Obesity may affect SRT treatment response in Gaucher disease
Case report: Splenectomy also could contribute to poor response
A 31-year-old woman with type 1 Gaucher disease (GD) experienced worsening symptoms and rising disease activity markers after switching from long-term enzyme replacement therapy (ERT) to Cerdelga (eliglustat), according to a recent case report.
The woman — who was obese and had her spleen surgically removed years earlier — developed increasing fatigue, liver enlargement, and higher levels of Gaucher biomarkers while on Cerdelga, an oral substrate reduction therapy (SRT). By contrast, when she restarted ERT, her blood counts and biomarkers improved within months, and her symptoms also eased.
Researchers emphasized that her obesity and prior splenectomy may have contributed to the poor response, noting that limited data exist on how these factors affect outcomes with Cerdelga. The case also “highlights the complexity of GD and underscores the need for personalized approaches to treatment and monitoring,” researchers wrote.
The case report, “Increased Lyso-Gb1 Levels in an Obese Splenectomized Gaucher Disease Type 1 Patient Treated with Eliglustat: Unacknowledged Poor Compliance or Underlying Factors,” was published in Metabolites.
SRT treatment for Gaucher disease works by reducing Gb1 production
GD is a rare genetic disorder caused by mutations in the GBA1 gene, which result in a missing or abnormal enzyme called glucocerebrosidase (GCase). Without enough of this enzyme, fatty molecules such as glucocerebroside (Gb1) and lyso-Gb1 build up inside cells. Over time, this buildup can damage organs, including the spleen, liver, and bones, and lead to problems such as low blood counts and fatigue.
Doctors often monitor Gaucher activity through biomarkers like lyso-Gb1 and chitotriosidase, along with clinical measures such as blood counts and organ size.
The standard treatment for Gaucher disease is ERT, in which patients receive regular infusions of a lab-made version of the missing GCase enzyme. SRT is a newer option that is taken orally and works by reducing Gb1 production rather than supplying the missing enzyme.
Cerdelga, marketed by Sanofi, is an SRT that has shown long-term safety and effectiveness in many patients, including those switching from ERT. Data on people with obesity or splenectomy remain limited, however, making it difficult to predict outcomes in these groups.
Woman’s disease gradually worsened after switching to SRT
In this report, researchers in Italy described the case of a 31-year-old woman diagnosed with GD type 1 who failed to respond adequately to Cerdelga after switching from ERT. The woman underwent a splenectomy at the age of 15 after a decade of low platelet and red blood cell counts, as well as severe spleen enlargement. Genetic testing revealed multiple GBA1 mutations, including the most common N409S mutation.
She first tried Zavesca (miglustat), another oral therapy approved for adults with mild to moderate GD1 who cannot use ERT, but stopped after three years due to gastrointestinal side effects and limited benefit. At age 18, she began treatment with Cerezyme (imiglucerase), an ERT, and responded well.
With ERT, her blood counts normalized, biomarkers of disease severity such as lyso-Gb1 and chitotriosidase dropped, and her liver volume reduced. However, she also gained about 20 kilograms (44 pounds) during this time.
At 26, she switched to Cerdelga due to her preference for an oral therapy. At that point, she weighed 119 kilograms (262 pounds), with a high body mass index, a standard measure based on weight and height, that indicated obesity.
Further studies are needed to clarify the role of genetic factors, obesity, and splenectomy in treatment outcomes.
Despite adherence confirmed by the hospital pharmacy and no side effects, her disease activity gradually worsened. Lyso-Gb1 levels rose, platelet counts started to decline, and her liver enlarged again.
After reporting worsening fatigue, she switched back to ERT. Within 1 to 2 months, the woman reported an improvement in her general well-being, and her platelet counts also rose. After three months, disease biomarkers had significantly dropped.
The researchers noted that her obesity likely affected how her body processed Cerdelga. In addition, previous genetic testing showed she carried a version of the CYP2D6 liver enzyme that causes drugs like Cerdelga to be broken down more quickly than the average, potentially leading to suboptimal drug levels in her system.
Finally, because spleen removal may affect Gaucher disease progression, it’s also possible that her splenectomy contributed to the poor response to treatment.
“Further studies are needed to clarify the role of genetic factors, obesity, and splenectomy in treatment outcomes,” the researchers concluded.
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