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30-04-2016 | Occular comorbidities | Review | Article

Beyond Joints: a Review of Ocular Abnormalities in Gout and Hyperuricemia

Journal:
Current Rheumatology Reports

Authors: Yael Sharon, Naomi Schlesinger

Publisher: Springer US

Abstract

Gout is a common inflammatory arthritis among middle-aged men and postmenopausal women and can be a debilitating disease. Gout results from an elevated body uric acid pool, which leads to deposition of monosodium urate (MSU) crystals, mainly in and around the joints. The MSU crystals trigger release of proinflammatory cytokines, such as interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α. Ocular manifestations have been uncommonly reported in patients with gout. These include descriptions of tophaceous deposits in different locations of the eye including the eyelids, conjunctiva, cornea, iris, sclera, and orbit. Some depositions were coincidentally diagnosed in asymptomatic patients, while the majority were symptomatic. Other ocular abnormalities include dry eye syndrome, red eye, uveitis, intraocular hypertension, glaucoma, and cataracts. Herein, we review the medical literature pertaining to ocular manifestations in gout and hyperuricemia and propose a possible association between ocular abnormalities, hyperuricemia, and gout, including their common risk factors and comorbidities.

Introduction

Gout is the most common inflammatory arthritis in adults, affecting an estimated 8.3 million adults in the USA [1]. The disease results from an elevated body uric acid (UA) pool, which leads to deposition of monosodium urate (MSU) crystals, mainly in the joints. These crystals trigger the release of proinflammatory cytokines, in particular interleukin (IL)-1β. IL-6 and TNFα are also upregulated, in a manner secondary to IL-1β generation [24]. Although hyperuricemia is the sine qua non without which gout cannot develop, most patients who have hyperuricemia never develop gout [1]. Comorbidities associated with hyperuricemia and gout include the metabolic syndrome: obesity, dyslipidemia, hypertension, and diabetes mellitus (DM), as well as chronic kidney disease (CKD) and congestive heart failure [58].
Acute gout is characterized by an abrupt onset of synovitis causing severe pain, warmth, redness, swelling, and decreased range of motion of the involved joint(s). Up to half of acute attacks in men involve the first metatarsophalangeal (MTP) joint, although involvement of other joints such as the insteps, heels, knees, wrists, fingers, and elbows is also common. Acute attacks usually resolve without treatment within one to several weeks [9, 10]. Tophaceous gout presents as firm swellings that can appear at any site, including feet, soft tissues such as the olecranon bursa, and in digits of the hands (in older women). Tophi usually develop after ≥10 years of disease, following years of acute attacks. Tophi and MSU crystal deposits can lead to a destructive arthritis [10].
The eye is one of the most vulnerable organs. It is vulnerable to vascular abnormalities, metabolic disturbances, and inflammation. For example, diabetic retinopathy is a leading cause of vision impairment, a result of metabolic stress, glucose-mediated microvascular damage and inflammation, and is frequently found in early stages of DM [11, 12]. Importantly, several of these processes are also found in conjunction with gout. Nonetheless, a link between gout and ocular abnormalities has been rarely investigated. Here, we review the literature identifying a possible relationship between ocular abnormalities, hyperuricemia, and gout, including their common risk factors and comorbidities. Could diagnosis of ocular disease lead to earlier diagnosis and treatment of gout?

