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Table of Contents
REVIEW ARTICLE
Year : 2022  |  Volume : 10  |  Issue : 1  |  Page : 3-7

Acute gout – A harbinger for more serious outcome


Senior Consultant in Internal Medicine and Diabetes, Prem Health Care, Mysore, Karnataka, India

Date of Submission26-Oct-2020
Date of Decision31-Oct-2020
Date of Acceptance07-Jan-2021
Date of Web Publication06-Jan-2022

Correspondence Address:
Dr. Manjunath Premanath
Prem Health Care, #671, Nrupatunga Road, M Block, Kuvempunagar, Mysore - 570 034, Karnataka
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ajim.ajim_83_20

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  Abstract 


Gout is a crystal-induced arthropathy which can start as an acute arthritis and over a few years become chronic and cause systemic complications. Acute gout can manifest as an emergency and cause misery. It is considered as one of the risk factors for hypertension, metabolic syndrome, and cardiovascular disease and when becomes chronic, may end in nephropathy. It may be primary or secondary. Recognition of gout is a simple exercise most of the times but may manifest with atypical features. This discussion is primarily on acute gout, hence its progression to chronic gouty arthritis and its attending complications has a passing mention.

Keywords: Acute gout, cardiovascular risk, crystal-induced arthropathy, hyperuricemia


How to cite this article:
Premanath M. Acute gout – A harbinger for more serious outcome. APIK J Int Med 2022;10:3-7

How to cite this URL:
Premanath M. Acute gout – A harbinger for more serious outcome. APIK J Int Med [serial online] 2022 [cited 2022 Jan 24];10:3-7. Available from: https://www.ajim.in/text.asp?2022/10/1/3/335086




  Introduction Top


Crystal-induced arthropathies are a group of conditions in which Gout is one, characterized by hyperuricemia and formation of uric acid crystals in the joints which manifest as acute gout, chronic tophaceous gout, uric acid nephrolithiasis, and gouty nephropathy.[1] Gout is derived from a Latin word “Gatta” which gave a meaning of drop. It was believed in 13th century that poison was falling in to the joint in the form of drops causing gout.[2] Of late gout is considered as a systemic disease and a serious risk factor for cardiovascular disease. Gout is a chronic disease with acute exacerbations.[3] This review article is on acute gout, hence will concentrate on the etiology and acute manifestations with its treatment and have a few words on chronic tophaceous gout, treatment of hyperuricemia, and the renal complications.


  Epidemiology Top


The incidence of gout is increasing worldwide due to poor dietary habits including fast foods, obesity, lack of exercise, and metabolic syndrome. Annual incidence increases by 0.26% worldwide. Its prevalence is 1%–4% in general population. It increases to more than 10% in men and more than 6% in women after the age of 80 years.[3] The prevalence in the UK was 1.36% in males and 0.64% in females.[1] In females it is more often postmenopausal where as it occurs at a younger age in males and is 2–6 fold more when compared to women.[3]


  Etiology and Natural History Top


Hyperuricemia is the hall mark of gout but by itself it may not confer the diagnosis of gout. Urate is the ionized form of uric acid in the body. Uric acid is a weak acid with its Ph being 5.8. Crystal formation starts when the serum uric acid levels goes beyond the threshold vale of 6.8 mg/dl.[3]

Hyperuricemia can be primary or secondary.

It is said to be primary when there are no acquired causes of increased uric acid production and there is no kidney damage. A few inherited disorders manifest hyperuricemia like X-linked hypoxanthine guanine phosphoribosyltransferase (HPRT) deficiency (Lesch–Nyhan Syndrome), X-linked increased phosphoribosylpyrophosphate synthetase (PRPP), and Autosomal recessive G6P deficiency (von Gierke's disease).[1]

Secondary causes could be either due to over production or under excretion of uric acid. Only 10%–15% is due to over production of Uric Acid (UA) of more than 660 mg/day and the rest 85%–90% is due to under excretion of UA of <330 mg/day.[4]

Increased UA production occurs in tumor lysis syndrome, myeloproliferative disorders, hemolysis, psoriasis, use of cytotoxic drugs, and warfarin and excessive ingestion of alcohol.

