Hydroxychloroquine Side Effects, Fabry Symptoms May Overlap
3 case studies compare rare side effects of HCQ with Fabry symptoms
Rare side effects caused by hydroxychloroquine, a medication used to prevent malaria and to treat several autoimmune diseases, may mimic some symptoms of Fabry disease, a case series suggests.
Hydroxychloroquine (HCQ) toxicity was associated with heart, kidney and muscle problems, as observed in Fabry disease. “A thorough investigation should be performed in these cases to properly elucidate the cause followed by the appropriate targeted therapy,” the researchers wrote.
The report, “Hydroxychloroquine and Fabry Disease: Three Case Reports Examining an Unexpected Pathologic Link and a Review of the Literature,” was published in the journal Case Reports in Rheumatology.
Fabry disease is a disorder caused by the lack of the alpha-galactosidase A (Gal A) enzyme, or in a reduction of its activity. Gal A breaks down fatty molecules, such as globotriaosylceramide (Gb3), in lysosomes, which are cell compartments that recycle proteins and other molecules. In the absence of Gal A, fatty molecules build up in small blood vessels and in many tissues, including the heart, kidneys, and skin.
Some patients experience progressive kidney damage, and ultimately kidney failure. Excessive thickening of the heart muscle, irregular heartbeat, and heart failure are among the several issues that can affect the hearts of Fabry disease patients.
HCQ is widely used for the treatment of autoimmune diseases, such as systemic lupus erythematosus (SLE) and rheumatoid arthritis. It works by crossing into lysosomes and decreasing the acidity of the environment within them. This reduces the production of certain signaling molecules and immune cells.
Lower acidity also inhibits the normal function of lysosomal enzymes such as Gal A. Therefore, researchers believe the action of HCQ, and the physiological processes associated with Fabry disease, share some similarities.
HCQ is generally considered safe and well-tolerated. Only a few cases of damage to the kidney and heart, and skeletal myopathy (muscle atrophy and weakness) have been reported.
In this report, researchers at the University of Colorado Denver and University of Nebraska Medical Center, described the cases of three women who experienced rare side effects with HCQ and compared their symptoms to those linked with Fabry disease.
The patients
The women — a 22-year-old with lupus nephritis (a form of kidney inflammation caused by lupus), a 72-year-old with SLE, and a 74-year-old with an undefined connective tissue disease — had been on HCQ for different time periods.
Microscopic examinations of samples from the kidney, the heart, and the skeletal muscle showed evidence of HCQ toxicity.
For example, kidney samples from the first patient had structures called lamellated myeloid bodies and zebra bodies. Although these changes previously were considered to be unique to Fabry disease, they also have been observed following the use of HCQ.
Myeloid bodies and curvilinear inclusion bodies — protein aggregates surrounded by a membrane — were found in heart samples from the second patient. Curvilinear bodies are highly specific for HCQ toxicity.
The third patient had been admitted previously to a hospital for muscle weakness. A muscle biopsy showed the presence of lysosomal curvilinear bodies. HCQ skeletal myopathy and Fabry disease typically present with proximal lower extremity weakness or atrophy, the authors noted.
“The rare side effects seen in our cases could result from a similar pathology as Fabry disease due to inhibition of [Gal A] and subsequent aggregation of [Gb3],” the team wrote.
“In the future, it would be interesting to investigate a correlation between partial or reduced [Gal A] activity and the higher risk of developing HCQ toxicity and if the activity level correlated inversely to the degree of toxicity,” they added.
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