1 Why Was GD Not Diagnosed Earlier? Why Was GD Not Diagnosed - - PDF document

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MODULE 3 Overcoming Diagnostic Challenges in Gaucher Disease Neal J. Weinreb, MD, FACP

Critical Conversations in Rare & Orphan Diseases: Challenges of Diagnosing and Caring for an Individual with Gaucher Disease

History

A 35 y/o woman, of Ashkenazi Jewish ethnicity, was hospitalized with abdominal pain, diarrhea, back pain, myalgia, and headache. Throughout childhood and teen years, she was short and thin with a protuberant abdomen. No acute or chronic bone pain Age 17: Polycystic ovary syndrome with progressive weight gain, metabolic syndrome and insulin resistance

Physical Exam

Obesity: weight 124 kg; height 1.63 m; BMI 46.9 kg/m2 Palpable splenomegaly (3 cm below LCM); no lymphadenopathy

Investigations

Hb 11.3 g/dL; MCV 75.9 fL; WBC 4000/µL; PLT 60,000/µL; LFTs wnl Ferritin 43 ng/mL; serum iron 28 µg/dL; transferrin saturation 7% Negative blood and stool cultures Abdominal ultrasound revealed only splenomegaly Abdominal CT: splenomegaly with multiple splenic nodules

Case 3: Consequences of Delay Diagnosing GD Case 3: Differential Diagnosis and Further Tests

• Differential diagnosis:

– Mononucleosis – Systemic lupus – Hairy cell leukemia – Lymphoma – Acute gastroenteritis

• Additional tests ordered:

– Bone marrow aspiration – PET scan

• The bone marrow was reported non-diagnostic.
• PET scanning showed “hot spots” in the spleen and in

mesenteric lymph nodes suggesting possible lymphoma. However, a diagnosis of lymphoma was never confirmed histologically.

• She was followed for four years without a definite diagnosis.

Splenectomy was contemplated because of persistent abdominal symptoms but not performed because of a determination of high risk.

• She was eventually diagnosed with GD—only after her sister

was found to have GD.

• Because of the diagnostic delay, she developed anxiety and

depression requiring prolonged treatment with SSRI anti- depressants and anxiolytics.

Why Was GD Not Diagnosed Earlier?

• Limitations of bone marrow examination for GD diagnosis

– Compared to a trephine biopsy, bone marrow aspiration is not a reliable diagnostic tool for the detection of

• GD1. Patients with long-lasting splenomegaly and/or thrombocytopenia in whom bone marrow aspirate

cytology is negative for Gaucher cells should be routinely referred for an enzymatic assay for GD.1 – Rarely, confirmed GD has been reported despite a negative bone marrow biopsy.2,3 – Pseudo-Gaucher cells4

• Macrophages induced by increased turnover in rapidly dividing tumor cells or due to erythroid hyperplasia associated

with peripheral and intramedullary red blood cell destruction with ineffective erythropoiesis

• Hematologic malignancies
• CML (often in association with sea-blue histiocytes)
• Myelodysplastic syndromes, AML, ALL
• B-cell lymphoma
• Myeloma and Waldenstrom’s macroglobulinemia
• Congenital dyserythropoietic anemia
• Hemoglobinopathies (thalassemia and sickle cell anemia)
• (Atypical) Mycobacterial infection
• 1. Machaczka M, et al. Pol Arch Med Wewn. 2014;124(11):587‐92; 2. Klibansky C, et al. Eur J Clin Invest. 1974;4(2):101‐7; 3. Ysla F et al. Bol Asoc Med P R. 2012;104(4):50‐3; 4. Cozzolino I, et al.
• Cytopathology. 2016;27(2)134‐6; Thomas AS, et al. Br J Haematol. 2014;165:427‐40; Villarrubia J, et al. Br J Haematol. 2014;165:164; Mistry PK, et al. Clin Adv Hematol Oncol. 2012;10:1‐16;

Standard Diagnosis for GD: Reduced Acid β-glucosidase Activity in Mononuclear WBCs

• Uses water-soluble artificial substrate 4-MU-b-GLU
• Patients with GD have up to 15% of normal activity

– Can use heparin or EDTA blood samples to isolate leukocytes

• Shipped ambient overnight

– Cut-offs are laboratory and sample specific

• Not reliable for carrier detection
• Cannot predict phenotype based on residual GBA

enzyme activity

• Possible alternatives:

– Dried blood spots

80 70 60 50 40 30 20 10 Healthy Controls n = 17 GD n = 42 ß-Glucosidase, µU/mg Protein

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Why Was GD Not Diagnosed Earlier?

