Hydroxychloroquine and Fabry Disease: Three Case Reports Examining an Unexpected Pathologic Link and a Review of the Literature

Abstract

Background. Hydroxychloroquine is an effective and widely used treatment in multiple autoimmune connective tissue diseases that gained a lot of publicity in the coronavirus disease 2019 (COVID-19) pandemic. Our case reports are unique in that they explore the rare and sometimes overlooked effects of this drug on multiple organ systems, specifically the kidney, cardiac muscle, and skeletal muscle. We include key histologic features in images which aid in identifying and distinguishing hydroxychloroquine toxicity from mimickers. Lastly, we report the very interesting similarity in the intracellular action of hydroxychloroquine to the pathology of Fabry disease (and its associated lysosomal enzyme, α-galactosidase A). Case Presentation. We will examine the case presentations of three female Caucasian patients: a 22-year-old with lupus nephritis class V, a 72-year-old with long-standing systemic lupus erythematosus, and a 74-year-old with undifferentiated connective tissue disease. All three patients were on hydroxychloroquine therapy for varying amounts of time with histologic evidence of hydroxychloroquine toxicity that is three is present in histological samples of the kidney, the heart, and the skeletal muscle. Conclusions. Hydroxychloroquine is a very important and beneficial medication used for various autoimmune connective tissue diseases. Clinicians should be aware of the rare but sometimes serious side effects that can result from the medication, which at times can mimic manifestations of the connective tissue disease itself or Fabry disease. A thorough investigation should be performed in these cases to properly elucidate the cause followed by the appropriate targeted therapy.

Hydroxychloroquine-Induced Renal Phospholipidosis: Case Report and Review of Differential Diagnoses

“…phospholipidosis are known. Despite the frequent use of hydroxychloroquine, the overall prevalence of hydroxychloroquine-induced renal phospholipidosis is still unclear, as mainly isolated cases have been described in the literature [11][12][13][14][15][16][17][18]. In published case studies, zebra bodies were detected after a very heterogeneous duration of medication (0.3 months-9 years and 8 months) and concomitant heterogeneous cumulative dose (3 g-1,412 g) [11][12][13][14][15][16][17][18][19].…”

“…Based on this, Manabe and colleagues [12] (2021) draw attention to the fact that a discontinued immunomodulatory medication with hydroxychloroquine could pose the risk for an increase in SLE activity with subsequent decline in renal function. In summary, most authors recommend discontinuation of medication and regular monitoring of renal function parameters and proteinuria when zebra bodies occur during hydroxychloroquine medication, if justifiable in the context of the underlying rheumatic disease [11,13,14,[16][17][18][19].…”

“…Table 1 summarizes the previously described causes of renal phospholipidosis. Several drugs, such as the immunomodulative drugs hydroxychloroquine [11][12][13][14][15][16][17][18][19] and chloroquine [7,26,27]; aminoglycoside antibiotics gentamicin [28][29][30][31], tobramycin [30], and amikacin [30]; as well as amiodarone [32], have already been shown to be able to evoke renal phospholipidosis. A heterogeneous group of other pharmaceuticals, namely sertraline [33,34], carbamazepine [35], ranolazine [36], oxymorphone [37], posaconazole [38], viomycin [28], and contrast media [39], have been described as potential causes of renal phospholipidosis when lamellar bodies were found in renal biopsy specimen and no other known causes of phospholipidosis were identified.…”

Neuroimaging of COVID-19

“…82 Fabry-disease-like toxicity of the kidney, heart, and skeletal muscle has been reported, but, to our knowledge, no report of Fabry-like CNS toxicity has been reported. 83 Since Fabry disease produces accelerated small vessel white matter abnormalities, these effects may be difficult or impossible to disentangle from the effects of COVID and common pathologies such as hypertension. 84…”