Imaging of non-neuronopathic Gaucher disease: recent advances in quantitative imaging and comprehensive assessment of disease involvement

As the most common lysosomal storage disorder, Gaucher disease manifests with abnormal accumulation of glucosylceramide within macrophage lysosomes in multiple organs resulting from an absence or deficiency of β-glucocerebrosidase (also termed β-glucosidase, a glycosphingolipid) enzyme activity [1, 2]. This disease is inherited in an autosomal recessive fashion with over 350 mutations in the glucosylcerebrosidase (GBA) gene identified to-date [3].

Although this condition is attributed to a single gene, there is substantial variability in the phenotypic presentation of Gaucher disease with three classically described types [3]. This article focuses on the chronic, non-neuronopathic form (type 1), manifesting with prominent involvement of the reticuloendothelial system with liver, spleen, and marrow involvement, whereas the other types (acute neuronopathic type 2 and subacute-chronic neuronopathic type 3, summarized in Table 1) are far less common [4]. It is worth noting that some experts propose conceptualizing these disease types as a phenotypic spectrum rather than as distinct entities. Some work has suggested subclinical neurological involvement in the “non-neuronopathic” type with abnormal brain magnetic resonance spectroscopy (MRS) findings reported in type 1 Gaucher disease patients, although subsequent investigations have failed to replicate these observations and further work is needed [5, 6]. Others have suggested an increased risk of Parkinsonism in individuals with GBA mutations that reflects a complex relationship between glucocerebrosidase and Lewy body disorders [7].

While type 1 Gaucher disease is most often diagnosed in childhood or early adulthood with a little under one-third of cases diagnosed by 10 years of age [8], this condition can come to clinical attention at any age due to gradations of residual enzyme activity and phenotypic variability [9]. Pediatric phenotypic expression, however, tends to be particularly severe [10]. The diversity of clinical manifestation and spectrum of disease severity underscore the importance of accurate assessment of multisystemic involvement at diagnosis and across the lifespan [9]; as this article will further discuss, diagnostic imaging plays an instrumental role in clinical evaluation and management of Gaucher disease.

While Gaucher disease is relatively uncommon overall with an estimated prevalence of approximately 1/40,000, certain groups have much higher carrier and disease prevalence with a carrier frequency of as high as 6–10% in Ashkenazi Jewish individuals [11, 12]. The majority of type 1 Gaucher disease patients are diagnosed during childhood, and type 1 Gaucher disease is most commonly due to biallelic p.N370S mutations in the Western world [4].

Detailed description of the diagnostic workup and clinical management of Gaucher disease is beyond the scope of this article, but it is helpful for radiologists evaluating patients with Gaucher disease to be familiar with commonly utilized clinical tests and available therapies. Laboratory tests and biomarkers are summarized in Table 2; these clinical tests are part of comprehensive patient assessment that also involves diagnostic imaging. Clinical severity scoring is often performed using the Gaucher Disease Type 1 Severity Scoring System (GD-DS3) [13], which incorporates bone involvement, hematologic parameters, and organ enlargement. The Pediatric Gaucher Severity Scoring System (PGS3) [14] additionally accounts for growth disturbance as a key consideration in the younger population.

Traditionally, Gaucher disease has been conceptualized as a single gene-related disease due to one enzyme with one treatment consisting of enzyme replacement therapy (ERT) [3]. Prior to the advent of ERT, treatment was largely based on addressing symptoms with splenectomy performed for extensive splenic infiltration in severe patients with poor prognosis. The earliest effective ERT, alglucerase, was introduced in the 1990s and has dramatically changed the prognosis of this condition. Subsequent newer forms of ERT with improved manufacturing techniques and safety profiles have been approved. Newer oral substrate reduction therapy (SRT) functions earlier in the biochemical pathway by mitigating the accumulation of glucosylceramide [15]. Both types of therapies are expensive, and each have disadvantages to consider with ERT requiring intravenous infusion every few weeks and SRT possessing a narrower safety profile with CYP2D6 and CYP3A metabolism considerations as well as being only approved for adult use [3, 4, 16]. Historic and currently available treatment options are summarized in Table 3, but we refer interested readers elsewhere for detailed description of clinical trials and advances in Gaucher disease treatment [17].

