Hyperuricaemia in type 1 Gaucher disease: is uric acid a biomarker for disease severity?

Abstract

Background

Elevated serum uric acid (SUA) levels were observed in Gaucher disease type 1 (GD1) patients followed for two decades in northern Israel. There are no previous reports regarding hyperuricaemia in GD1 patients.

Aims

We aimed to evaluate the frequency of hyperuricaemia in GD1 patients and its correlation to disease severity, lymphoproliferative neoplasms and other malignancies.

Methods

Clinical and laboratory data of 69 GD1 patients, 25 treatment‐naïve and 44 on enzyme replacement therapy (ERT), were evaluated for SUA levels, biomarkers and the presence of lymphoproliferative neoplasms and other malignancies.

Results

In 36 females and 33 males, the mean age was 51.6 ± 16.2 years, and the mean severity score index was 8.94. SUA levels were significantly higher in patients with severe disease compared to patients with mild disease. ERT had no significant effect on SUA levels. A linear correlation between SUA levels and disease severity was found. A linear correlation was also detected between acid phosphatase (AP) levels and SUA. Among patients with severe disease, 11% presented with a lymphoproliferative neoplasm, compared to 4% in patients with mild disease. A statistically significant difference in malignancy frequency between the two patient groups was not found.

Conclusion

SUA levels are significantly elevated in severe GD1 patients and correlate with AP levels. AP was used in GD as a clinical biomarker, especially tartrate‐resistant acid phosphatase, which reflects GD macrophage activity and inflammation status, thus associated with disease severity. No correlation between SUA levels and lymphoproliferative neoplasms was found. SUA levels may be helpful in estimating Gaucher cell burden and GD1 severity.

Introduction

Gaucher disease (GD) is a rare lysosomal storage disorder caused by autosomal recessive mutations in the β‐glucocerebrosidase (GBA1) gene that leads to a deficiency in the activity of glucocerebrosidase, the enzyme responsible for lysosomal glucosylceramide degradation. ¹ , ² , ³ Lack of GBA activity results in accumulation of glucosylceramide in the lysosomes of macrophages, causing hepatosplenomegaly, pancytopenia and bone manifestations. ¹ , ⁴ , ⁵ GD is a pan‐ethnic disorder, classified into three clinical subtypes. The most common is type 1 (GD1), a non‐neuronopathic form, with manifestations ranging from asymptomatic adults to young patients with significant haematological, visceral and skeletal involvement. Type 2, the most severe form, is associated with acute neurologic symptoms in infancy and is usually fatal by 2 years of age. Type 3, the subacute neuronopathic form, presents with chronic, milder neurologic symptoms, during childhood, adolescence or adulthood. ⁵ , ⁶ , ⁷ , ⁸ , ⁹ Although GD1 was labelled ‘non‐neuropathic’, over two decades ago, evidence for the association of GD1 and Parkinson disease (PD) was established among GBA1 mutations carriers and GD1 homozygous patients. ¹⁰

Treatment options in GD1 include enzyme replacement therapy (ERT) and substrate reduction therapy (SRT), which almost universally lead to significant improvement and reversal of most non‐neuronopathic disease manifestations. ¹¹ , ¹²

GD patients have a higher incidence of haematological malignancies and solid tumours, including lymphoproliferative neoplasms (LPNs), multiple myeloma and hepatocellular carcinoma. ¹³ The increased risk for haematological malignancies in GD has been related to B‐cell proliferation, gene modifiers, immune system dysregulation triggered by cytokines, a chronic inflammation state and endoplasmic reticulum stress. ¹⁴

GD‐specific biomarkers are used for diagnosis, monitoring disease progression, disease severity and assessment of treatment response. These have included angiotensin‐converting enzyme (ACE), acid phosphatase (AP), tartrate‐resistant acid phosphatase (TRAP), chitotriosidase and chemokine ligand 18 (CCL18). ¹⁵ , ¹⁶ Reduced levels of high‐density lipoprotein (HDL) in GD were previously reported by our group. ¹⁷ Recently, levels of the deacylated form of glucosylceramide, glucosylsphingosine (lyso‐Gb1, also termed lyso‐GL1), have been reported as a biomarker of GD used for disease severity assessment at diagnosis and during follow‐up. ¹⁸ , ¹⁹

