gout

from Wikipedia, the free encyclopedia
Classification according to ICD-10
M10 gout
ICD-10 online (WHO version 2019)
The Gout , engraving by James Gillray , 1799

The gout , also Urikopathie or gouty arthritis , is a metabolic disease characterized by high uric acid concentrations untreated blood results in changes to joints and kidneys. Deposits of uric acid crystals (urate) in various peripheral joints and tissues lead to bone resorption and cartilage changes ( gouty arthritis ). In addition, damage to the kidneys can occur, which in the long term ultimately leads to renal insufficiency ("gout kidney"). The damage to the kidneys is painless, but because of the importance of the kidney as an excretory organ, it is more critical than the painful gout attacks on the joints.

The disease progresses in phases .

Symptoms

Acute

Acute podagra

Acute symptoms include sudden severe pain in a joint and severe pain to the touch: uric arthritis . The joint is red, extremely painful, severely swollen and overheated ( Rubor - Dolor - Tumor - Calor - Functio laesa ), there are also general signs of inflammation such as fever , an increase in the number of white blood cells and increased uric acid levels before the attack (in an acute gout attack often normal uric acid levels), rarely headaches occur.

In an acute gout attack, a joint becomes extremely painful, swollen and hot without an injury or any other traceable cause. The metatarsophalangeal joint of the big toe is often affected, then one speaks of the podagra (from Greek podágra , in Latin used by Seneca, Cicero, etc.; ágra stands for 'catch, fetter', pod for 'foot'). From antiquity to modern times, podagra not only refers to gout or the symptoms of acute gout - especially the painful inflammation or pain in the metatarsophalangeal joint of the big toe during a gout attack - and similar arthritis, but also other painful joint diseases. Chiragra are gout-related pain in the wrist ( chir stands for 'hand'), gonagra in the knee joint and omagra in the shoulder joint. Basically, an acute attack of gout - even the first one - can affect any joint. The gout attack usually lasts two to three weeks if left untreated, and the duration of the attacks can increase as the disease progresses. The seizures can also merge into one another in the chronic phase, so that there are no longer any pain-free intervals.

Chronic

Gout on the x-ray of the foot. Typical (main) location at the metatarsophalangeal joint of the big toe. The swelling of the soft tissue around the joint is also noticeable

After several seizures, chronic gout develops with destruction of the joints. In the X - ray image, punch defects in the cancellous bone (inner parts of the bone) near the joint are characteristic, and the joint head shows clear defects. The consequences are reduced performance, uric acid crystal deposits in joints, joint deformation , kidney stones, kidney failure . As the gout moves into the chronic phase, the acute attacks often become less pronounced and less painful.

Hyperuricemia

There are two causes of hyperuricemia , i.e. H. the increased level of uric acid in the blood: the primary and the secondary form.

  • The primary form (approx. 90%) is a disorder of the purine metabolism. It is caused by an elimination disorder of the kidneys . In very rare cases, overproduction of uric acid can also be the cause.
  • In the secondary form (approx. 10%), various concomitant diseases cause the increased uric acid level (e.g. due to cell death in tumor diseases (especially leukemia ), hemolytic anemia or systemic diseases such as psoriasis ).

An asymptomatic hyperuricemia alone does not constitute indication for treatment in general.

causes

In well over 99% of all cases (without external influence), hyperuricemia is based on a kidney dysfunction, which can be inherited as an autosomal dominant trait. These patients have a hereditary uric acid elimination disorder of the kidneys with otherwise normal kidney function. Hyperuricemia can also be caused by kidney dysfunction of another cause, such as B. diabetes mellitus , can be a consequence, since a too high blood sugar level damages the blood vessels over a long period of time , whereby the kidney function is impaired. Excessive alcohol consumption is also harmful , as carboxylic acids compete with uric acid in the kidney's excretion mechanism. In addition, fermented foods provide uric acid-forming purines due to the yeast and bacterial residues they still contain .

There may also be a disorder of the purine metabolism . Usually there is a disruption of the HGPRT enzyme in the recycling of the purine bases . In the complete absence of this enzyme, this leads to Lesch-Nyhan syndrome .

Important stations of the purine metabolism

Furthermore, a long-term study was able to establish a positive relationship between obesity , measured as a body mass index , and the risk of a gout attack. For example, the combination of increased meat and seafood consumption in combination with a BMI ≥ 25 leads to a considerable risk of gout. Consuming dairy products , on the other hand, reduces the chances of developing gout.

