Gout is one of the oldest diseases documented in humans. It was described by the Egyptians in 2640 B.C. Hippocrates later called it the arthritis of the rich due to its increased association with excessive binges of alcohol and food [20]; however, gout is a disease that remains underestimated and undertreated up to the present day. The aim of this three-part review is to consider the pathogenesis, clinical features and diagnosis and treatment of gout and calcium pyrophosphate arthritis in detail, emphasizing its special features in elderly persons.

Epidemiology

In the General Practice Research Database (GPRD), a large epidemiological study, gout prevalence was shown to depend highly on age. The prevalence in men in the 35–44 years age group is about 1% but prevalence increases to over 7% in the over 65 years age group [25]. Furthermore, a similar rise in incidence was found with 11 cases (95% confidence interval CI 9.9–12.5) in the under 44 years age group and 53 (95% CI 49–57.9) in the over 65-year-olds per 10,000 patient years [25]. The prevalence of hyperuricemia, i. e., a serum urate level above the reference range of 2.3–6.1 mg/dl (137–363 µmol/l) in adult women and 3.6–8.2 mg/dl (214–488 µmol/l) in men, is approximately 10–20% of all adults [12]. Men predominate with a ratio of 3–4:1 [35] and other authors report even higher predominance in men with a ratio of 7:1–9:1 compared with women [1, 42]. The risk of developing significant hyperuricemia in a 5-year period (cumulative gout incidence per 1000 patient years) depends on sex and increases with the urate level. If the risk corresponding to a serum urate level ≥8 mg/dl is considered over 5 years, this is only 4.8 (95% CI 2.4–9.5) in men and 2.3 (95% CI 0.9–5.6) in women [2]; however, if the urate range of 9–9.9 mg/dl is considered, the cumulative incidence is over 20% and over 30% at a level of over 10 mg/dl [35]. This association will be discussed in conjunction with consideration of the indications for treatment of hyperuricemia (see the continuation of this series). Gout has now been identified as an independent risk factor for increased cardiovascular mortality, as summarized in a table in the review by Roddy and Doherty [35]. It was shown in a meta-analysis by Kim et al. that the association of hyperuricemia and cardiovascular events due to coronary heart disease (CHD) is independent of traditional risk factors for CHD [17]; however, the association, although significant, can be regarded as moderate. It was apparent in subgroup analyses that women have a significantly raised risk for a cardiovascular event, whereas men do not exhibit increased mortality. The urate level above which there is actually an increased cardiovascular risk is still unclear. Evidence is increasing that initiation of uric acid-lowering treatment, e. g., by allopurinol, can reduce both the mortality risk and blood pressure [14, 19]. The level that the uric acid should be lowered to in order to reduce the cardiovascular risk is currently unclear. Possibly, the association of gout with cardiovascular mortality is stronger than hyperuricaemia alone [18].

Predisposing factors reported for gout include alimentary factors [35] and osteoarthritis of different joints [22]. Previously damaged joints appear to predispose to urate crystal precipitation with a consequent gout attack. This is possibly based on the observation that deposits of calcium pyrophosphate dihydrate (CPP deposition) occur in aging hyaline and fibrous cartilage. If CPPD crystals get into the free joint cavity, inflammation of varying intensity may occur, with clinical features like those of gout with urate crystals. A possible explanation would be that milder undulating inflammation associated with CPPD lowers the pH in the synovial fluid, further reducing the solubility of urate. Therefore, CPPD-associated acute joint inflammation is also called pseudogout or activated osteoarthritis. The prevalence of deposits of CPPD crystals in cartilage is reported to increase with age from 15% in over 60-year-olds to up to 30% in over 80-year-olds [22]. Gout and pseudogout or CPPD are thus the most common inflammatory joint diseases in elderly (multimorbid) patients and present the treating physician with a complex differential treatment challenge, especially with regard to the frequently impaired renal function, hypertension, diabetic metabolic status, vascular morbidity and heart failure.

Pathophysiology of gout

Uric acid crystals were first described as a gout-associated pathogenetic substrate by Max Freudweiler in 1899. In 1961 Jarvis Edwin Seegmiller demonstrated that the uric acid crystals trigger inflammation in gout [20]. With the introduction of the xanthine oxidase inhibitor allopurinol in 1965, it was mistakenly believed initially that the pathophysiology of gout had been fully elucidated and that gout had finally been conquered. In recent years, new knowledge in genetics and immunology has led to better understanding of the underlying pathophysiological mechanisms of gout.

