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Niemann-Pick Disease and the Sea blue Histiocytes:          Doctor are you using social media ?

Dr Sampurna Roy MD           

 

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Niemann-Pick disease : A rare lysosomal storage disorder causing histiocytic hyperplasia due to enzymatic defect. There is accumulation of lipid in cells of mononuclear phagocytic system and central nervous system.

  1  2

Microscopic images of liver in Niemann-Pick disease 1 and 2. 

Image (1) shows clusters of foam cells. Image (2) highlights the pale staining clusters of sphingomyelin containing foam cells in a backround of PAS positive glycogen containing hepatocytes.

The Niemann-Pick disease group is now divided into two distinct entities:

(1) Lysosomal acid sphingomyelinase-deficient Niemann-Pick disease (ASM-deficient NPD) resulting from mutations in the SMPD1 gene and encompassing type A and type B as well as intermediate forms;

(2) Niemann-Pick disease type C (NP-C) including also type D (“Nova Scotian” form ), resulting from mutations in the NPC1 or NPC2 gene. The precise functions of the encoded proteins remain unresolved. 

Both Niemann-Pick diseases have an autosomal recessive inheritance and are lysosomal lipid storage disorders, with visceral (type B) or neurovisceral manifestations.

 

Niemann-Pick disease is characterized by hepatosplenomegaly and mental retardation.

The disease classically affects infants.

Sphingomyelinase-deficient type A variant  is the most common form.

Types A and C are always associated with severe neurological involvement.

Niemann-Pick disease types A and B are related disorders that are associated with a deficiency of sphingomyelinase and consequent accumulation of sphingomyelin in mononuclear phagocytes and many other cell types.

Type B Niemann-Pick disease (NPD-B) is a rare, autosomal recessive, lysosomal storage disorder with a broad range of disease severity. 

Type B variant is characterized by hepatosplenomegaly with progressive hypersplenism, worsening atherogenic lipid profile, gradual deterioration in pulmonary function, and liver dysfunction.

Niemann-Pick type C disease is a sphingolipid-storage disorder that results from inherited deficiencies of intracellular lipid-trafficking proteins, and is characterised by an accumulation of cholesterol and glycosphingolipids in late endosomes and lysosomes. 

Niemann-Pick type D disease ("Nova Scotian" form ) is a progressive neurodegenerative disorder characterized by the accumulation of tissue cholesterol and sphingomyelin.

This disorder is relatively common in southwestern Nova Scotia.

Pathology of Niemann-Pick Disease :

- The histiocytes accumulate sphingomyelin, which is derived from cell membranes and myelin sheaths.

The histiocytes of Niemann-Pick disease appear foamy in microscopic section in constrast to the more distinctive apparance of 'Gaucher cell' which appears striated ( crumpled tissue paper type appearance).

- In Niemann-Pick disease, the globules in the cytoplasm are small and uniform in size. It is also described as mulberry-like in appearance.

The sphingomyelin-containing histiocyte stains blue when stained with Giemsa stain and this blue granular, foamy appearing histiocyte has been called 'sea-blue histiocyte'.

In frozen sections of fresh tissue the vacuoles stain for fat with Sudan black B and oil red O. Niemann-Pick cells are CD-68 positive histiocytes.

        1      2   

            Diagrams of sea-blue histiocytes (1 and 2)

- Brain and eye: In brain the gyri are shrunken and sulci are widened. Diffuse neuronal involvement lead to cell death and shrinkage of the brain.

All parts of nervous system is affected.

  

    Diagram of the brain

There is vacuolation and ballooning of the neurons.

In the eye there is a retinal cherry-red spot similar to that in Tay-Sachs disease.

It is due to accumulation of sphingomyelin.

 

- Spleen, Liver, Lymphnodes and Bone marrow:  Massive accumulation of lipid-laden cells of the mononuclear phagocytic system, giving rise to huge splenomegaly (sometimes 10 times its normal weight), enlargement of liver and lymph nodes.

There is infiltration of the bone marrow.

The colour of these organs is paler due to accumulation of sphingomyelin.

                   

                Diagram of liver , lymphnodes, spleen and bone marrow

- Visceral involvement affecting the gastrointestinal tract, lungs, and tonsils have been reported.

Sea Blue Histiocytes:

The appearance of the sea blue histiocyte is nonspecific and similar histiocytes can be found in the spleen or marrow in many different hereditary and acquired conditions.

Sea blue histiocytes may be present in small numbers in normal bone marrow.

These are increased in any disorder associated with massively increased intramedullary cell destruction (Example- Chronic myelogenous leukemia.)

Sea Blue Histiocyte Syndrome:

The syndrome of splenomegaly of unknown cause with pupura secondary to hypersplenism manifested by severe thrombocytopenia has been referred to as Sea Blue Histiocyte Syndrome.

The macrophages in Sea Blue Histiocyte Syndrome stains blue in Romanowsky stained smears and yellow to tan in sections stained with Hematoxylin and eosin stain.

Positive reaction is noted with PAS and Sudan black B stains. The substance appears to be ceroid hence  "Sea Blue Histiocyte Syndrome" is also known as "Ceroid Histiocytosis".

Ceroid, a form of lipofuchsin results from the peroxidation and polymerization of unsaturated lipids.

It is present in macrophages as a light, yellow or brown autofluorescent pigment and is usually associated with lipid vacuoles.

 Points to remember about Niemann-Pick disease

  

   Sea-blue histiocytes

- A rare lysosomal storage disorder seen in infant due to deficiency of sphingomyelinase.

- There are 4 types of Niemann-Pick disease - A, B, C and D.

- The disease mainly affects liver, spleen, lymphnodes, bone marrow and central nervous system.

- The histiocytes of Niemann-Pick disease appear foamy in microscopic section. The sphingomyelin - containing histiocyte stains blue when stained with Giemsa stain and this blue granular, foamy appearing histiocyte has been called 'sea-blue histiocyte'.

 

Further reading:

Liver failure and the sea-blue histiocyte/adult Niemann-Pick disease. Case report and review of the literature.

[Sea-blue histiocyte syndrome: type B Niemann-Pick disease].

Adult Niemann-Pick disease masquerading as sea blue histiocyte syndrome: report of a case confirmed by lipid analysis and enzyme assays.

Adult Niemann-Pick disease: its relationship to the syndrome of the sea-blue histiocyte.

Biochemical, genetic and ultrastructural study of a family with the sea-blue histiocyte syndrome/chronic non-neuronopathic Niemann-Pick disease.

Case report. Pulmonary involvement in an adult male affected by type B Niemann-Pick disease.

Sea blue histiocytosis in a patient with chronic non-neuropathic Niemann-Pick disease.

Niemann-Pick diseases.

Niemann-Pick disease types C and D.

The Nova Scotia (type D) form of Niemann-Pick disease is caused by a G3097-->T transversion in NPC1.

Nova Scotia Niemann-Pick disease (type D): clinical study of 20 cases.

Niemann-Pick's disease. Clinical, biochemical and ultrastructural findings in a case of the infantile form.

Prenatal diagnosis and fetal pathology of Niemann-Pick disease.

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Dr  Sampurna Roy  MD

Consultant  Histopathologist (Kolkata - India)

 

 


 

 

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