Many asymptomatic patients with mild disease may not receive treatment at first; most children with milder genotypes perhaps may not require treatment initially. However, active bone disease, even if asymptomatic, and significant hepatosplenomegaly are considered indications for initiating ERT in asymptomatic children [18]. Therefore, monitoring of patients not currently on therapy with imaging is clearly important in guiding clinicians as to early disease involvement [18].

As some patients may respond poorly to particular therapies, imaging can be important to inform clinicians regarding changes in an individual patient’s response to specific therapies to provide personalized therapy decisions. The management of treated individuals who are asymptomatic despite biomarker and imaging findings of Gaucher disease poses a unique challenge, leading some clinicians to propose a concept of minimal disease activity wherein some treated patients may have mild persistent abnormalities on imaging and laboratory investigations without clinically significant disease [19]. Moreover, the substantial financial burden incurred by these therapies with annual treatment costs ranging between 70,000 and 380,000 USD [8, 20] may also motivate the use of imaging assessment of treatment response in well-controlled patients to assist in verifying efficacy and safety of reduced dosing schedules or alternative strategies to reduce the overall cost of therapy.

In patients with type 1 Gaucher disease, bone marrow involvement represents a spectrum of disease (Fig. 6) with some level of involvement in nearly every patient [4, 57, 58]. Recognition that musculoskeletal manifestations may be the presenting symptom of Gaucher disease is important to avoid confusion with other conditions with overlapping symptoms and signs such as hematopoietic malignancies and rheumatologic conditions [59]. Infiltration of the bone marrow with Gaucher cells with concomitant osteopenia progressively compromises the bone density of the axial then appendicular skeleton with prominent lower extremity involvement of the proximal femurs and tibias [22, 60, 61]. Upper extremity involvement, while less commonly recognized, is also a substantial contributor to musculoskeletal morbidity with many children and adolescents reporting upper extremity pain.

Greater severity of musculoskeletal involvement often corresponds with severe organ involvement. Early investigations of bone involvement in Gaucher disease believed bone changes were irreversible [56]. However, newer studies have shown that treatment results in substantial improvement of early bone marrow changes in many patients. The prognosis of skeletal involvement once complications have occurred remains poor and bone marrow responses take longer than organ responses [55, 62]. Bone turnover biomarkers have largely failed to risk stratify patients, making imaging evaluation of musculoskeletal involvement indispensable to clinical management [57].

Diagnostic imaging of hepatic and splenic involvement should consist of sequences tailored for volumetric organ measurement and screening for focal lesions. In conjunction with these conventional acquisitions, MR elastography should be considered, when available, to provide non-invasive assessment of liver and splenic stiffness. While the role of elastography in the clinical management of hepatic fibrosis in Gaucher disease is not yet established, acquisition of organ stiffness measurements may afford insights into disease and treatment effects in the future with wider clinical adoption. It is important to note that elastography results should be interpreted in the context of known limitations including inaccuracy of gradient recalled echo(GRE)-based elastography in patients with iron deposition and massive ascites [42]; as such, performance of both GRE and spin-echo echo-planar imaging elastography sequences is recommended. In addition, assessment of fat fractions and iron quantification may be helpful in providing additional quantitative information for disease severity and treatment response assessment, although these methods also require additional validation in larger populations.

Newer proton density fat fraction (PDFF) sequences allow for single breath-hold acquisition of the entire liver to provide triglyceride fat fractions, R2* mapping, and some also provide automated liver volumes (mDIXON Quant, Philips Healthcare; LiverLab, Siemens Healthineers; IDEAL-IQ, GE Healthcare) [126‐128]. These measurements are reliable and highly reproducible across vendors, making them ideal for multi-center investigations that are essential in studying rare conditions such as Gaucher disease [127, 128]. However, these measurement packages often require significant capital and are not yet widely available outside of major research institutions.

Single-voxel MRS for fat fraction measurement may also be considered as a supplement or alternative if PDFF sequences are not available. DWI is included in our protocol as it may also be provide indirect assessment of organ cellularity with ADC as a possible quantitative marker of disease severity [37].