Ocular Manifestations in Patients With Gout and Hyperuricemia

One of the first notations of a possible association between ocular abnormalities and gout is Dr. Jonathan Hutchinson’s lecture on “The relation of certain diseases of the eye and gout” in 1884 [13]. In his lecture, various presentations of ocular diseases in different locations of the eye and their relation to gout were described. Dr. Hutchinson presented cases of acute and recurrent attacks of conjunctival congestion, pain, and warmth in the eye accompanied by blurred vision, described as acute attacks of iritis, and referred to them as though they were gout attacks without joints involvement. According to Dr. Hutchinson, the paroxysmal character of the ocular attacks resembled gouty attacks in their sudden development, great pain, and rapid resolution. Cases of gout with involvement of ocular structures, such as the cornea (causing keratitis and band keratopathy), lens (causing cataract), sclera (causing scleritis), optic nerve (causing glaucoma and optic neuritis), and retina and blood vessels (causing retinal hemorrhages and thrombosis) were described as well [13].
Since Dr. Hutchinson’s lecture, over 130 years ago, ocular manifestations have been reported infrequently in patients with gout and hyperuricemia. These include descriptions of tophaceous deposits in different locations of the eye (Table 1). Tophi have been described in the eyelids and medial and lateral canthi [1418], conjunctiva [1922, 30], cornea [23••, 2428, 32], anterior chamber and iris [29], sclera [23••, 30], and orbit [31].
Table 1
Tophus deposition according to ocular site
Site of tophi
No. of cases
Study, year, ref
Age (years)
Gender
Crystal identification
Size of tophus (cm)a
Serum urate (mg/dl)
Urate-lowering therapy
Anti-inflammatory drug therapy
Duration of: (months)
Tophi
Gout
Eyelids
1
Yang, 2008 [14]
64
Male
Yes
1.5
NA
Dialysis
NA
108
NA
1
Morris, 2003 [15]
44
Male
Yes
0.9
NA
NA
NA
12
NA
1
Chu, 2005 [16]
27
Male
Yes
1.3
10.4
No
NA
3
36
1
De-Monteynard, 1986 [17]
62
Female
No
NA (multiple)
5
No
No
1/4
NA
1
Jordan, 2008 [18]
68
Male
Yes
0.9
NA
No
Yes (colchicine)
24
240
Conjunctiva
1 (BE)
Lo, 2005 [19]
59
Female
Yes
NA (multiple)
NA
NA
NA
12
300
1
Mc Wiilliams, 1952 [20]
NA
Male
Yes
2
11.4
No
No
NA
336
1
Yourish, 1953 [21]
71
Male
Yes
0.5 (multiple)
6.9–10.4
NA
NA
NA
336
1
Sarma, 2010 [22]
80
Female
Yes
0.1 (multiple)
WNL
Yes (allopurinol)
No
NA
3
Cornea
2
Lin, 2013 [23••]
NA
NA
No
0.6 (X3 deposits)
9.4
NA
NA
NA
240
  