Uric acid production and elimination

Uric acid is the degradation product of the purine bases adenine and guanine; it is increased either endogenously with cell destruction (fragile tumor cells, trauma and fasting diets) or exogenously due to unbalanced consumption of, e. g. sausage, offal, rinds, crustaceans, certain types of fish (e.g. sardines, anchovies and herrings),and also brassica vegetables and legumes. Moreover, increased alcohol and fructose consumption can contribute to hyperuricemia because of an interaction with adenine metabolism [7]. The key enzyme xanthine oxidase catalyzes the final steps in the biochemical degradation of adenine and guanine to uric acid. Humans lost the uricase gene, which converts uric acid into the much more water soluble allantoin, some 45 million years ago. One of the evolutionary advantages for humans could be a water-saving effect when excreting toxic nitrogen from DNA. Nowadays, with unlimited liquid available, injection of uricase is used to treat severe tophaceous gout; however, the effect of uric acid as an in vivo adjuvant in cells dying non-apoptotically appears much more important. The uric acid concentration in the cytosol is approximately 4 mg/ml. During cell destruction, DNA and RNA are degraded locally so local supersaturation can occur with crystallization of uric acid. This leads to activation of the inflammasome, a cytosol protein complex in neutrophils and macrophages. Following activation, it induces a series of reactions that culminates in activation of caspase-1, which in turn leads to activation of interleukin-1 beta, which is secreted by macrophages and triggers an inflammatory reaction. This stimulation of the innate and adaptive immune system leads to effective clearing away of the detritus [4]; however, autoimmunity can also develop in this context on account of the activation of the adaptive immune system [39].

Under physiological conditions, roughly 350 mg of uric acid are produced daily by endogenous catabolism or as a result of food metabolism. About two thirds of the uric acid are excreted through the kidneys and one third via the bowels (Fig. 1). The serum uric acid level is determined by the balance between absorption and secretion of uric acid in the proximal renal tubules [7, 34, 40]. This principle utilizes newer treatment strategies, which will be discussed in the second part of this series. Numerous single nucleotide polymorphisms (SNPs) have been described for both absorption and secretion transporters [43]. In a recent review article, current knowledge of the genetics of hyperuricemia and gout was succinctly summarized [33]; however, the genetic variations can explain less than 6% of cases of hyperuricemia and gout. The serum uric acid continues to be the best predictor for the risk of developing gout. To understand the principle of uric acid regulation, some clinically relevant transport proteins will be emphasized. At the molecular level, urate anion transporter (URAT)-1 and organic anion transporter (OAT)-4 located luminally in the kidneys play a crucially important role in the reabsorption process [33]. Moreover, OAT-4 is induced by thiazide diuretics so it can contribute to the hyperuricemia that occurs with diuretic therapy through increased tubular reabsorption [41]. URAT-1 is inhibited by the uricosuric agents probenecid and benzbromarone, which leads to increased renal excretion of uric acid; however, URAT-1 can also be partially inhibited by medications such as low-dose acetylsalicylic acid and cyclosporine [27]. Genetic polymorphisms of the highly efficient ATP-binding cassette transporter G2 (ABCG2) [35] are found in approximately10% of Caucasians, leading to a 75% reduction in uric acid excretion by both the renal and gastrointestinal routes [24]. If less uric acid is excreted through the bowels, the serum uric acid level rises, which can lead to renal overloading and hence to hyperuricemia [23].

Fig. 1
figure 1

Purine metabolic pathway – humans, monkey species and birds have no uricase. Renal expression of ATP-binding cassette subfamily G 2 (ABCG2), urate anion transporter 1 (URAT-1) and organic anion transporter 4 (OAT4) is increased by diuretics + (green) promotes uric acid excretion, − (red) inhibits uric acid excretion through reabsorption (copyright: Peter Härle)

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On the other hand, gene mutations that lead to loss of function of tubular reabsorption transporters result in increased excretion and therefore a reduction of serum uric acid. Mutations in the SLC2A9 and SCL22A12 genes should be mentioned, which code for GLUT-2 and URAT-1 transport proteins, respectively, leading to hypouricemia in different populations [37]; however, as a consequence, renal failure and renal urate calculi occur more in these patients due to elevated uric acid concentrations in the urine [37]. The GLUT-2 transporter is also regarded as a fructose–uric acid transporter and thus might reabsorb less uric acid because of competition when tubular fructose concentrations are high [33]. Elevated fructose concentrations in the urine would then have a uricosuric effect. These uricosuric effects of tubular fructose contrast with the epidemiologic association with the hyperuricemia-promoting influence of foods high in fructose, as shown in a prospective cohort study [6]. The fructose-gout causal link has to date been explained by classical biochemistry: in brief, the increased consumption and intracellular metabolism of fructose leads to depletion of inorganic phosphate and therefore to a relative surplus of adenosine monophosphate, which is then metabolized to uric acid through inosine monophosphate, causing an increased amount of this [8].