Under excretion is mainly due to renal insufficiency, drugs like salycilates, diuretics, laxatives, levodopa, ethambutol, pyrazinamide, and cyclosporine.

Lead toxicity causes renal impairment and alterations in purine turnover to cause hyperuricemia.[1]

The natural history of articular gout follows four stages: (1) Asymptomatic hyperuricemia where in despite increased serum UA levels the patient does not manifest any symptoms. This is because of the fact that crystallization of UA is a slow process, and that is why symptoms occur after 35 years in males and after menopause in females.[4] (2) Stage of acute gouty arthritis where the person manifest severe arthritis, which is going to be described in detail a little later. (3) Stage of intercritical gout, where the patient will be symptom free after the acute attack and (4) the chronic tophaceous gouty arthritis.


  Pathogenesis Top


The increase in UA has to exceed the super saturation threshold value of >6.8 mg/dl for deposition of monosodium urate (MSU) crystals in the joints[3] These crystals are pro-inflammatory and can amplify and sustain an acute inflammatory response[4] and they become the triggering factor for the acute manifestations. These crystalsonce they are deposited in the joints are engulfed by the synovial phagocytic cells leading to release of lysozymal enzymes and production of inflammatory cytokines. The stability of the cell membranes of the phagocytic cells are altered by the UA by direct cross linkage with the lipids and glycol proteins in the membrane which leads to triggering of G protein, Phospolipase A2, C and D, tyrosine kinase, and other kinases. This leads to increased production of IL-8 in the phagocytes resulting in the activation of neutrophils. The activation of monocytes and mast cells along with less differentiated macrophages which engulf MSU crystals followed by activation neutrophils lead to increased production of tumor necrosis factor-alpha, interleukin-1 (IL-1), IL-6, and IL-8. Mast cells release histamine and IL-1, which increase vasodilation and increased vascular permeability leading to neutrophil chemotaxis.[3] This acute attack is self-limiting as the macrophages remove the crystals, clear the debris and secrete transforming growth factor β which eliminates IL-1, there by the inflammation is curtailed.[3]


  Precipitating Factors Top


Acute attack of gout is precipitated by many factors. Stress, heavy exercise, cold, alcohol, over eating may all induce an acute attack basically by increase in the degradation of Adenosine Tri Phosphate (ATP) to adenosine monophosphate (a precursor for UA). Alcohol increases UA by dehydration and metabolic acidosis. Beer is the worst culprit whereas wine is manageable. Urate precipitation is increased by decrease in temperature at night outside as well as inside the foot joints which leads to intra articular fluid dehydration, increase in cation concentration in the presence of nucleating agents such as collagen, proteoglycans, cartilage fragments, and immunoglobulin G.[4]

Purine-rich organ meats such as liver, kidney, thymus, pancreas of calf, sea food, fructose-rich drinks like corn syrup, ice cream, and sweetened soft drinks, when consumed in excess are likely to increase the UA.[4] In contradiction to the earlier thinking, purine-rich vegetables such as beans, lentils, mushroom, peas, legumes, and dairy products do not increase UA and hence do not precipitate acute gout. Leptin has been found to increase UA which may be the cause of more gout in obesity.[3] Insulin resistance causes decreased clearance of MSU and insulin increases increased tubular reabsorption of urate both can precipitate gout in diabetes.[2] Infections causing lactic acidosis, fasting causing ketoacidosis, trauma, or surgery causing break down of the tissues and sudden decrease in serum UA by the hypouricemic drugs below the saturation levels can all precipitate an acute attack of gout.[4]