NA
NA
No
NA (multiple)
10.5
NA
NA
NA
36
1
Fishman, 1966 [24]
72
Male
Yes
NA
6.7
Yes (probenecid)
Yes (colchicine)
12
144
1
Slansky, 1968 [25]
65
Male
Yes
NA (multiple and diffuse)
5.6
Yes (probenecid)
No
NA
60
1 (BE)
Bernad, 2006 [26]
54
Male
Yes
NA (multiple)
10.1
No
No
NA
(Long standing)
1 (BE)
Ferry, 1985 [27]
42
Male
No
0.14 (multiple)
NA
NA
NA
NA
204
1
Wood, 1936 [28]
46
Female
No
0.1
4.4
No
No
1
24
Iris
1
Coassin, 2006 [29]
68
Female
Yes
NA (multiple)
11
No
Yes (valdecoxib)
NA
NA
Sclera + conjunctiva
1
Martínez-Cordero, 1986 [30]
75
Male
Yes
NA (multiple)
9.8
No
Yes
NA
384
Sclera
1
Lin, 2013 [23••]
NA
NA
No
0.5
7.8
NA
NA
NA
144
Orbit
1
Topping, 2003 [31]
41
Male
Yes
2
WNL
No
No
1
NA
BE both eyes, WNL within normal limits, NA not available
aIn order to generalize the studies’ different dimensions of tophi size, we calculated an estimated diameter of a round sphere
The most common ocular abnormality described in patients with gout is a red eye, usually bilateral, caused by conjunctival and episcleral hyperemic vessels. Vascular changes at the ocular surface in early stages of gout, including tortuosity, thickness, congestion, and persistent subconjunctival hemorrhage have been described [23••, 27]. Other ocular manifestations (Table 2) include uveitis [28, 3540], increased intraocular pressure [27, 29, 37], and glaucoma [27]. Episcleritis and chronic conjunctivitis were also noted in a series of patients with gout [35]. In a study investigating the relationship of inflammatory systemic markers to retinal vessel diameter, a history of gout was associated with smaller retinal arteriolar diameters and increased retinal venule diameter [43]. Scleritis has also been associated with gout [44, 45]. Whereas in two studies asteroid hyalosis was implicated to be an ocular presentation of gout [27, 42], a third study found no such relationship [46].
Table 2
Ocular abnormalities in gout
Ocular manifestation
Study, year, ref
No. of cases
Age (years)
Gender
Laterality
Serum urate (mg/dl)
Clinical course of ocular involvement
Duration of gout (years)
Dry eye syndrome
Chia, 2003 [33]
86
NA
NA
NA
NA
Chronic
NA
Moss, 2000 [34]
313
NA
NA
NA
NA
Chronic
NA
Serpell, 1978 [35]
6
NA
3 Female 3 Male
NA
NA
NA
NA
Red eye
Lin, 2013 [23••]
12
18–72
NA
NA
NA
Persistent
<5
9
22–77
NA
NA
NA
Persistent
5–10
11
38–81
NA
NA
NA
Persistent
>10
Ferry, 1985 [27]
43
NA
Male (mostly)
Bilateral
NA
Persistent
NA
Serpell, 1978 [35]
13
NA
Male (mostly)
NA
NA
NA
NA
Uveitis
Wood, 1936 [28]
4
60
Female
Unilateral
NA
Numerous, recurrent attacks
NA
66
Male
Bilateral
4.6
Recurrent attacks
2
46
Female
Unilateral
4.1
Recurrent attacks
2
50
Male
Unilateral
NA
Recurrent attacks
1
Killen, 1968 [36]
1
34
Male
Bilateral
9
Numerous, recurrent attacks
NA
Yulek, 2009 [37]
1
55
Male
Bilateral
Elevated
Single attack
NA
Kimura, 1967 [38]
2
NA
Male
Bilateral
6.9
Recurrent
NA
32
Female
Unilateral
NA
NA
NA
Davenport, 1956 [39]
1
33
Female
Bilateral
WNL
Numerous, recurrent attacks
16
Schwelnitz, 1902 [40]
1
55
Female
Bilateral
Elevated
Numerous, recurrent attacks
15
Serpell, 1978 [35]
5
NA
NA
NA
NA
NA
NA
Ocular hypertension
Ferry, 1985 [27]
10
NA
Male (mostly)
NA
NA
NA
NA
Glaucoma
Ferry, 1985 [27]
5
NA
Male (mostly)
NA
NA
Chronic
NA
Cataract
Mc Carty, 2000 [41]
24
>40
NA
NA
NA
Chronic
>10
Asteroid hyalosis
Ferry, 1985 [27]
3
61
Male
Unilateral
NA
NA
34
49
Male
Unilateral
NA
NA
10
66
Male
Unilateral
NA
NA
20
Safir, 1990 [42]
7
74
Male
NA
3.7
NA
NA
64
Female
NA
NA
NA
NA
75
Male
NA
7.5
NA
NA
66
Male
NA
8.9
NA
NA
84
Female
NA
3.1
NA
NA
72
Male
NA
5.4
NA
NA
75
Male
NA
8.6
NA
NA
WNL within normal limits, NA not available
Association between gout and nuclear, posterior subcapsular and cortical cataracts has been described, with gout suggested to constitute a significant risk factor for cataract development [41]. Furthermore, the duration of gout has been shown to be associated with prevalence of cataracts in gout patients [41]. It is unclear whether treatment with allopurinol is cataractogenic or not [47, 48]. Oral corticosteroids are an effective first-line option for treatment of acute gout [49]. However, systemic corticosteroids are also a well-known risk factor for development of cataracts, specifically posterior subcapsular cataracts, with the risk being higher with longer use of corticosteroids [50].
Dry eye syndrome was noted in patients with gout [35] and was found to be more prevalent among gout patients in two studies [33, 34]. However, in a larger cohort and longer follow-up, no relationship between dry eye syndrome and gout was found [51]. Therefore, the association between dry eye syndrome and history of gout remains controversial.

