapy
What is the main corticosteroid used to treat gout?
Prednisolone
How is prednisolone given?
20-40mg orally once daily then decrease by 5-10mg increments every 3 days until discontinuation.
Or 1mg/kg orally as a single dose
What is the mechanism of prednisolone?
It is lipophilic and readily crosses the membrane to combine irreversibly with the glucocorticoid receptor.
Activated complex then enters the nucleus where it acts as a transcription factor leading to gene activation
When should prednisolone be used with caution?
In diabetics, as it can increase blood sugar
Patients with history of GI problems, bleeding disorders or CVD
What are the adverse effects of prednisolone?
Fluid retention of the face,
Acne
Can cause ulcers, constipation and mood swings
What is the aim of using Allopurinol?
To reduce uric acid levels to below 0.36mmol/L
What is the mechanism of allopurinol?
Reduces uric acid production by inhibiting xanthine oxidase (which is a Structural isomer of hypoxanthine )
Is allopurinol active?
No. 60-70% of allopurinol undergoes hepatic conversion to the active metabolite oxipurinol
How is allopurinol given?
Start on a low dose of 100mg PO OD
Increase by 100mg/day every week according to serum urate level until maximum 800mg/day
When is allopurinol co administered with colchicine or NSAID?
Usually in the first 3 months of chronic therapy until serum urate levels <0.36mmol/L
What are the adverse effects with allopurinol use?
Hypersensitivity reactions (dose related): skin rash
GI upset
Severe data rash occurs in 2% of patients
What does allopurinol interact with?
Cytotoxic agents
Alcohol interferes with effectiveness
Probenecid decreases concentration of allopurinol
How much should allopurinol dose be decreased in patients with renal impairment?
200mg/day for CrCl 60mL/min or less
100mg/day for CrCl 30mL/min or less
Should allopurinol be given for acute attacks?
No. But if an attack occurs while patient is on allopurinol, the allopurinol should not be stopped
Why must patients be given a low dose of allopurinol and then slowly increase it?
A sudden decrease in serum urate levels can precipitate an attack
What are the uricosurics used for long term gout?
Probenecid
Sulphpyrazone
Benzbromarome
Febuxostat
How do probenecid, sulphinpyrazole and benzobromarome work?
Increases renal clearance of uric acid by inhibiting tubular resorption of uric acid
Probenecid:
Give 250-1000mg orally BD
Sulphinpyrazole:
Give 100-400mg orally OD
Benzobromarome:
Give 100-200mg orally OD
When should probenecid, sulphinpyrazole and benzobromarone be used?
In patients who underexcrete uric acid
AVOID in patents with poor renal function (CrCl< 20-30mL/min) or who overproduce uric acid)
What are the adverse effects with probenecid, sulphinpyrazole and benzbromarone use?
GI irritation
Rash
Hypersensitivity
Precipitation of acute gouty arthritis and stone formation
What is Febuxostat?
A non purine selective inhibitor of xanthine oxidase.
It is tolerated in renal impairment
How does Febuxostat work?
By inhibiting xanthine oxidase, it reduces serum uric acid
How is Febuxostat given?
40-80mg orally OD
What are The adverse effects with Febuxostat ?
Nausea diarrhoea headache and rash
When should long term therapy for gout be initiated?
When patient has two or more attacks per year
Monitored serum urate levels every 3-6 months and adjust therapy according to levels in symptomatic patients
What are the key things to remember with long term gout therapy?
Use uricosurics if a atient is allergic to allopurinol
Consider co adminstration with colchicine until serum urate levels have been lowered
What are the non pharmacological treatments of gout?
Reduce dietary intake of saturated fats and meats high in purines (organ meats) Increase fluid intake Decrease salt consumption Promote joint exercise Avoid applying heat to the area Weight loss through caloric restriction Restrict alcohol intake Withdraw drugs that induce gout Joint rest for 1-2 days encouraged Local application of ice, insoles in shoes may be beneficial Avoid diuretics
Why is alcohol highly correlated with gout symptoms?
Alcohol contains guanosine which is converted to uric acid by bacteria
What monitoring is involved in gout?
Most medications (esp. Allopurinol) have multiple drug interactions, requiring adjustments to medication dosages.
When initiating allopurinol, patients should be closely monitored for hypersensitivity (such as dermatitis and multi system failure)
Long term colchicine use may be assoc. with neuromyopathy Probenecid may increase risk of nephrolothiasis
Acute pain of an initial attack of gouty arthritis should begin to ease within 8 hours of treatment initiation
Complete resolution of pain erythema and inflammation occurs within 48-72 hours
Patients should be monitored for the development of trophi and radiographic changes
Patients taking uric acid lowering agents showed be followed up every 1-3 months initially, then every 6 months (target level is <0.36mmol/L)
FBC, renal function test and LFTs should be obtained every 3-6 months to test for adverse effects of NSAIDs and colchicine, especially if they are used for prolonged periods
How is gout different from osteoarthritis?
Age of onset usually over 35 years of age in men, and after menopause in females (earlier than osteoarthritis)
Sudden onset of disease (OA is slow)
Big toe joint most common. Other affected joints are ankle, heel, knee, wrist, fingers, elbow etc (OA is one side of body large weight bearing joints, usually limited to ONE set of joints like finger joints next to fingernail)
Duration of morning stiffness is not seen in gout (but lasts less than 1 hour in OA and returns in the evening)
Chills and mild fever along with general malaise can accompany severe pain and inflammation in gout, but not in OA
Tophi may form in gout, whereas in OA symptoms occur in isolation with no systemic symptoms