Diagnosis

Urate crystals in synovial fluid

An increased uric acid level can be detected in the blood. However, one should bear in mind that the blood level can fluctuate very quickly depending on what has been eaten or drunk. If a gout attack occurs, the uric acid level in the blood can be in the normal range; this does not rule out gout. The clinical picture is usually sufficient.

Laboratory
(optional changes)

If the uric acid rises to> 8 mg / dl, 25% of the patients suffer; if the uric acid rises to> 9 mg / dl, almost every patient suffers a gout attack.

In addition, if the disease is chronic, typical changes in the bones can be demonstrated in the X-ray image (e.g. joint destruction and bone loss near the joint, tophi ). In urography , the indirect representation of individual urate stones is used to establish the diagnosis (cannot be represented in the X-ray image). Finally, if there is any uncertainty, a direct joint puncture in the presence of urate crystals in the synovial analysis can confirm the diagnosis.

To the model of the purine-uric acid metabolism

Model of the purine-uric acid metabolism in humans
  • The behavior of uric acid in this model is comparable to that of water in a reservoir: In proportion to the difference to the current uric acid level, it flows off up to the "water level mark" shown of 3 mg / dl, i.e. H. will be eliminated.
  • Above 6.5 mg / dl, uric acid passes very slowly from the blood into a urate deposit in the body, below 6 mg / dl urate is broken down very slowly from the urate deposit.
  • In addition to the 300 to 1000 mg of purines that are ingested with food, the body itself produces 300 to 400 mg of purines per day.
  • The uric acid level in the blood can be 3 to 10 mg / dl; Values ​​above 6.5 mg / dl on average lead to the deposition of urate in the connective tissue (so-called tophi) and can lead to an attack of gout.
  • The excretion of uric acid with the urine at a level of 6 mg / dl is normally around 800 mg per day, but only around 400 mg when excretion is reduced (hyperuricemia). For other values ​​of the mirror, the values ​​are proportionally larger or smaller.
  • The excretion of uric acid is worsened by the consumption of alcohol (regardless of the type of drink), it is improved by consuming 2 liters of fluid per day (even more fluid does not flush out additional uric acid).
  • The adjustment of the mean uric acid level in the blood, e.g. B. on a diet , lasts 6 to 10 days.
  • The build-up and breakdown of urate deposits in the connective tissue takes place very slowly and takes many months to a few years.
  • The only way to permanently avoid gout is through a suitable low-purine diet that keeps the mean uric acid level below 6 mg / ml. In the case of hyperuricemia, permanent prophylaxis is also necessary, e.g. B. with allopurinol .

Therapy options

Acute attack of gout

Tophus on the elbow joint
NSAIDs
NSAIDs inhibit the synthesis of prostaglandins by inhibiting an enzyme of the inflammatory metabolism ( cyclooxygenase ), which leads to a reduction in pain and anti-inflammatory effects. This is best documented for indomethacin , which however often causes undesirable side effects. More common drugs with fewer side effects are ibuprofen and diclofenac . In the 19th century, salicylates were introduced into gout therapy by Germain Sée. Acetylsalicylic acid is not suitable for gout therapy as it can slow down the excretion of uric acid.
Colchicine
Colchicine prevents leukocytes (especially macrophages ) from taking up uric acid crystals (urate), thus reducing the inflammatory response sustained by these cells and their cytokines . The use of the poison of the autumn crocus for gout was already known in Mesopotamia, in ancient Egypt and in ancient Greece. Colchicine used to be used in high doses, which regularly resulted in side effects, particularly diarrhea. Therefore, a lower dose (e.g. 3 × 0.5 mg / day) is recommended today, which is also effective, but is better tolerated. Renal insufficiency is a contraindication .
Cortisol
Cortisol is an endogenous hormone that has powerful anti-inflammatory effects. Corticosteroids, administered intra-articularly and / or systemically, have become more important in gout therapy in recent years without their effect having been investigated in meaningful studies. Steroids are not contraindicated in renal insufficiency.

All of these drugs only fight the symptoms.

The previous recommendation to start uric acid-lowering therapy only after the acute gout attack has completely subsided no longer applies. Concern that early uric acid-lowering therapy might aggravate a gout attack could not be confirmed , especially when NSAIDs or colchicine were administered at the same time .

