The immense clinical diversity of LSDs means that hematologists across the entire spectrum of the specialty (pediatric, malignant, transplantation, coagulation and hemostasis, transfusion medicine, general and laboratory) are likely to encounter these conditions. In large teaching hospitals, hematologists often practice clinical and laboratory medicine, and may be consulted about appropriate investigations in patients with a systemic disease presenting as a diagnostic conundrum.
The next section considers selected presenting features in more detail; and then focuses on one disease in particular, GD, which is the province of the hematologists.
Splenomegaly
The spleen is an integral part of the reticuloendothelial, immunological, and hepatobiliary systems. Splenomegaly will lead to anemia, thrombocytopenia, and leukopenia, which raise concerns about hematologic malignancy; hence hematologists and hepatologists will encounter affected patients. In the neonatal period and during child hood, LSDs (particularly the MPS disorders and some GSLs including GD) must be considered as part of the differential. Among adult and adolescent patients, splenomegaly in the absence of cirrhosis leads to suspicion of an infiltrative or storage disorder, and hematologists must be aware of rare causes, including LSDs. GD is discussed in more detail below. Splenectomy will improve peripheral blood counts but will accelerate deposition of substrate in other organs and tissues (e.g., liver, bone), leading to further complications.
Niemann-Pick disease types A and B (NPDA/B) present with thrombocytopenia, anemia, leukopenia, and splenomegaly. Some patients with NPDB have excessive bleeding without significant thrombocytopenia or coagulopathy. Frequent and prolonged epistaxis can be particularly problematic, and in some extreme cases may require cauterization, packing, and blood transfusions.
As with GD, a primary cellular site of pathology in NPDA/B is the monocyte-macrophage system, and the characteristic pathological cells are referred to as Niemann-Pick cells. These can be distinguished from Gaucher cells by an experienced pathologist, but are frequently misclassified. NPDC is caused by primary defects in cholesterol transport, and many patients present with mild hematologic findings including splenomegaly, albeit less severe than in NPDA/B (see Fig. 1B).
Fig1. (A) Macrophage, bone marrow, Gaucher disease. (B) Macrophage, bone marrow, Niemann-Pick B. (C) Macrophage, bone marrow, Neuronal Ceroid Lipofucsinosis 1. (D) Lymphocyte, peripheral blood, Neuronal Ceroid Lipofucsinosis 3 (Batten disease). (E) Macrophage, bone marrow (unstained; DIK microscopy), Cystinosis. (F) B lymphocyte, peripheral blood, mucolipidosis II (“I cell” disease). (G) B lymphocyte, peripheral blood, MPS I (Hurler disease). (H) B lymphocyte, peripheral blood, MPS II (Hunter disease). (I) Plasma cell, bone marrow, MPS IIIA (Sanfilippo disease A). (J) Neutrophil, peripheral blood, MPS IVA (Morquio A disease). (K) Eosinophil and neutrophil, peripheral blood, MPS VI (Maroteaux-Lamy disease). (L) Monocyte and lymphocyte, peripheral blood, MPS VII (Sly disease). (M) T-lymphocyte and neutrophil, peripheral blood, generalized gangliosidosis GM1 type I (Landing disease). (N) Lymphocyte, peripheral blood, Fucosidosis. (O) Lymphocyte, peripheral blood, Sialidosis. (P) B lymphocyte, peripheral blood (Wright and PAShiff stains), Pompe disease.
Wolman disease (cholesterol ester storage disease) presents in adults with liver disease (classically as non-alcoholic fatty liver dis ease) and splenomegaly. It is under-diagnosed, results from acid lipase deficiency, and is supremely responsive to ERT.
Excessive Bruising/Bleeding
Thrombocytopenia due to splenomegaly occurs in several childhood and adult LSDs. However, splenomegaly usually causes asymptomatic thrombocytopenia, with platelet counts ranging from 50 to 120 × 109/L, and, if unexplained, should alert the physician to seek a definitive diagnosis. Massive splenomegaly, for example in GD, can cause thrombocytopenia and may be associated with spontaneous bruising, and excessive bleeding from mucous membranes (menorrhagia, epistaxis), or in response to trauma, after surgery or delivery. Marrow infiltration, or disturbed function of hemopoietic stem cells, is reported in some LSDs (e.g., GD), and may be a contributory factor. Excessive bleeding with moderate to severe thrombocytopenia should raise suspicion of platelet dysfunction. Platelets release lysomal granules containing glycohydrolases capable of degrading glycoproteins, glycolipids and glycosaminoglycans upon activation. Hermansky Pudlak syndrome (see Table 1) is an autosomal recessive disorder characterized by prolonged bleeding with oculocutaneous albinism, a storage pool deficiency of platelets, and lysosomal accumulation of ceroid lipofuscin; it is rare worldwide but is one of the commonest inherited disorders in Puerto Rico.
Table1. Classification of Lysosomal Storage Disorders
Thrombosis
Thrombosis and fibrinolysis with excessive consumption of platelets and coagulation factors is an important pathophysiologic component of LSDs. Tissue infarction may result in osteonecrosis in GD; sub-clinical thrombotic events, in part induced by inflammation, are likely to be involved in the neurologic pathology of many LSDs. Fabry disease warrants particular mention. Adults with mild missense mutations develop late-onset organ damage often restricted to a single organ, for example, the heart, kidney, or the CNS. Stroke, both thrombotic and hemorrhagic, often in the posterior fossa, is a frequent presenting feature among adults with Fabry disease. Structural abnormalities of blood vessels and disturbed regulation of blood flow are likely to be important contributory factors, but Fabry patients often have renal and cardiac disease, which will independently increase the risk of stroke.
Abnormal Morphologic Appearances: Bone Marrow and Peripheral Blood
It is frequently quoted, in articles and textbooks, that in lysosomal diseases “vacuoles in leukocytes” can be found. This assertion suggests that these changes are non-specific or of little diagnostic value. In a study of more than 1000 cases of LSDs, in the past 50 years, the Journal of Cardiac Failure (JCF) has found distinctive morpho logic changes in peripheral blood or bone-marrow cells that, in many cases, suggest the specific diagnosis and, in some cases, are completely diagnostic.
The morphologic changes consist of macro-molecules that have not been degraded in the lysosome due to specific enzyme deficiencies. Fig. depicts 16 of the most characteristic cells. The diagnosis, in all cases, has been confirmed by enzyme and molecular methods. Romanowsky-stained blood or bone-marrow smears are an easy, cheap and rapid method for the initial evaluation of many LSDs. Detailed explanation of the findings in each of the different LSDs is complex and beyond the scope of this chapter.