Gouty Inflammation: Does It Contribute to Ocular Changes in Gout Patients?

As noted earlier, production of pro-inflammatory cytokines including TNF-α [52, 53], IL-1β [54, 55], and interleukin IL-6 [56], induced by exposure to MSU crystals and released by monocytes and synovial M1 macrophages, is associated with gouty inflammation. In contrast, differentiated M2 macrophages play a significant role in the resolution stage of an acute gout attack. In this stage, accumulation of macrophages continues after neutrophil infiltration has already diminished. The differentiation process to mature M2 macrophages results in their inability to further release pro-inflammatory cytokines [57, 58]. While proinflammatory cytokines are more dominant in the early stages of an attack, the anti-inflammatory molecule transforming growth factor (TGF)-β1 is present at higher levels in the resolution phase of attack [59]. In chronic tophaceous gout, the hallmark of the disease is granulomas consisting of macrophages surrounding deposits of MSU crystals [60]. The crystals are accumulated within the tophus, possibly due to the inability of the remaining macrophages to overcome the formation rate of crystals, as a result of persistent high serum urate (SU) [4].
Cytokines such as IL-1β, TNF-α, and IL-6 are also found in high levels in inflammatory ocular diseases, where they may prime and enhance the maturation of monocytes to macrophages. Acute anterior ocular inflammation is characterized by infiltration of macrophages and neutrophils in the anterior chamber of the eye and the release of pro-inflammatory cytokines. Studies using an induced uveitis rat model reported a dramatic upregulation of IL-1β and TNF-α gene expression in the stage of active intraocular inflammation [61, 62], as well as elevated intraocular levels of IL-6 [63]. In patients with a history of acute anterior uveitis, monocytes release TNF-α in response to LPS (lipopolysaccharide) exposure at a level that is increased compared to the response in healthy subjects [64]. High levels of IL-6 were observed in ocular fluids obtained from patients with active intermediate and posterior uveitis [6567]. Furthermore, intravitreal injection of IL-1β and TNF-α can cause severe intraocular inflammation in a rabbit model [6870]. Thus, pro-inflammatory cytokines, which are part of the body’s innate immune system, are seen at higher levels in both intraocular inflammation processes and in gout. CRP, a marker of systemic inflammation, is also found to be in higher titers in the serum of patients with gout as well as those with uveitis [64]. The innate immune response is probably more pronounced in patients with a history of recurrent acute uveitis, and there is a persistent low level of systemic inflammation in those patients, even without acute intraocular inflammation. This observation is similar to that seen in gout. In chronic tophaceous gout, chronic ongoing inflammation, including pro-inflammatory activation and maturation of macrophages is sometimes present [4]. However, coincidence of uveitis in a patient with gout attack has only rarely been reported, as described earlier [28, 3640]; it is unclear whether the coincidence of gout and uveitis is truly rare and randomly found, or whether there is underdiagnosis of concurrent disease.

Hyperuricemia: Does It Contribute to Ocular Changes Seen in Gout Patients?