  Acute Attack of Gout Top


Most of the patients know when an imminent attack of gout is going to occur. They complain of itching due to mast cell degranulation and release of histamine. “Suspect gout when the attack of arthritis begins early in the morning between 2 and 7 am”[2] The most common joint involved is the first metatarsophalangeal joint of big toe in more than 70% of cases (Podagra). The joint becomes acutely swollen with severe pain and will be exquisitely tender. Hyperemia and warmth are also present. There could be severe hyperalgesia. Inflamed and tender Heberden and Bouchard nodes may be the first manifestation. Other joints that could be frequently involved are ankle, foot, knee, wrist, elbow, and the finger joints and bursae.[1] The affected person can be perfectly normal going to sleep, and waking up in the middle of the night with severe pain in the big toe ending up with swollen red painful big toe in the morning. Gout commonly occurs in the 1st MTP joint of the big toe as degenerative changes are common in that joint.[2] The same thing happens with other joints too [Figure 1], [Figure 2], [Figure 3]. The attack subsides with treatment in a few days, and there could be a period of remission when another attack could occur depending on the control of hyperuricemia. Repeated attacks lead to tophi, tophic ulcers, and deformities in the joints.
Figure 1: Acute gout of 1st MTP joint of big toe[9]

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Figure 2: Acute inflammation of finger joint[9]

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Figure 3: Olecrenon bursitis[9]

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  Scoring System for Classification of Gout Top


[Table 1] Adopted from the American College of Rheumatology, European League Against Rheumatism 2015 Gout Classification Criteria.[5]
Table 1: Scoring system for classification of gout

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If diagnosis cannot be made with clinical signs and if doubt exists, this table can be used where >8 points will convey the diagnosis of gout.


  Differential Diagnosis Top
[1]

Calcium pyrophosphate dehydrate disease or pseudo gout, basic calcium phosphate disease (arthritis) cellulitis, infective arthritis, trauma, rheumatoid arthritis, reactive arthritis, psoriatic arthritis, erythema nodosum can mimic gout and has to be ruled out. Special caution has to be exercised with infective arthritis as the clinical manifestation could be very similar but treatment is poles apart.


  Investigations Top


Hyperuricemia is the hall mark of gout. Serum uric acid levels of more than 8 mg/dl is common. Serum uric acid may be normal in acute attack of gout in 25% of patients and it may not reflect the pre attack levels.[1],[2],[6]

Synovial fluid analysis is the gold standard investigation. However, much the clinical diagnosis suggests gout, examination of synovial fluid from the affected joint is a must. This is all the more important in infective arthritis which mimics gout very closely. The synovial fluid should not only be examined for UA crystals but should also be sent for culture and sensitivity of organisms. The presence of typical, negatively charged, birefringent, needle-shaped crystals seen with the polarized light confirm the diagnosis. Pseudo gout shows crystals of CPP which have positive birefringence.

X-ray of the affected joint will be normal during the acute phase, except for the soft-tissue swelling and may not help much. Later stages it may show lot of changes.

Ultrasound examination of the joint may show a double contour sign which is a very specific sign of gout. It is an abnormal hyperechoic band over the superficial margin of the articular cartilage in patients with asymptomatic hyperuricemia. It can disappear if serum uric acid is decreased to <6 mg/dl for 7 months[3] [Figure 4].
Figure 4: Double contour sign on US[7]

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Conventional computed tomography (CT) is not much helpful in acute gout as it cannot recognize inflammation, synovitis, tenosynovitis, and osteitis.[3]

Dual energy CT is an improvement over CCT and shows the deposits of urate, in the tendons and joints and may avoid invasive joint aspiration in some cases. It is expensive and not freely available. However, this investigation has demonstrated deposition of MSU in those who have had asymptomatic hyperuricemia without an acute attack there by hypouricemic treatment can be started before an acute attack[7] [Figure 5].
Figure 5: Dual energy computed tomography[7]

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Nuclear imaging and magnetic resonance imaging are not very useful in an acute attack.