Chronic gout

Diet change
A low-purine diet is recommended, but only shows a moderate reduction in uric acid levels. More pronounced effects on uric acid in the blood were achieved with a moderately energy - and carbohydrate - reduced diet with an increased proportion of proteins and unsaturated fatty acids . As protein-rich foods , low-fat dairy products are more suitable than meat or fish.
Urikosurika
Uricosurics inhibit the reabsorption of uric acid in the kidneys and thus promote its excretion; in the case of renal insufficiency or a history of kidney stones, its use is not recommended.
Commercially available uricosuric drugs are:
Uricostatics
Inhibitor of xanthine oxidase result in decreased production of uric acid by competitive inhibition of xanthine oxidase, the hypoxanthine into xanthine and further oxidized to uric acid. In addition, the resulting increased hypoxanthine concentration inhibits purine synthesis. Active ingredients are allopurinol and febuxostat . Allopurinol has been the drug of choice since 1964. According to current guidelines, allopurinol is indicated after the first attack of gout. The daily therapy costs with febuxostat are ten times higher than with the generic allopurinol. An increased cardiac risk is also discussed. Febuxostat, however, is of value in patients with impaired renal function, as it is largely metabolized via the liver, intolerance to allopurinol and polymedication due to the lower potential for interaction.

Uric acid formation through food (selection)

Structure of organic compound: 7,9-dihydro-1H-purine-2,6,8 (3H) -trione
Structural chemical formula of uric acid
  • High uric acid concentration (over 200 mg / 100 g): trout, herring, sprats, grilled chicken, liver, kidney, sweetbreads , meat broth, soup cubes and baker's yeast.
  • Fruit sugar ( fructose ), which can be contained in dairy products, for example, is converted into inosine monophosphate (IMP) after consumption , which increases the concentration of uric acid in the body through the breakdown of purine.
  • For drinks, beer (10–23 mg / 100 g) and cola (10 mg / 100 g) are primarily sources of purine. Beer is also harmful due to the alcohol content.
  • Medium amount of uric acid (80–150 mg / 100 g): plaice fillet, beer ham, muscle meat (beef, pork, chicken, game), legumes and peanuts
  • No / little uric acid (0–50 mg / 100 g): milk, yoghurt, egg, pumpkin, paprika, potato, apple, whole-grain bread, white bread and cheese.
  • The purines contained in coffee , black tea and cocoa are not broken down into uric acid; these drinks are therefore innocuous with regard to gout.

Gout in animals

Gout is also found in birds and reptiles, as well as pigs and dogs. Gout has already been detected in dinosaurs. After observing bone lesions similar to those found in gout patients in the metacarpal bones of a Tyrannosaurus rex , an additional 83 skeletons were examined. Only one other specimen showed similar changes. Holes were observed in the affected bones and new bone formation was observed along the edges. The bone density of the intact bone was not abnormal. However, it was not possible to detect remains of gout crystals with any method in order to provide clear evidence of the etiology of the bone change. The bone changes typical of gout, which are clearly different from those of similar diseases such as reticulohistiocytosis or amyloidosis , remain indications of urate-driven genesis .

Niggles

An outdated term for gout (Middle High German gout , older giht ; cf. also the gihte in the sense of "gout, cramps, pain in general", for example in darmgegiht / darmgiht as "intestinal colic") or gouty arthritis, which was already used by the Hippocrats (in Hippocrates the "illness where one cannot walk") was distinguished from other forms of arthritis , Zipperlein , which was derived from the late Middle High German zipperlīn , Middle High German from zipfen for 'tripple' and referred to the patient's gait. The meaning was expanded to include other ailments . In his dictionary published in 1801, Adelung described Zipperlein as

“A term that is largely outdated in High German, both for Podagra and Chiragra . Got the niggles. The pinch on the hands. It is not healthy from that . Cyprian , the saint against this disease, as Zeiler wills, but from a verb that is still present in the lower forms of speech, zipping, zipping, twitching and tugging often and in small paragraphs, like Podagrian patients tend to do in the pains of Podagra. This low level of the verb is also the reason why the noun derived from it is let out of date, especially since its form, as a diminutive, has no comprehensible reason. "

- Adelung : Grammatical-Critical Dictionary of High German Dialect, 1801

Adelung's explanations are outdated today. Its use as a remedy gave rise to the name of Zipperleinskraut (ground elder) .