UA, the end product of metabolic turnover of purine nucleotides, is involved in endothelial dysfunction, oxidative stress, vasoconstriction, and platelet aggregation and is a marker of systemic inflammation [71]. Hyperuricemia refers to a serum UA level >6.8 mg/dl. Elevated serum UA levels may be a marker for the metabolic syndrome [72], as well as a risk factor for coronary heart disease, hypertension, heart failure, stroke, and chronic kidney disease [73•, 74, 75].
Elevated levels of serum UA have been shown to have a strong association with development of microvascular complications, including retinopathy, in diabetic patients. Serum UA was associated with worsening of retinopathy in patients with DM in a 3-year period [76•]. Serum UA has also been proposed as a simple marker for progression of diabetic retinopathy [77, 78]. Furthermore, UA concentration in the vitreous was significantly higher in diabetic patients than in non-diabetic patients, and in diabetic patients, UA concentration in the vitreous was higher in proliferative compared with non-proliferative diabetic retinopathy [79]. Abnormal levels of UA in the vitreous may be an important factor in the pathogenesis of retinopathy and vascular retinal abnormalities; however, the exact relation and specific mechanism are still not fully understood.
Our review of the literature reveals few acute uveitis case reports in patients with hyperuricemia [28, 36, 37, 80, 81]. Two case reports described patients with episodes of acute uveitis and elevated serum UA levels, without gout [37, 81]. Unfortunately, no laboratory examination of aqueous humor from the anterior chamber or biopsy was performed in order to confirm the diagnosis in these cases [37, 81]. However, in one of the case reports, the sudden onset of uveitis at night, after alcohol consumption, in the presence of high serum urate, has led to the suggestion that the acute attack was a gout attack with eye involvement only [81]. Treatment with topical corticosteroids improved the patient’s condition remarkably with resolution of the uveitic attack, and prevention of recurrences was achieved by allopurinol treatment [81]. In the other case report, combination therapy with oral corticosteroids, colchicine, and a drug with uricosuric effect was started with rapid and significant improvement [37]. A case of acute scleritis associated with hyperuricemia, treated with colchicine, has also been reported [82].

Conclusions

Gout is a common, debilitating inflammatory arthritis among middle-aged men and postmenopausal women. Its incidence is increasing worldwide [83]. Ocular manifestations in patients with gout have been uncommonly reported. Depositions of MSU crystals in different locations of the eye have been described in the literature, with some depositions coincidentally diagnosed in asymptomatic patients, while the majority were symptomatic. Tophi are prone to develop at avascular tissues, which may explain reports of tophus deposition in the cornea. Other suggested factors that favor the precipitation of MSU crystals in the cornea and conjunctiva include the poor solubility of UA in the setting of a low pH level or a pH gradient between the plasma and the tissue, and with decreased local temperature [29]. The pathogenesis of MSU crystal deposition in the eye is poorly understood. The rarity of reported cases may be due to ocular structures being a poor solvent for MSU crystals, leading to less MSU crystal deposition in the eye or possibly MSU crystal deposition in ocular structures may remain asymptomatic below a certain size threshold; thus, patients might not seek medical attention or be examined by an ophthalmologist. Furthermore, MSU crystal depositions may be difficult or even impossible to detect in a routine ophthalmological examination with a slit lamp. Most of the case reports that were discussed earlier had remarkable symptoms and significant findings on the ophthalmological examination. These cases may represent rare and extreme cases in a spectrum of ocular abnormalities in gout patients.
How common is ocular involvement in gout patients? Intraocular inflammatory diseases are very similar to acute gout attacks, regarding the type of immune response, involved pro-inflammatory cytokines and inflammatory cells and course of disease. Do patients with gout can have higher prevalence of intraocular inflammation than has been reported to date? In addition, uric acid can induce endothelial dysfunction, oxidative stress, inflammation, and microvascular disease. Could it be involved in ocular abnormalities in gout patients and patients with hyperuricemia?
Larger studies are needed in order to determine the frequency of ocular abnormalities in gout patients. Increasing awareness of ocular diseases in patients with gout and hyperuricemia may lead to earlier medical attention, treatment, and evaluation of possible silent ocular disease.

Compliance With Ethical Standards

Conflicts of Interest

YS declares that she has no conflicts of interest. NS reports advisory board membership with Novartis, Takeda, Astra Zeneca, Alkermes, and Sobi; consultancy (paid to institution) for BMS, SGS, and Sobi; grants/grants pending (paid to institution) from Astra Zeneca; and payment for lectures from Takeda.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.
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