  Treatment Top


Rest, Ice packs are helpful for the affected joints

Nonsteroidal anti-inflammatory drugs (NSAID's) are useful to decrease pain and inflammation. Indomethacin (20–50 mg tid), naproxen (500 mg bd), ibuprofen (800 mg tid), diclophenac (50 mg tid), celecocoxib (800 mg) followed by 400 mg after 12 h,[8] are all equally good but indomethacin is used most often. If the patient has renal insufficiency, these drugs have to be used carefully and in reduced dosage.

Colchicine is useful but has a very narrow therapeutic index. It works by inhibiting urate crystal phagocytosis by neutrophils. It cause diarrhea first before the relief of pain (”patients on colchicine run before they can walk”). If there is renal impairment the dosage has to be reduced. Bone marrow suppression, and myopathy are other complications.[2] Colchicine works best if started within 36 h. Various doses are used. 1 mg loading followed by 0.5 mg after 1 h, and 0.5 mg tid later. For elderly dose to be reduced to 0.5 mg daily or on alt days.[4] It is also used as 0.6 mg given tid with subsequent tapering, or 1.2 mg loading followed by 0.6 mg after 1 h, with daily dosing depending on the response. It is not the drug of choice as it has a narrow therapeutic index.[2]

Steroids are very effective. Should be used when multiple joints are involved. Can be used orally, intra articular or intramuscular. Prednisolone in 25–40 mg doses to be tapered in a week to 10 days. Intra-articular triamcinolone 40–80 mg is also very effective, but one has to be extra cautious and rule out infective arthritis as steroids would be disastrous in that condition. Injectable depot steroids can also be used. ACTH 25–40 iu tid can also be given for 1–14 days.[4]

Biologic response modifiers are used when gouty attacks are more frequent (>3 attacks in a month) and NSAID and Colchicine are proving ineffective. Most of them inhibit IL-1 in reducing inflammation. Anakinra is an IL-1 receptor antagonist. It inhibits both IL-1α and IL-1 β receptors and is given in a dose of 100 mg sc daily for three days. Rilonacept is a soluble decoy receptor binding protein which binds to both IL1α and IL1 β receptors. It is given in a dose of 80-160 mg weekly. Canakinumab is a fully human anti IL1 β monoclonal antibody given in a dose of 150 mg Sc. This drug was not approved by the US Food and Drug Administration for the treatment of acute gout whereas European agencies have approved it for the same indication.[4],[8]


  Uric Acid Lowering Therapy Top
[1],[3]

Uric acid lowering therapy is the main stay in the management of gout mainly to prevent recurring events. That is to say that they are used as prophylactic agents. They should not be started immediately after an acute attack. The earlier dictum was that they should not be started during an acute attack, which has changed off late. They can be started in lower doses during the attack under cover of anti-inflammatory agents. UA lowering drugs should not be stopped during the acute attack, if the patient is already on it. Allopurinol in a dose of 100–900 mg/day, most often 100–300 mg/day, or Febuxostat 40–80 mg/day are used. Both are Xanthine oxide inhibitors. The other one is Pegloticase which is a recombinant uricase. It enzymatically degrades uric acid in to soluble allontoin. It is not used as a first line agent. Reduction of UA to <6 mg/dl should be the aim. Fenofibrate and Losartan can be used as uricosuric agents especially in those who have hypertension and dyslipidemia. Prophylactic treatment is indicated in all patients who have frequent attacks.[2]


  Preventing Acute Attacks Top
[1],[3]

Weight reduction, hypertention control, avoiding diuretics, and reduction of alcohol consumption have their role in prevention but not adequately proven. Purine-rich organ meats such as liver, kidney thymus, pancreas of calf, and sea foods are to be avoided, fructose-rich drinks and ice creams are to be taken less and low fat or nonfat dairy products, vegetables, Vitamin C, and coffee are to be encouraged as they reduce serum urate levels.


  Impact of Systemic Diseases on Gout or Vice Versa Top
[4],[9]

Gout affects joints affected by osteoarthritis more often

Hypertension causes reduced glomerular filtration rate which in turn reduces excretion UA, so also increase in UA itself increases blood pressure.

