Hyperferritinemia and diagnosis of type 1 Gaucher disease

Abstract

A 61-year-old Caucasian man presented with persistent hyperferritinemia known since his forties in the presence of components of metabolic syndrome. History revealed longstanding obesity, with maximum weight and BMI of 100 kg and 32 kg/m 2 , respectively. At the age of 45 years, routine blood examination showed marked hyperferritinemia (1738 μg/L) with normal transferrin saturation (TSat 41%), very mild thrombocytopenia (140 × 10 9 /L), normal Hb (139 g/L) and white blood cell count (8.93 × 10 9 /L), and polyclonal hypergammaglobulinemia (21.5%). He also had low HDL cholesterol (0.8 mmol/L), mild hypertriglyceridemia (2.33 mmol/L), impaired fasting glucose (5.66 mmol/L), and oral glucose tolerance test (OGTT) consistent with glucose intolerance (glucose 9.49 mmol/L at 2 hours). Liver function tests were normal, as well as C-reactive protein, coagulation, renal and thyroid function tests. At that time, he reported an unbalanced diet with moderate alcohol consumption, sedentariness, and positive family history for type 2 diabetes mellitus. Abdominal ultrasonography (US) showed mild liver enlargement with increased echogenicity consistent with moderate steatosis; the major diameter of the spleen was 12.4 cm; no signs of portal hypertension were detected. Liver biopsy demonstrated micro-macrovesicular steatosis in 50% of hepatocytes, and hypertrophic Kupffer cells with mild siderosis (Figure 1). A first-level genetic test for HFE-hemochromatosis was negative, only showing heterozygosity for the H63D variant. Sequencing of the SLC40A1 gene (encoding ferroportin) did not reveal pathogenic mutations. A provisional diagnosis of dysmetabolic iron overload syndrome (DIOS) was suggested, and lifestyle changes as well as alcohol withdrawal were recommended.Initially, Gaucher disease (GD) was not suspected. The patient had ≥2 alterations of the metabolic syndrome, liver steatosis and normal TSat, fitting the criteria for the diagnosis of DIOS, 1 which represents a far more frequent cause of hyperferritinemia than GD. A possible Ferroportin Disease, suggested by iron accumulation in Kupffer cells, 2 was ruled out by SLC40A1 sequencing.In the following 15 years, the patient lost weight (8 kg, leading to BMI reduction to 28 kg/m 2 ), and substantially improved his metabolic profile (fasting glucose 4.88 mmol/L, OGTT normalization, HDL cholesterol 1.39 mmol/L, triglycerides 0.93 mmol/L); he also underwent irregular phlebotomies (total n = 12). Nonetheless, serum ferritin was only mildly reduced (1056 μg/L). Of note, hypergammaglobulinemia (21%) was confirmed, and platelet count further decreased § Alberto Piperno and Domenico Girelli equally contributed to the work.

Ferroptosis and Its Modulation by Autophagy in Light of the Pathogenesis of Lysosomal Storage Diseases

“…The authors confirmed these results by creating a Gaucher disease cell model and by observing the gradual restoration of ferroportin and hepcidin levels from the time of induction of the disease with a glucocerebrosidase inhibitor in macrophages [69]. The effectiveness of ERT in restoring the correct level of ferritin is also evidenced by recently published case reports [70].…”

Hemochromatosis Mimicked Gaucher Disease: Role of Hyperferritinemia in Evaluation of a Clinical Case

“…When GD is suspected, further investigations should be adjusted based on the strength of the clinical suspicion. Analysis of enzymatic activity should be performed as a first-line screening strategy [ 29 , 30 ], followed by genetic analysis and lyso-Gb1 detection if enzymatic analysis results are positive [ 7 ]. Misdiagnosis and delayed diagnosis in metabolic diseases can lead to irreversible organ damage and delayed start of specific therapy for these patients.…”

“…However, different conditions affecting other organs can reveal high iron levels that simulate hemochromatosis. Among these, Gaucher type I disease can also manifest as hyperferritinemia [ 7 ], leading to a misdiagnosis of hemochromatosis. Total clinical features of hyperferritinemia or its association with HFE gene mutations are unknown.…”

Early diagnosis of Gaucher disease in Korean patients with unexplained splenomegaly: a multicenter observational study

“…The patient who was diagnosed with GD in this study showed classical features of splenomegaly, thrombocytopenia, anemia, bone lesion, and hyperferritinemia. Hyperferritinaemia is commonly observed in patients with GD1 and recent studies have proposed GD-focused diagnostic flow charts starting from hyperferritinemia [ 11 , 14 ]. It would be reasonable to propose more targeted screening using splenomegaly as an overarching symptom with additional consideration of other key hematologic manifestations such as thrombocytopenia and hyperferritinemia in hemato-oncology clinics.…”