Ferritin, an acute phase reactant, is frequently elevated in patients with GD and correlates with disease severity. ²⁰ , ²¹ , ²² Uric acid (UA), the end product of purine degradation in humans, has a positive association with serum ferritin levels as previously reported. ²³ , ²⁴ Several studies have shown that exposure to elevated iron concentrations enhances xanthine oxidoreductase activity, a crucial purine metabolism enzyme contributing to UA synthesis. Iron overload was also found to be associated with insulin resistance, which is related to a decrease in UA renal excretion resulting in hyperuricaemia. ²⁵ , ²⁶ , ²⁷ Elevated levels of SUA were observed in a cohort of GD1 patients followed at the Gaucher Clinic in Rambam Medical Center, Haifa, Israel. To our knowledge, there are no previous reports regarding hyperuricaemia in GD1 patients.

The goals of this study were to assess the incidence of elevated SUA in GD1 patients, study the correlation between SUA, GD severity and concurrent LPNs and to examine the potential use of UA as a potential biomarker or predictor of disease severity and the risk of developing concomitant malignancy.

Patients and methods

A cohort of 69 GD1 patients followed at the Gaucher Clinic in the Rambam Health Care Campus, Haifa, Israel, since 1990 was evaluated. The cohort comprised 36 (52.2%) females and 33 (47.8%) males, with an age range of 21 to 87 years (median, 54 years). Twenty‐five patients were treatment‐naïve (untreated) and 44 were receiving ERT. The study was approved with a waiver of consent by the institutional review board at Rambam Health Care Campus, Haifa (approval number 0195‐12).

The patients were evaluated for medical history of LPN and other malignancies. Levels of UA (reference range: females – 0.15–0.33 mmol/L, males – 0.18–0.42 mmol/L), creatinine, ferritin, acid phosphatase, ACE and chitotriosidase were measured and monitored in the naïve GD patients during follow‐up and in patients on ERT (for over 2 years) before ERT initiation and at several points during treatment. Disease severity was estimated according to Zimran severity score index (SSI). ²⁸ The data included in the SSI include cytopenia, splenomegaly, hepatomegaly, liver function, CNS manifestations and skeletal involvement, among other parameters, with a derived score in the range of 0–30 points, where higher scores indicate more severe disease.

Statistical analysis

The data were analyzed using SPSS version 18 (SPSS Inc. Chicago, IL, USA). The normality distribution of the quantitative variables was tested by the Kolmogorov‐Smirnov Z test. Mann–Whitney U test was used to analyze differences between groups. Wilcoxon signed rank test was used for demonstrated differences before and after treatment. Pearson correlation was used to determine the relationship between quantitative variables. Fisher exact test was used to examine the relationship between categorical variables. P < 0.05 was considered to be significant.

Results

The cohort of GD1 patients was divided into two groups: untreated patients and patients on ERT. The characteristics of both groups are shown in Table 1. The cohort included 69 patients, of whom 25 were untreated (10 males and 15 females) and 44 patients were treated with ERT (23 males and 21 females). The median age of the whole group was 54 years (range, 21–86 years), the untreated group was 59 years (range, 32–78 years) and the ERT‐treated group was 52.2 years (range, 21–86 years). The median age at diagnosis was 28 years (range, 1.3–80 years), 40 years (range, 6–68 years) in untreated patients and 22.5 years (range, 1.33–80 years) in ERT‐treated patients. The median SSI among the ERT‐treated patients was 11 (11.8 ± 0.624), compared to 4 (4.48 ± 0.569) in untreated patients (P < 0.0001), confirming that treated patients had a more severe course of the disease compared to those for whom ERT was not indicated.

Table 1.