There is an increase in the production of UA in diabetes due to failure of oxidative phosphorylation leading to increased adenosine level, leading decrease in UA excretion. Treatment with insulin increases UA due to increased absorption from the renal tubules. All these factors increase the cardiovascular (CV) risk. The presence of hyperuricemia should make one to suspect and search for CV risk factors like hypertension which may result in cardiac enlargement, IHD, and cardiac failure. Uric acid stones can cause obstructive uropathy and its antecedent complications. Mortality in Gout is increased due to its cardiovascular and renal complications.


  Conclusion Top


Acute gout is a painful experience which occurs bolt from the blue. The diagnosis is mainly clinical, but to be confirmed by demonstration of UA crystals in the joint fluid. Recent investigations have helped in the diagnosis of acute gout even without the join fluid aspiration for UA crystals. To prevent recurrent attacks of acute gout, keeping the UA levels to <6 mg by using XOI or uricosuric agents is a must. Hyperuricemia should make one to search for CV risk factors and metabolic syndrome. Chronic gout can cause deformities, Gouty ulcers and renal impairment which would affect the heart indirectly. All these may increase the mortality. Hence, proper treatment of acute attacks along with the prevention of recurrent attacks and keeping the UA in desirable limits has to be done diligently.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Hakim AJ, Clunie GP, Haq I. The crystal arthropathies-gout and hyperuricaemia. In: Oxford Hand Book of Rheumatology. 3rd ed. Oxford: Oxford University Press, Great Clavendon Street; 2011. p. 269-74.  Back to cited text no. 1
    
2.
Suresh E. Diagnosis and management of gout-a rational approach-Review. BMJ J More 2004;81:959.  Back to cited text no. 2
    
3.
Ragab G, Elshahaly M, Bardin T. Gout: An old disease in new perspective – A review. J Adv Res 2017;8:495-511.  Back to cited text no. 3
    
4.
Saigal R, Agrawal A. Pathogenesis and clinical management of gouty arthritis. J Assoc Physicians India 2015;63:56-63.  Back to cited text no. 4
    
5.
Neogi T, Jansen TL, Dalbeth N, Fransen J, Schumacher HR, Berendsen D, et al. 2015 Gout Classification Criteria: An American College of Rheumatology/European League Against Rheumatism collaborative initiative. Arthritis Rheumatol 2015;67:2557-68.  Back to cited text no. 5
    
6.
Gout Pictures Slide Show. Available from: https://www.webmed.com/arthritis/SS/slide show-Gout. [Last accessed on 2019 Mar 24].  Back to cited text no. 6
    
7.
Igel TF, Krasnokutsky S, Pillinger MH. Recent Advances in understanding and managing Gout. Version 1 FI000 Res 2017;6:247.  Back to cited text no. 7
    
8.
Ralph Schumacher H, Chen LX. Gout and other crystal associated arthropathies. In: Kasper D, Fauci A, Hauser S, Longo D, Jameson JL, Loscalzo J, editors. Harrisson's Principles of Internal Medicine. 19th ed., Vol. 2, Ch. 395. USA: McGraw Hill; 2015. p. 2233-7.  Back to cited text no. 8
    
9.
Hellman DB, Imboden JB Jr. Rheumatologic, immunologic and allergic disorders-crystal deposition arthritis-1 gouty arthritis. In: Pappadakis MA, Mcphee SJ, editors. Current Medical Diagnosis and Treatment. 57th ed., Ch. 20. New Delhi: McGraw Hill Education; 2018.p. 837-42.  Back to cited text no. 9
    


    Figures

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  In this article
Abstract
Introduction
Epidemiology
Etiology and Nat...
Pathogenesis
Precipitating Fa...
Acute Attack of Gout
Scoring System f...
Investigations
Treatment
Conclusion
Differential Dia...
Uric Acid Loweri...
Preventing Acute...
Impact of System...
References
Article Figures
Article Tables

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