Increased alcohol consumption, even 10–14.9 g per day (0.3 l beer or 125 ml wine or 2 measures of spirits) is a risk factor for gout. On the one hand, less uric acid is excreted due to the degradation of ethanol to acetate competitively on the URAT-1/OAT4 transport protein in the proximal tubules of the kidneys. On the other hand, more acetyl-CoA is produced through the breakdown of ethanol, which leads to increased consumption and breakdown of adenosine triphosphate and thus can explain a rising uric acid level [5]. Interestingly, various alcoholic drinks differ with respect to the hyperuricemic effect. Because of the high DNA content of yeast (especially guanosine), beer drinking is associated with a higher risk compared with spirits. Consumption of wine, however, appears to have little or no effect on the rise in uric acid [5].

In summary, it is apparent that the equilibrium between uric acid production and excretion, genetic mutations of the different absorption and excretion transport proteins and also diet decide whether hyperuricemia will occur and possibly overt gout when the serum uric acid level is persistently elevated above the solubility limit. It is not possible to explain the pathophysiology of gout by considering any of these factors in isolation.

Uric acid precipitation and gout attack

In physicochemical terms, the solubility of uric acid in blood and tissue is decisive for the development of gout. The pathogenic monosodium urate crystals only form when the solubility product is exceeded. At normal body temperature and physiological pH, this can occur above a uric acid concentration of approximately 7 mg/dl (0.4 mmol/l) [34]. At lower body temperatures or pH in the acid range, the solubility product for monosodium urate is much lower. This also explains the particular danger for the extremities (lower body temperature, poorer perfusion) and arthritic joints (lower pH, CPPD deposits) as the site of predilection for gout [38]. In addition to the aforementioned factors, other unknown factors that inhibit or promote crystal formation are probably also important for urate crystallization. Finally, it has been known since the nineteenth century that deposits of urate in tissues and joints can be clinically asymptomatic. In recent years, this has again become important in the discussion of gout stages.

In general, crystals are identified as foreign bodies by the innate immune system through membrane receptors so they cause an inflammatory reaction that varies in strength. This principle is not restricted only to urate crystals, even if uric acid crystals have the greatest inflammatory potency of all crystals. Urate crystals, CPP crystals, basic calcium phosphate (BCP), octa calcium phosphate (OCP) in joints and tissues, and also cholesterol crystals as part of the arteriosclerosis process in vessel walls (Fig. 2) can lead to inflammation [9, 32]. Both toll-like receptors [28] and direct interaction of urate crystals with cholesterol components of the cell membrane appear to trigger cascade-like intracellular signals, which finally activate the NALP3 inflammasome. This results in activation of interleukin-1 (IL-1) converting enzyme (a caspase), which converts the inactive form of IL-1 beta and IL-18 to the active form. These cytokines are released from the immune cell and, via specific membrane cytokine receptors, they activate proinflammatory signal transduction pathways through NF-kB and MAP kinase. The result is massive activation of the innate and acquired immune system.

Fig. 2
figure 2

The figure shows in the first line the purely medical evidence in green, hyperuricemia, calcinosis of hyaline or fibrous cartilage (chondrocalcinosis), osteoarthritis with loss of cartilage with the possibility of bone erosion (BCP), and hypercholesterinemia. Under certain biological circumstances the medical evidence converts into a state, such that danger receptors are stimulated (second line in yellow). Danger receptors are receptors which recognize danger-associated molecular pattern molecules (DAMPs) from the host which are able to initiate and perpetuate a noninfectious inflammatory response. Toll-like receptors (TLRs) can function as danger receptors. This happens under conditions of urate crystal formation, CPP (calcium pyrophosphate), BCP (basic calcium phosphate) and derivatives, cholesterol crystals getting in contact with immune cells and then causing disease, e. g. gout, CPPD, activated osteoarthritis caused by BCP crystals, and atherosclerosis, which are depicted in red. All these processes lead to the same final common pathway, that is inflammation as shown in the last line of the figure in black. (Copyright: Peter Härle)

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Since the urate crystals cannot dissolve spontaneously and can also be detected in the intercritical stage of gout, the question arises as to the mechanisms that terminate the gout attack. Recent data have shown that urate crystals provoke the production of neutrophil extracellular traps (NETs) by neutrophilic granulocytes [26]. NETs consist of chromatin elements and various proteins [3, 31] and can terminate the massive immunostimulation in the gout attack through aggregation and degradation of chemokines and cytokines and shielding of the uric acid crystals from immune cells [28, 37].