Characteristics of untreated and ERT‐treated GD patients

		Untreated patients	ERT‐treated patients	Total	P‐value
No.		25	44	69
Sex	Male	10	23	33	0.327
	Female	15	21	36
Age (years)	Median	59	52.5	54	0.318
	Range	32–78	21–86	21–86
Age at diagnosis (years)	Median	40	22.5	28	0.131
	Range	6–68	1.33–80	1.33–80

ERT, enzyme replacement therapy; GD, Gaucher disease.

UA levels and GD severity

High levels of UA were observed in nine (20%) patients with severe disease and in four (16%) patients with mild disease. Abnormal creatinine levels were observed only in three (7%) patients with severe disease, whereas all patients with mild disease had normal creatinine levels. UA levels were significantly higher in patients with a severe disease course compared to patients with mild disease (0.35 ± 0.10 mmol/L and 0.29 ± 0.09 mmol/L respectively, P = 0.032), as shown in Table 2.

Table 2.

UA levels and Zimran SSI

UA and severity score
GD patients, n = 69	Disease severity (SSI)	UA (mmol/L)
Treatment‐naïve n = 25	4.48 ± 2.84	0.29 ± 0.09
Taking ERT n = 44	11.6 ± 4	0.35 ± 0.10
		P = 0.032

ERT, enzyme replacement therapy; GD, Gaucher disease; SSI, severity score index; UA, uric acid.

UA levels correlation with GD severity

The correlation between SUA level and GD severity (calculated according to SSI) was evaluated for all patients in this cohort and is presented in Figure 1. There was a linear and statistically significant correlation found between SUA levels and disease severity.

Figure 1.

Correlation of uric acid levels (mmol/L) and Zimran Severity Score. ²⁸

Correlation between SUA and AP levels

A statistically significant linear correlation was detected between levels of AP and SUA, as shown in Figure 2. However, no significant correlation was detected between SUA levels, ferritin and ACE.

Figure 2.

Correlation between uric acid levels (mmol/L) and acid phosphatase levels (U/ml).

Effect of ERT on SUA levels

SUA levels were evaluated in ERT‐treated patients, prior to treatment initiation and after 2 years of treatment (Table 3). A statistically significant increase in SUA level was observed prior to and during ERT in patients with severe GD. The effect of ERT on SUA levels was more pronounced in the male cohort, as shown in Table 3.

Table 3.

Effect of ERT on UA levels

UA (mmol/L)	Total, N = 30	Males, n = 18	Females, n = 12
Before ERT	0.35 ± 0.10	0.39 ± 0.09	0.29 ± 0.07
Following 2 years of ERT	0.39 ± 0.14	0.45 ± 0.13	0.34 ± 0.11
P‐value	0.054	0.011	NS

Reference range of uric acid (UA): females – 15–0.33 mmol/L, males – 0.18–0.42 mmol/L. ERT, enzyme replacement therapy; NS, not significant.

SUA and lymphoproliferative neoplasms

There was no statistically significant difference between SUA levels observed in GD patients with LPN and GD patients with no LPN, as shown in Table 4. Among patients with a severe disease course, five presented with LPN (11.4%), compared to one in patients with mild disease (4%) (P = 0.41). The type of LPN diagnosed in our cohort was low‐grade B‐cell lymphoma. There was no statistically significant difference in malignancy rate between the two groups of patients: 6.8% and 12% respectively (P = 0.66).

Table 4.

UA levels and incidence of lymphoproliferative disorders and malignancies

SUA (mmol/L)	Range	Median
LPN	0.37 ± 0.12	0.37
Malignancy	0.36 ± 0.12	0.36
No LPN or malignancy	0.32 ± 0.09	0.03

LPN, lymphoproliferative neoplasm; SUA, serum uric acid; UA, uric acid.