Illness of Kings

It was known early on that gout is less common in times of need than in times of prosperity. Thomas Sydenham wrote in the 17th century: "The gout mostly afflicts those people who lived lavishly in earlier years and who enjoyed wine and other spirits over copious meals". In Egyptian mummies, indications of changes caused by gout about 7000 years ago have been found.

Based on the symptoms described in the Talmud, it can be assumed that King Asa of Judah (9th century BC) suffered from gout. After the pathological anatomist Giovanni Battista Morgagni described gout as the disease of the rich in 1761, it was considered the disease of the kings until the 19th century and was interpreted as a privilege of the rich - only they could afford a lifestyle that triggered gout. Until this time, the normal population inevitably had a low-purine diet, i.e. mainly bread, dairy products and potatoes. Meat, fish and alcohol were only available on Sundays and public holidays. In 1778, William Cullen described the typical gout patient as "robust and well-fed, with a large head and broad chest, blood-rich and corpulent". Many famous people in world history (including members of the Habsburgs such as Charles V and Philip II ) suffered from the symptoms of acute gout. Since around the 1950s, gout is no longer a rare and elitist disease, mainly due to the changed nutritional behavior of people.

Famous gout sufferers included Titus Pomponius Atticus , Henry VIII , Charles V , Peter Paul Rubens , Wallenstein , Herman Boerhaave and Thomas Sydenham .

literature

Overview representations

  • C. Müller: Gout disease - low-purine food against pain. from: UGB-Forum. 2/00, pp. 68-71, UGB-Verband, 2000.
  • Anne-Kathrin Tausche et al .: Gout - Current Aspects in Diagnostics and Therapy . In: Dtsch Arztebl Int . tape 106 , no. 34–35 , 2009, pp. 549-555 ( aerzteblatt.de ).
  • Ursula Gresser : Diagnosis and therapy of gout. In: Deutsches Ärzteblatt. Volume 100, No. 44, 2003; S. A-2862 / B-2379 / C-2235 ( aerzteblatt.de )
  • Gerhard Heidelmann, Peter Thiele (ed.): The gout syndrome. Arthritis, nephropathy, uric acid nephrolithiasis, diabetes mellitus, hyperlipoproteinemia, obesity, hypertension, myocardial infarction, arterial occlusion. Dresden 1974.

On the history of gout

  • Jean Robert d'Eshougues: Gout and Rheumatism. In: Illustrated History of Medicine. German arrangement by Richard Toellner a . a., special edition (in six volumes) Salzburg 1986, volume IV, pp. 2260–2291.
  • Gerhard Eis: Erhard Knab's gout regimen (1469). In: Medical monthly. 7, 1953, pp. 523-527.
  • Horst Kremling : Historical considerations on preventive medicine. In: Würzburg medical history reports. Volume 24, 2005, pp. 222-260, here p. 242.
  • Ange-Pierre Leca: Histoire illustrée de la Rhumatologie. Goutte, rhumatismes et rhumatisants. Paris 1984.
  • Primus Lessíak : Gout. In: Journal for German Antiquity and German Literature 53, 1911, pp. 101–182.
  • Maurice A. Schnitker: A history of the treatment of gout. In: Bulletin of the History of Medicine 4, 1936, pp. 89-120.
  • Markwart Michler †: Gout. In: Werner E. Gerabek , Bernhard D. Haage, Gundolf Keil , Wolfgang Wegner (eds.): Enzyklopädie Medizingeschichte. De Gruyter, Berlin / New York 2005, ISBN 3-11-015714-4 , p. 492 f.