Pathophysiology of calcium pyrophosphate arthritis (CPPD)

Unlike uric acid crystals, which occur only when the solubility product in synovial fluid is exceeded, calcium pyrophosphate dihydrate (CPP) crystals are formed in the cartilage close to the surface of the chondrocytes. These cells are embedded in the collagen and proteoglycan-containing matrix. Inorganic pyrophosphate (PPi) in particular plays an important part in the formation of calcium pyrophosphate crystals. Chondrocytes are able to produce PPi enzymatically from ATP and other nucleoside triphosphatases. This is mediated by a number of enzymes with nucleoside triphosphatase pyrophosphohydrolase activity (NTPPPH), such as nucleotide pyrophosphatase/phosphodiesterase (NPP1). The degradation or hydrolysis of PPi to orthophosphate is catalyzed by inorganic pyrophosphatases, such as tissue non-specific alkaline phosphatase (TNAP). The production of inorganic pyrophosphate by NPP1 and its hydrolysis by TNAP are in equilibrium. If there is dysregulation of this homeostasis, which is modulated by additional factors such as age, growth factors (e. g., TGF-beta), chemokines (e. g., IL-1 beta), transport proteins, enzymes and enzyme substrates, NPP1 activity predominates in aging osteoarthritic cartilage, which results in accumulation of PPi. This in turn leads to pathological deposition of CPP crystals [29].

Polymorphisms in the progressive ankylosis protein homolog (ANKH gene) also appear to play a part in the transport of pyrophosphate and in the release of ATP by chondrocytes, which ultimately contributes to the formation of the CPP crystals [16, 36].The pathophysiological processes in CPP crystal-induced arthritis have great similarity with gout. The pro-inflammatory cytokine IL-1 beta is produced in several stages by activation of the NALP3 inflammasome; however, the inflammatory reaction caused by the CPP crystals tends to have a subclinical course, which can be explained by the interaction of the crystals with phagocytic cells and their mitogenic activation and release of the proinflammatory cytokines [11, 21].

Parkinson’s disease and gout

A growing number of studies show that elevated uric acid levels appear to have a neuroprotective effect. Why uric acid precisely should have this effect is the object of research. It seems that dopaminergic neurons in the substantia nigra possess increased vulnerability to reactive oxygen radicals. Antioxidant properties are attributed to uric acid. The elevated uric acid level could therefore represent an endogenous protective mechanism against developing Parkinson’s disease [10]. The precise pathomechanism has not yet been fully elucidated. A possible explanation is that dopaminergic neurons contribute to neurotoxicity by generating radicals in the presence of oxygen molecules and produce neuromelanin by auto-oxidation. Dopaminergic neurons are therefore exposed to increased oxidative stress, which makes them vulnerable to genetic mutations and toxins [13]. Whether an “unhealthy” diet with increased consumption of purines and alcohol ultimately leads to a lower risk of developing Parkinson’s disease has not been confirmed consistently even though there are a few studies in this respect [15, 30]. Future research will have to show whether routine clinical measurement of the uric acid level can help to establish the diagnosis and prognosis of Parkinson’s disease. At the present time, routine measurement in this context is rejected. Consideration of the uric acid level alone without involving other parameters does not appear expedient in future either. Nevertheless, the correlation is an interesting approach for further research in this area.

Conclusion for practice

  • Both the prevalence and the incidence of gout and CPPD increase with age.

  • Gout and CPPD are among the most frequent inflammatory joint diseases in elderly patients. The differential diagnosis can be clearly made by microscopic analysis of synovial fluid.

  • Hyperuricemia is closely linked with the metabolic syndrome so optimization is associated with a reduction of the uric acid levels.

  • Renal insufficiency is closely linked with the risk of hyperuricemia so optimal therapy of the renal insufficiency should be ensured.

    A gout attack is due to a severe inflammatory reaction that activates the NALP3 inflammasome in a cascade-like sequence. The further process is then mediated by cytokine activation, ultimately leading to activation of the innate and acquired immune system.

  • Monosodium urate crystals form when the solubility product exceeds about 7 mg/dl.

  • Arthritic joints in which deposits of CPP crystals cause a mild inflammatory reaction, which shifts the pH in the synovial fluid to lower levels, are a predisposing factor.

  • Increased consumption of alcohol is a risk factor for gout. Because of the high DNA content in the yeast, drinking beer (over 0.3 l) has a greater effect than consumption of drinks such as spirits with a high percentage of alcohol. Wine appears to have little or no effect on the elevation of uric acid.

  • Increased consumption of fructose-containing foods such as soft drinks, fruit yoghurts and prepreparedmeals promotes hyperuricemia and is therefore unfavorable.