If suspicious focal lesions are noted on this surveillance evaluation, dedicated lesion work-up with dynamic hepatocyte-specific contrast-enhanced MRI, multiphase contrast-enhanced CT, or contrast-enhanced ultrasound should be recommended, depending on institutional resources [54, 129, 130].

Qualitative imaging of both the axial (lumbar spine) and appendicular skeleton (proximal femurs) is important for assessment of global marrow involvement, as these sites may respond differently to treatment [64]. While a few recent studies have explored the use of whole-body MRI to screen the entire skeleton, none of the cases of humeral involvement were asymptomatic and therefore screening of the upper extremities may be less salient [78]. As emphasized throughout this article, quantitative measurement of bone marrow fat fractions is of increasing importance in estimating disease severity and tracking treatment response. Similar PDFF acquisitions (mDIXON Quant, Philips Healthcare; LiverLab, Siemens Healthineers; IDEAL-IQ, GE Healthcare) employed to measure fat fractions in the liver may be employed to measure fat fractions in the proximal femur (neck) and lumbar spine (L5), although marrow measurements using these sequences have not been validated in Gaucher disease [88]. Single-voxel MRS is a reliable alternative quantitative method that has been used in Gaucher disease and shows good concordance with Dixon-based methods [92, 131], although acquisition times may be greater for this method. MRS additionally requires expertise in analysis for fat fraction determination, but may be more reliable for lower fat fractions. Both PDFF and MRS generally require the contributions of a medical physicist dedicated to the successful implementation of these protocols. Therefore, institutions without such expertise in quantitative imaging may rely on conventional acquisitions and subjective assessment of marrow involvement by radiologists familiar with semi-quantitative scoring methods such as BMB.

Discrete parameters for the frequency of follow-up of Gaucher disease patients with imaging are informed by consensus recommendations and institution-specific practices [18, 24, 132, 133]. Comprehensive imaging evaluation of the liver, spleen, and bone marrow of the femurs and lumbar spine should be performed at initial diagnosis, annually for asymptomatic, untreated pediatric patients and biannually for asymptomatic, untreated adults. While some recommend less frequent skeletal imaging evaluation of asymptomatic patients, subclinical marrow involvement appears to be relatively common and asymptomatic individuals may benefit from regular monitoring [24, 58]. Abdominal imaging is generally recommended on a more frequent basis, every 6 months, in younger pediatric patients [18]. Given the convenience of the previously described comprehensive MRI evaluation (when appropriate sequences and equipment are available) and the observation that musculoskeletal complications indicative of treatment failure sometimes only brought to clinical attention by serial imaging [110], we recommend annual MRI of the bone marrow and abdominal organs. Follow-up evaluation in actively treated patients is typically performed annually as well, although marrow responses may plateau after 4 to 5 years of successful therapy [24, 93]. Ultimately, the frequency and nature of imaging follow-up may need to be adjusted on an individual basis dependent on the availability of imaging techniques, severity of involvement, and trends on prior imaging assessments.

As part of clinical severity scoring and recommended care for patients, bone mineral density measurement is recommended beginning at 6 years of age with follow-up obtained every 1 to 2 years [14, 18, 31]. DXA in children should be performed at institutions with technical and interpretive expertise specific to pediatric populations [18, 23]. DXA may be performed less frequently in adults depending on extent of marrow infiltration and risk of osteoporosis-related complications.

Regional radiographic assessment of acute bone pain should be the first-line examination to assess for the presence of pathologic fracture [24]. However, we advocate a low threshold for the evaluation of affected osseous structures with MRI, given the markedly improved sensitivity for osteonecrosis and collapse [72].

Decisions regarding routine imaging assessment of cardiac abnormalities with echocardiography and cardiac MRI are beyond the scope of this review with some authors recommending baseline echocardiographic screening in all ages at diagnosis and follow-up evaluation in adults on treatment [121, 122]. These clinical approaches to cardiac involvement may be best individually tailored on the basis of clinical presentation and genotype in the absence of more definitive evidence to support widespread use. Chest CT is valuable in the assessment of patients with suspected primary pulmonary involvement or secondary hepatopulmonary syndrome and may be helpful in symptomatic patients, but routine use of chest CT is not recommended due to the rarity of these abnormalities in asymptomatic type 1 patients [10].