Discussion

GD severity assessment is usually based on the degree of organ involvement including bone marrow, spleen, liver and bone. Levels of ACE, AP, CCL18, ferritin, HDL, chitotriosidase activity and, the most recently used, glucosylsphingosine (lyso‐Gb1), serve as biomarkers for GD activity. ²⁹

In this study of a cohort of GD1 patients, a significant increase in SUA levels in patients with a severe disease course was detected, as compared to more mildly affected patients. A linear correlation between SUA, AP levels and GD severity (measured by SSI) was found. The patients with severe GD had high levels of SUA even following ERT. The higher urate levels detected in patients with a severe course, although treated, might relate to enhanced macrophage purine nucleotides metabolism, similar to hyperuricaemia observed in tumour lysis syndrome, which is commonly associated with cytotoxic treatment for hematologic malignancies. ³⁰ Also, it is known that one of the unmet goals of ERT is its influence on the inflammatory processes, immune dysregulation and autoimmunity in GD. For example, it has no significant effect on monoclonal gammopathies in GD. ³¹ We postulate that SUA levels may be helpful in estimating Gaucher cell burden as related to GD severity.

Hyperuricaemia is considered a hallmark of gout disease and a risk factor for gout arthritis and nephropathy. SUA has also been strongly associated with metabolic syndrome, ³² including non‐alcoholic fatty liver disease (NAFLD), which is a cardinal aspect of this condition. ³³ NAFLD is potentially a leading cause of hepatic fibrosis. Elevation in SUA and hyperferritinaemia have been reported in NAFLD. ³³ Liver involvement has been reported in most GD patients and comprises hepatomegaly, occasional high transaminase levels, abnormal coagulation factors, fibrosis and cirrhosis, portal hypertension, liver nodules and cholelithiasis. ³⁴ , ³⁵ As shown in the present study, SUA was related to GD severity, in which hepatic complications play a major role.

The presumed pathogenesis of these conditions includes the pro‐inflammatory and pro‐oxidative effects of SUA. ³⁶ , ³⁷ These processes might be applicable for the visceral and bone phenomena in severe forms of GD. The high incidence of immune dysregulation, occurrence of lymphoproliferative and immunoproliferative disorders in GD might relate to cytokine release and inflammatory response. ¹⁴ , ³⁸ However, the incidence of LPN in our GD1 cohort was very low and thus the correlation between SUA and LPN incidence in our study was unremarkable.

Serum concentrations of ferritin correlated positively with SUA levels in healthy individuals. ³⁹ Moreover, previous studies have shown that elevated levels of SUA are associated with hyperferritinaemia and may serve as a risk stratification variable for the presence of iron overload. ⁴⁰ Hyperferritinaemia has been reported in the majority of GD patients. ⁴¹ In this cohort of GD1 patients, ferritin levels were elevated in all investigated patients; however, no statistically significant correlation was found between SUA and ferritin levels among these patients. This might relate to the lack of true iron overload in the GD1 cohort, and the elevation of ferritin reflects the inflammatory state in GD. As was reported by several studies, Glucosylceramide accumulation in GD1 macrophages induces an inflammatory response resulting in impaired iron metabolism and immune dysregulation, leading to chronic metabolic inflammation. ⁴² , ⁴³ Another possible explanation for the absence of a correlation between SUA and ferritin levels in GD1 is the fact that ferritin relates to hepatic lipid accumulation and concomitant metabolic inflammation. ⁴⁴

We assume that UA is a major contributor to metabolic inflammatory processes that characterise GD. Hence, we hypothesise that SUA reflects the proinflammatory state of GD1, which enables prediction of the disease course related to the severity and development of complications.

GD is a rare lysosomal storage disease which is commonly misdiagnosed or diagnosed late in the disease course. Biomarkers are helpful in the diagnosis and follow‐up of GD patients. Urate and ferritin levels are commonly investigated, and when high levels of these markers are detected, GD should be suspected. In the era of ERT and SRT, early diagnosis of GD1 would reduce serious or irreversible late‐onset complications. SUA level may be used as a marker of Gaucher cells burden, turnover and severity of GD.

As the test for SUA is readily available and reliable, our study highly suggests that SUA levels should be included in the GD biomarker ‘basket’ for the diagnosis and monitoring of patients. Since Lyso‐Gb1 is considered a useful biomarker for the diagnosis and monitoring of disease severity and response to treatment modalities in GD, ⁴⁵ it is essential to evaluate the correlation between SUA and Lyso‐Gb1 in the future.