Introduction

Niemann-Pick disease (NPD) is a lysosomal storage disease, with a deficiency in enzymes involved in the degradation (break-down) of lipids and other fatty products, particularly the lipids sphingomyelin and cholesterol. The inability to break down these lipids results in accumulation in various tissues, causing the progressive dysfunction of organs and many severe clinical manifestations.¹ 

NPD is classified into three primary groups: NPD types A, B, and C. These three groups were all present with different clinical manifestations and underlying mechanisms.

While this disease has severe implications in other parts of the body, namely the brain and lungs, it is important to understand how it affects the function of the liver, due to its central role in metabolism and homeostasis.^2,3 

In NPD, the extent of the liver involvement significantly affects the progression of the disease and causes severe health concerns. 

Niemann-Pick disease

As previously mentioned, NPD is classified in three primary subtypes: Types A, B, and C. 

Niemann-Pick disease type A and B

Types A and B NPD are caused by mutations in SMPD1 genes encoding for the enzyme acid sphingomyelinase (ASM), resulting in deficiency of ASM and thus accumulation of sphingomyelin in various tissues. More than 180 such mutations have been identified, with each mutation leading to different levels of severity.⁶ 

ASM is essential for the breakdown of the lipid sphingomyelin, a crucial component of cell membranes, into ceramide and phosphorylcholine, and is important for the regulation of function and homeostasis of our cells.⁴ 

Today, NPD Types A and B are also broadly referred to as acid sphingomyelinase deficiency (ASMD). 

The most common mode of inheritance of NPD Types A and B is autosomal recessive, meaning that two dysfunctional copies of the ASM-encoding gene must be inherited, one from each parent, in order to develop the disease. However, there is evidence that some individuals who are carriers (with only one dysfunctional copy) may exhibit mild symptoms of the disease.⁵

The most severe form of ASMD, NPD Type A is a progressive neurodegenerative disease that shows up in the first few months of age and often leads to death in early childhood.⁸ Patients of Type A NPD have a complete loss of ASM activity.⁷ 

On the other hand, NPD Type B patients have shown measurable amounts of residual ASM activity (~2-10%).⁷ As such, Type B has a milder phenotype and is less severe, often presenting later in childhood and adolescence, with patients frequently surviving to adulthood.⁶ Unlike Type A, Type B NPD has minimal neurological involvement, with the primary affected organs being the liver, lungs, spleen, and bone.⁹ 

Intermediate patients of Type A/B NPD have been reported, with clinical manifestations being closer to that of Type A despite the later onset of the disease, or manifestations similar to Type B but with the involvement of the brain.¹⁰

Niemann-Pick disease type C

Unlike Types A and B, NPD Type C is caused by mutations in the NPC1/2 genes, which are primarily responsible for the transport of cholesterol within cells, leading to the build-up of cholesterol within lysosomes.¹¹ 

NPD Type C is also autosomal recessive and may present at any age, most commonly between the ages of 2 and 15.12 Depending on the age of onset, the severity and presentation of the disease may be different.11 Organs implicated in NPC Type C are the liver, spleen, lungs, bone, and brain.¹³

Symptoms of Niemann-Pick disease

Given the many types of NPD, the symptoms and manifestations of the disease may vary significantly, depending on the type of NPD and the age of onset. 

Here are some signs to watch out for:^10,12,14

• Slurred or slowed speech
• Loss of acquired motor skills
  • Muscle weakness, loss of muscle control, difficulty with coordination and balance, stiffness
  • In infants, this may present as delays in developmental milestones like rolling over, sitting, standing, etc
• Hepatosplenomegaly: the abnormal enlargement of the liver and spleen
  • Can cause recurrent bleeding, and ultimately liver and spleen dysfunction
• Vomiting and diarrhoea
• Poor weight gain and growth, particularly in infants and young children
• Cherry-red spot in the eyes
• Recurring respiratory infections, which may cause pneumonia
• Increasing occurrence of seizures
• Children may have sleeping disorders, waking frequently and crying for hours
• Difficulty breathing
• Joint pain
• Abnormal bruising
• Chronic exhaustion and low energy levels
• Difficulty swallowing
• Progressive cognitive decline
• Vision problems, including difficulty controlling eye movements
• Yellowing of the skin and eyes

How is it diagnosed? 