Web links

Wiktionary: Gout  - explanations of meanings, word origins, synonyms, translations
Wikibooks: Pharmacology and Toxicology: Metabolism: Gout  - Learning and Teaching Materials
Commons : Gout  - Collection of pictures, videos and audio files

Individual evidence

  1. ^ Max Höfler: German book of names of diseases. Munich 1899, p. 478.
  2. ↑ Wolfgang Miehle: Joint and spinal rheumatism. Eular Verlag, Basel 1987, ISBN 3-7177-0133-9 , pp. 10 and 175.
  3. ↑ Gundolf Keil : "blutken - bloedekijn". Notes on the etiology of the hyposphagma genesis in the "Pommersfeld Silesian Eye Book" (1st third of the 15th century). With an overview of the ophthalmological texts of the German Middle Ages. In: Specialized prose research - Crossing borders. Volume 8/9, 2012/2013, pp. 7–175, here: p. 10.
  4. ↑ Ekkehard Grundmann (ed.): Introduction to general pathology and parts of pathological physiology. 5th edition. Stuttgart / New York 1985, p. 168.
  5. ^ Hyon K. Choi, Karen Atkinson, Elizabeth W. Karlson, Walter Willett, Gary Curhan: Purine -Rich Foods, Dairy and Protein Intake, and the Risk of Gout in Men . In: The New England Journal of Medicine . tape 350 . Boston March 11, 2004, p. 1093-1103 , doi : 10.1056 / NEJMoa035700 , PMID 15014182 .
  6. ↑ The principle of this model and many other facts come from Wolfgang Gröbner et al. Uric acid metabolism, Springer 1980 and from conversations with Wolfgang Gröbner.
  7. ^ Effect of Prophylaxis on Gout Flares After the Initiation of Urate-Lowering Therapy: Analysis of Data From Three Phase III Trials . In: Clinical Therapeutics . tape 32 , no. 14 , p. 2386-2397 , doi : 10.1016 / j.clinthera.2011.01.008 .
  8. ↑ William Charles Kuzell, Guy-Pierre Gaudin: gout. (= Documenta Rheumatologica. Volume 10). JR Geigy, Basel 1956, p. 11.
  9. ↑ William Charles Kuzell, Guy-Pierre Gaudin: gout. (= Documenta Rheumatologica. Volume 10). JR Geigy, Basel 1956, p. 11.
  10. ↑ Attila Dunky, Rudolf Eberl: Gout and hyperuricemia. G. Braun, Karlsruhe 1981 (= Rheuma-Forum. Volume 11), ISBN 3-7650-1632-2 , pp. 11 and 13 f.
  11. ↑ U. Kiltz, R. Alten, M. Fleck et al .: Long version of the S2e guideline on gouty arthritis (specialist doctor) Evidence-based guideline of the German Society for Rheumatology (DGRh) . In: Journal of Rheumatology . tape 75 , no. 2 , August 1, 2016, p. 11-60 , doi : 10.1007 / s00393-016-0147-6 .
  12. ↑ TH Taylor, et al .: Initiation of allopurinol at first medical contact for acute attacks of gout: a randomized clinical trial . In: The American Journal of Medicine . tape 125 , no. 11 , November 1, 2012, p. 1126–1134.e7 , doi : 10.1016 / j.amjmed.2012.05.025 , PMID 23098865 .
  13. ↑ PH Dessein, et al .: Beneficial effects of weight loss associated with moderate calorie / carbohydrate restriction, and increased proportional intake of protein and unsaturated fat on serum urate and lipoprotein levels in gout: a pilot study. In: Ann Rheum Dis . 2000; 59, pp. 539-543.
  14. ↑ HK Choi, et al .: Purine-rich foods, dairy and protein intake, and the risk of gout in men. In: The New England Journal of Medicine. 2004, 350 (11), p. 1093.
  15. ↑ MA. Becker, HR. Schumacher, RL. Wortmann, et al .: Febuxostat Compared with Allopurinol in Patients with Hyperuricemia and Gout . In: The New England Journal of Medicine . tape 353 , no. 23 , December 8, 2005, pp. 2450-2461 , doi : 10.1056 / NEJMoa050373 , PMID 16339094 .
  16. ↑ Lüllmann, Heinz, Mohr, Klaus, Hein, Lutz, Wehling, Martin, Georg Thieme Verlag KG: Pharmacology and Toxicology Understand the effects of drugs - use drugs in a targeted manner . 18th edition. 2016, ISBN 978-3-13-368518-4 .
