Early diagnosis and treatment: The key to improved outcomes for patients with Gaucher disease

The success of recent advances in the treatment of Gaucher disease (GD) has highlighted the importance of early diagnosis. Without timely intervention, this progressive disorder can cause a number of disabling and potentially lethal complications.1

Early diagnosis is the key

Whilst GD is the most common lysosomal storage disorder, it is rare with an incidence of 1 in 57,000 live births in Australia, with non-neuronopathic, or type 1 GD, comprising approximately 90% of these cases.^2,3

Clinical professor and director of the Genetic Services & Familial Cancer Program of WA Jack Goldblatt says about 70 Australian patients are receiving enzyme replacement therapy and there are possibly several more patients not severe enough to apply for therapy.

The rarity of the disorder combined with significant variation in presentation has meant that the initial diagnosis of Gaucher disease is often delayed due to the disorder not being considered within the differential diagnosis of many attending physicians.¹ Indeed, a survey of 406 haematologist/oncologists found that only 20% of respondents included GD within their differential diagnosis for classical symptoms of GD including hepatosplenomegaly, cytopaenia and bone pain.¹ Research also found that in a review of 136 patients with GD, there was an average delay of four years between initial GD symptoms and final diagnosis, confirming the fact that early identification of GD symptoms is problematic.¹

Additional barriers to timely diagnosis include misconceptions that GD is confined solely to Ashkenazi Jewish populations and the late onset of certain subtypes of type 1 GD, in particular homozygous N370S subtypes.¹ Whilst Jewish patients displaying classical features of GD are likely to have a higher pretest probability of the disease, being non-Jewish or older in age certainly should not exclude consideration of the diagnosis.

Understanding the signs and symptoms of Gaucher disease

Professor Goldblatt says he sees a number of presenting features of Gaucher disease, including asymptomatic splenomegaly, abnormal blood counts, skeletal symptoms and unexplained lethargy.

However, he says "not thinking of a rare disorder when considering some of the non-specific symptoms, such as the bone and joint pains in older patients," is an impediment to early diagnosis.

It should be noted that the diagnosis of GD requires biochemical confirmation of deficient glucosylceramidase activity.⁴Whilst clinical suspicion on the basis of presenting symptoms alone is insufficient to make the diagnosis, a high index of suspicion for GD is vital when classical GD signs and symptoms are present in order to guide the necessary investigations to expedite diagnosis. Whilst a myriad of signs and symptoms exist for GD, the three classical features are bone pain, hepatosplenomegaly and cytopaenia.¹

The most common presenting complaint on clinical history with GD is an abdominal mass that may or may not be symptomatic.^3,5 A symptomatic abdominal mass can present as early satiety, abdominal distension or discomfort, weight gain or increase in abdominal girth.⁶ These are the presenting symptoms of hepatosplenomegaly, which can be massive with splenic enlargement to 3kg or more.⁴

Abnormal haematological blood results are very common, if not universal, in the disease process with anaemia, thrombocytopaenia and leukopaenia all common findings.⁷ There is also a correlation between the degree of splenic involvement and severity of thrombocytopaenia.⁷ Bone marrow infiltration and possible medullary infarction are additional precursors to deranged haematological blood results.⁴ Associated symptoms also include recurrent epistaxis, menorrhagia, lethargy, malaise and bruising.

Bone pain is common and is the result of the bone disease that occurs with the disorder.⁵Bone disease occurs in 70–100% of patients with type 1 GD that may be apparent clinically or via radiographic investigation.⁴ Acutely, such bone disease may manifest as a so-called febrile ‘bone crisis’ presenting with significant deep bone pain with an accompanying leukocytosis, yet on investigation is culture negative.⁸ Generalised lymphadenopathy is also common, and routine questioning should explore for recurrent chest infections, splenectomy and multiple fractures.^2,3,5 In addition to the abovementioned symptoms, a history of diplopia or squint may indicate the onset of neurological symptoms in type 3 GD.⁴

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Making the diagnosis

The definitive diagnostic investigation for GD is an assay of acid β-glucocerebrosidase enzyme activity* in peripheral blood leukocytes or other nucleated cells that should be reduced to 10–15% of normal function in the case of type 1 GD and 0–9% of normal function in types 2 and 3 GD.^4,9 It should be noted that bone marrow biopsy, although not a reliable diagnostic test, remains a common investigation due to the predominance of unexplained cytopaenia and bone pain as hallmarks of the presenting complaint.⁴ Electron microscopy of bone marrow aspirate from GD samples typically show so-called Gaucher cells – 9 lipid laden macrophages that have a crumpled silk appearance to the cytoplasm and an eccentrically placed nucleus.¹⁰