Differential diagnosis—other more common hematologic diseases

Why Was GD Not Diagnosed Earlier?

Only 1 out of 5 hematologists suspected GD in a patient with 6 of the most common signs and symptoms of GD

It’s not on the diagnostic radar!

Implications of Missed Diagnosis

• When a GD diagnosis is missed:

– A patient may experience delays for up to 10 years until a correct diagnosis is rendered. – GD is progressive over time and, if left untreated, may lead to:

• Premature death from bleeding complications
• Pulmonary hypertension
• Liver disease
• Sepsis
• Growth failure
• Complications from advanced bone disease
• Negative effect on quality of life

Story of a Diagnostic and Therapeutic Odyssey: An Ashkenazi Jewish Woman (N370S/N370S)

• “When I was 10 y/o, I began to experience terrible pains in my
• legs. My mother thought that these were growing pains and left it

at that. But, as I grew older, my pain symptoms worsened and, in addition, I had severe bleeding episodes as well as bouts of

• fatigue. I used to think I was the laziest person in the world

because I felt so lethargic and tired. Through the following years, the cause of the symptoms was never properly diagnosed. It was only at age 23, right after my marriage, that a hematologist finally gave my disease a name, Gaucher disease, and recommended removal of my spleen. My husband and I were against this and so I remained with my symptoms unabated. I still vividly remember how I had hemorrhage for 17 days in the hospital after the birth of my first child.”

“Relief finally came after we retired and moved to Florida in 1980 where I was referred by my cardiologist to [a Gaucher disease expert]. He helped me manage my disease and gave me medicine to treat my pains, but we were both frustrated because there was still no other real treatment. In 1991, I started treatment with alglucerase*, the enzyme that had just become available for treating Gaucher disease. It took a while for me to respond because my platelets were very low, but after about 3 years, even the platelet count was a lot better. I was eventually switched to imiglucerase, the newer version of the enzyme, and have been on treatment now for more than 13 years. (2005). It has helped me tremendously, alleviating bone pain and fatigue symptoms. I still occasionally have bleeding problems but that is mainly due to medication that I have to take for my heart. Through the years, I have had several major surgeries, and had I not been treated for the Gaucher disease, I would have had severe complications or worse. I feel fortunate to lead a normal life at 81 years of age. I read, keep busy and have a positive attitude.”

Patient died in 2011 at age 88 of renal failure and CHF.

Story of a Diagnostic and Therapeutic Odyssey: An Ashkenazi Jewish Woman (N370S/N370S)

Points to Remember

• Gaucher disease shares many features in common with other benign and

malignant illnesses.

• Before GD is ever considered, hematologic malignancy is often suspected and

the diagnosis of GD is then discovered serendipitously.

• Most physicians, including hematologists, do not think of GD sufficiently early in

the diagnostic process to avoid testing that may be unnecessary.

• Diagnostic odysseys, delayed diagnosis and procrastination in starting treatment

can lead to chronic patient anxiety as well as irreversible complications, significant morbidity and even premature mortality.

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Points to Remember (continued)

• Testing for GD should be considered in any person presenting with combinations
• f bone pain, hepatosplenomegaly, or hematologic cytopenias.
• Bone marrow aspiration and biopsy can yield false diagnostic positives and false

diagnostic negatives.

• The gold standard for diagnosis is measuring leukocyte acid β-glucosidase

activity, which is typically <10% of control values.

• Bone marrow examinations are not a necessary part of a work up for GD unless a

concurrent hematologic disorder such as myeloma is suspected based on clinical

• r laboratory evidence.