  17. ↑ P Christalla, K. Witt Köpper, A. Al-Armouche: febuxostat, a new drug for the treatment of gout , cardiologist, January 2011, pp 45-50.
  18. ↑ Table of foods with high uric acid content , (PDF; 85 kB) Bavarian State Ministry for the Environment, Health and Consumer Protection.
  19. ↑ Duk-Hee Kang, Richard J. Johnson: Hyperuricemia, Gout, and the Kidney. In: Robert W. Schrier: Diseases of the kidney & urinary tract. 8th edition. Lippincott Williams & Wilkins, 2007, ISBN 978-0-7817-9307-0 , pp. 1986-1988.
  20. ^ Nepomuk Zöllner, Brigitte Zöllner: Diet for gout and uric acid stones. Falken Verlag, Niedernhausen / Ts. 1990, ISBN 3-8068-3205-6 .
  21. ↑ Table of foods with a medium uric acid content , (PDF; 83 kB) Bavarian State Ministry for the Environment, Health and Consumer Protection.
  22. ^ Table of foods with a very low uric acid content , (PDF; 198 kB) Bavarian State Ministry for the Environment, Health and Consumer Protection.
  23. ↑ William Charles Kuzell, Guy-Pierre Gaudin: gout. (= Documenta Rheumatologica. Volume 10). JR Geigy, Basel 1956, p. 53 f.
  24. ↑ Bruce M. Rothschild, Darren Tanke, Ken Carpenter: Tyrannosaurs suffered from gout . In: Nature . I VOL 387, No. 122 , 1997, doi : 10.1038 / 387357a0 .
  25. ^ Max Höfler: German book of names of diseases. Piloty & Loehle, Munich 1899 (Reprographic reprint: Olms, Hildesheim and New York 1970 and 1979, ISBN 1-174-35859-9 ), p. 190.
  26. ↑ Jürgen Martin: The 'Ulmer Wundarznei'. Introduction - Text - Glossary on a monument to German specialist prose from the 15th century. Königshausen & Neumann, Würzburg 1991 (= Würzburg medical-historical research. Volume 52), ISBN 3-88479-801-4 (also medical dissertation Würzburg 1990), p. 130 ( given ).
  27. ↑ Attila Dunky, Rudolf Eberl: Gout and hyperuricemia. G. Braun, Karlsruhe 1981 (= Rheuma-Forum. Volume 11), ISBN 3-7650-1632-2 , p. 11.
  28. ^ Max Höfler: German book of names of diseases. Munich 1899, p. 854 f.
  29. ^ Zipperlein in duden.de, accessed on October 25, 2012.
  30. ↑ Adelung: Grammatical-Critical Dictionary of High German Dialect. Volume 4. Leipzig 1801, p. 1724. here online at zeno.org .
  31. ↑ Zipperlein. In: Jacob Grimm , Wilhelm Grimm (Hrsg.): German dictionary . tape 31 : Z-Zmasche - (XV). S. Hirzel, Leipzig 1956 ( woerterbuchnetz.de ).
  32. ↑ Zipperlein . In: Universal Lexicon of the Present and Past . 4., reworked. and strongly increased edition, Volume 19:  Weck – Zz and supplements , self-published, Altenburg 1865, p.  652 .
  33. ^ GE Smith, FW Jones: The archeological survey of Nubia, report for 1907-89. Volume 2. National Printing Department, Cairo 1910, pp. 44 and 269.
  34. ↑ Attila Dunky, Rudolf Eberl: Gout and hyperuricemia. G. Braun, Karlsruhe 1981 (= Rheuma-Forum. Volume 11), ISBN 3-7650-1632-2 , p. 9 (quoted) and 11-13.
  35. ↑ Wolfgang Miehle: Joint and spinal rheumatism. 1987, p. 45.
  36. ↑ Markwart Michler: Gout. 2005, p. 493.
  37. ↑ Attila Dunky, Rudolf Eberl: Gout and hyperuricemia. 1981, p. 11.
  38. ↑ Dieter Paul Mertz: The Habsburgs and the gout. In: Journal of General Practice. Volume 68, Issue 29, 1992, pp. 959-962.
  39. ↑ William Charles Kuzell, Guy-Pierre Gaudin: gout. (= Documenta Rheumatologica. Volume 10). JR Geigy, Basel 1956, p. 11.
  40. ↑ Felix Rotaru: Gout attacks often come out of the blue. In: Gesund-durch.de. January 4, 2017, accessed January 30, 2020 .
  41. ^ Gout - the illness of kings on deutschlandfunk.de ; accessed on October 21, 2017
  42. ↑ Attila Dunky, Rudolf Eberl: Gout and hyperuricemia. 1981, pp. 10-12.