Determination of the specific genetic mutation via targeted mutation analysis and sequence analysis in each individual may provide additional diagnostic information. For instance, homozygous N370S allelic subtypes are most likely to present later in life with predominant skeletal involvement, whilst heterozygous N370S subtypes present earlier and have a greater visceral and haematological involvement.¹¹ Similarly, the presence of at least one N370S allele is important prognostically as this excludes the possibility of neurological involvement.¹²

In order to qualify for enzyme replacement therapy (ERT) with imiglucerase (Cerezyme), additional diagnostic information will be required, including:^4,6,13

MRI of the abdomen to assess for splenic and hepatic volume.
MRI of the femora, including:
- T1 weighted to assess for marrow infiltration; and
- T2 weighted to assess for bone infarcts.
Dual energy X-ray absorptiometry (DEXA) of the lumbar spine to assess for osteopaenia.

The full criteria can be found here.

Finally, chorionic villus sampling is possible to diagnose GD via function enzyme assay prenatally.¹⁴

Depending how severe the manifestations are at the commencement of therapy, most symptoms are typically reversible with Cerezyme therapy, according to Professor Goldblatt.

Professor Goldblatt said Cerezyme is able to change health outcomes dramatically.

"If treated prior to the development of irreversible complications, treatment will maintain the individual in a ‘healthy’ state."

Current epidemiological data indicates patients with type 1 Gaucher disease are likely to have a life expectancy approximately 9 years less than the normal population.

"The data on lifespan is based on a registry analysis which likely has numerous confounders due to the nature of the data collection," Professor Goldblatt says.

"If treated early with appropriate dosing, there is every chance of a normal lifespan."

However, for type 3 Gaucher disease patients, he says most will have a reduced lifespan even on treatment.

"Cerezyme is not efficacious in treating the neurological symptoms of type 2 and type 3 Gaucher disease as the enzyme administered parenterally does not cross the blood-brain barrier," he said.

Recent submissions to the PBAC for PBS listing of miglustat (Zavesca) have been unsuccessful; however, the PBAC has recommended that miglustat (Zavesca) be included under the Life Saving Drugs Program, similar to imiglucerase (Cerezyme).²⁴

Professor Goldblatt said miglustat (Zavesca) will have "a limited role for patients unsuitable for first-line therapy (i.e. enzyme replacement). Further data from a trial currently underway may provide further indications in the future."

Delayed diagnosis – the complications of untreated Gaucher disease

Treatment in Australia with imiglucerase (Cerezyme) ERT is subsidised under the Life Saving Drugs Program (LSDP). Imiglucerase (Cerezyme) is indicated for treatment of patients with a confirmed diagnosis of GD resulting in one or more of the following conditions:^15-17

Anaemia;
Thrombocytopenia;
Bone disease; and/or
Hepatomegaly or splenomegaly.

There is currently insufficient evidence to support the use of imiglucerase (Cerezyme) for treatment of neurological symptoms associated with type 2 or 3 Gaucher disease.^15,16 Current guidelines also do not include the management of acute bone crises as an indication for treatment.^15,16 However, there is new evidence to suggest that significant improvements can be achieved with imiglucerase (Cerezyme) in treating the acute skeletal manifestations of the disease, including lytic lesions, avascular necrosis and bone infarctions.¹⁸

In the event of diagnostic delay, there may be avoidable progression of the disease including hepatosplenomegaly and significant bone disease. Significant complications can also arise as a result of non-treatment due to diagnostic delay including avascular necrosis and malignancies, in particular multiple myeloma in N370S homozygotes.^1,19 Where a delay of two years or more exists between diagnosis of type 1 GD and treatment, new research has found that patients have an increased risk of avascular necrosis.¹⁹

The benefits of treatment

In type 1 GD, imiglucerase (Cerezyme) has been shown to decrease organomegaly by up to 60%, bone pain resolves in a majority of patients, and haematological abnormalities typically return to near normal levels within 6–12 months.²⁰ Early treatment in childhood can also aid in reducing complications, especially skeletal abnormalities later in life.⁶

In neuronopathic GD (type 2 and some cases of type 3), imiglucerase (Cerezyme) appears to achieve similar results for non-neurological symptoms but offers little benefit for neurological disease, most likely due to the fact that imiglucerase (Cerezyme) cannot cross the blood-brain barrier.^21-23

* There are two labs in Australia that currently perform the assay:

SA Pathology at Adelaide Women’s and Children’s Hospital. Tel: 08 8161 6701
Royal Brisbane and Women’s Hospital, Division of Chemical Pathology. Tel: 07 3636 8428

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