Imaging techniques 

In order to assess the severity of liver involvement and the involvement of other organs, imaging is important. Non-invasive imaging methods like ultrasound help with the primary identification of hepatosplenomegaly. Subsequent MRI (Magnetic Resonance Imaging) and CT (Computed Tomography) scans provide detailed images of the liver and spleen as well as providing quantitative measurements of organ volume, allowing the identification of any abnormalities in the structure of the organs.

Using a combination of imaging techniques on not only the spleen and liver, but any other organs implicated in the disease such as the brain and lungs, is useful with evaluating NPD.¹⁵ 

Genetic testing and biomarkers

Blood samples are drawn and enzyme assays are performed to measure the level of ASM enzyme activity in white blood cells for NPD Types A and B. In the case of NPD Type C, a small skin sample is taken and stained with a special stain ‘filipin’ to measure the enzyme activity. Blood samples are also taken to measure the level of cholesterol in the blood, as abnormal levels are characteristic of the disease.¹ 

Genetic testing helps with further evaluating the disease, by identifying any causative mutations in the SMPD1, NPC1 or NPC2 genes.¹ 

Liver biopsy

By examining a small sample of liver tissue, a liver biopsy is considered the standard for assessing extent of liver damage and identifying more specific signs of the disease, including inflammation, scarring (known as fibrosis), and the presence of fat-filled cells known as foam cells. Despite the invasive nature of a liver biopsy, it is crucial in guiding treatment decisions and monitoring the progression of the disease.¹⁶ 

Management and treatment of Niemann-Pick disease

Enzyme-Replacement Therapy (ERT)

Considered to be the best therapeutic option for Type B NPD, supplementing the deficient ASM enzyme by introducing the human recombinant enzyme Olipudase α. This treatment is targeted to alleviating the systematic aspects of the disease, and has shown success with this in both adults and children - reducing liver and spleen volumes, improving lipid levels, and improved lung capacities.^17,18 

Organ transplantation

Given the frequent involvement of the liver and its contribution to mortality in NPD Types A and B, liver transplantation is considered as a therapeutic option in severe cases. Its success as a therapeutic option has been demonstrated in the past in patients.

However, it is important to note that given that the symptoms of this disease are rarely concentrated in only one organ, and replacing the damaged liver may not prevent recurrence of the disease in other parts of the body, not to mention the significant risks that often come with organ transplantation. 

Substrate-Reduction Therapy (SRT)

Only one disease-modifying drug, Miglustat, has been approved for the treatment of Type C NPD. Approved in the European Union, Canada and Japan, but not the United States, the drug targets the neurological complications of the disease by reducing lipid accumulation in the lysosomes of the central nervous system. However, while this method has shown success, its accompanying side effects on the gastrointestinal system have limited its use and still need to be addressed.¹⁹

Symptomatic and supportive care

Supportive care and therapy remains the primary treatment method for NPD. Potentially involved organs are regularly assessed to ensure that function is maintained and to ensure symptom-targeting therapy can begin in a timely manner, and blood lipid levels are kept low with statin. Mobility aids and rehab programmes help with improving and maintaining mobility. Maintaining a balanced healthy diet with sufficient protein intake and cutting down on fatty foods is also important.

Summary

Niemann-Pick Disease (NPD) is a complex lysosomal storage disorder that impacts multiple organ systems due to the accumulation of lipids in various tissues. Liver involvement in the disease can lead to significant health concerns and is among the leading causes of mortality in NPD.

As such, it is incredibly important that we have a good understanding of the dysfunction of the liver in this disease. Accurate and timely diagnosis and management is crucial, as the disease can be rapidly progressive. While management of the disease is complicated, continued research and advancements in NPD are optimistic for more targeted and improved treatments.