Cirrhosis and Liver Failure: Expanding Phenotype of Acid Sphingomyelinase-Deficient Niemann-Pick Disease in Adulthood

Lidove, Olivier; Sedel, Frédéric; Charlotte, Frédéric; Froissart, Roseline; Vanier, Marie T.

doi:10.1007/8904_2014_306

Cited by 13 publications

(14 citation statements)

References 17 publications

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“…Two of the patients (39 and 40 years of age) had frank cirrhosis in the absence of any clinical symptoms of liver failure [ 34 ]. A recent case report of a patient who died at the age of 31 years from refractory encephalopathy related to cirrhosis and hepatic failure, further illustrates that hepatic tests may be normal despite evidence of extensive cirrhosis in liver biopsies [ 41 ].…”

Section: Disease Manifestations and Natural Historymentioning

confidence: 99%

Disease manifestations and burden of illness in patients with acid sphingomyelinase deficiency (ASMD)

McGovern

Avetisyan

Sanson

et al. 2017

Orphanet J Rare Dis

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108

176

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Acid sphingomyelinase deficiency (ASMD), a rare lysosomal storage disease, is an autosomal recessive genetic disorder caused by different SMPD1 mutations. Historically, ASMD has been classified as Niemann-Pick disease (NPD) types A (NPD A) and B (NPD B). NPD A is associated with a uniformly devastating disease course, with rapidly progressing psychomotor degeneration, leading to death typically by the age of 3 years, most often from respiratory failure. In contrast, the clinical phenotype and life expectancy of patients with NPD B may vary widely. Almost all patients have hepatosplenomegaly and an atherogenic lipid profile, and most patients have interstitial lung disease with progressive impairment of pulmonary function and hematologic abnormalities including cytopenias. Other common clinical manifestations include liver dysfunction, heart disease, skeletal abnormalities and growth delays. Some patients with ASMD who survive beyond early childhood have intermediate phenotypes (variant NPD B) characterized by combinations of non-neurologic and mild to severe neurologic symptoms. The physical and psychosocial burden of illness in patients with NPD B is substantial. Common symptoms include shortness of breath, joint or limb pain, abdominal pain, bleeding and bruising. The disease often leads to chronic fatigue, limited physical or social activity and difficulties in performing daily activities or work. Many patients die before or in early adulthood, often from pneumonia/respiratory failure or liver failure. Available treatments are limited to symptom management and supportive care. An enzyme replacement therapy currently in clinical development is expected to be the first treatment addressing the underlying pathology of the disease. Early diagnosis and appropriate management are essential for reducing the risk of complications. While knowledge about ASMD is evolving, more evidence about ASMD and the natural history across the disease spectrum is needed, to improve disease recognition, timely diagnosis and appropriate disease management.

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Section: Disease Manifestations and Natural Historymentioning

confidence: 99%

Disease manifestations and burden of illness in patients with acid sphingomyelinase deficiency (ASMD)

McGovern

Avetisyan

Sanson

et al. 2017

Orphanet J Rare Dis

Self Cite

108

176

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“…In the more severely affected patients, a major complication of the disease is progressive pulmonary deterioration (Schuchman and Desnick, 2014 , 2017 ). In addition, liver damage with fibrosis and cirrhosis has been recently recognized as a relevant complication of this disease (Moles et al, 2012 ; Thurberg et al, 2012 ; McGovern et al, 2013 ; Lidove et al, 2015 ; Cassiman et al, 2016 ). NPA patients have a dramatic reduction in ASMase activity and typically present <5% of its physiological activity (Smith and Schuchman, 2008 ; Vanier, 2013 ; Schuchman and Desnick, 2014 ).…”

Section: Np Diseasesmentioning

confidence: 99%

Lysosomal and Mitochondrial Liaisons in Niemann-Pick Disease

et al. 2017

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Lysosomal storage disorders (LSD) are characterized by the accumulation of diverse lipid species in lysosomes. Niemann-Pick type A/B (NPA/B) and type C diseases Niemann-Pick type C (NPC) are progressive LSD caused by loss of function of distinct lysosomal-residing proteins, acid sphingomyelinase and NPC1, respectively. While the primary cause of these diseases differs, both share common biochemical features, including the accumulation of sphingolipids and cholesterol, predominantly in endolysosomes. Besides these alterations in lysosomal homeostasis and function due to accumulation of specific lipid species, the lysosomal functional defects can have far-reaching consequences, disrupting intracellular trafficking of sterols, lipids and calcium through membrane contact sites (MCS) of apposed compartments. Although MCS between endoplasmic reticulum and mitochondria have been well studied and characterized in different contexts, emerging evidence indicates that lysosomes also exhibit close proximity with mitochondria, which translates in their mutual functional regulation. Indeed, as best illustrated in NPC disease, alterations in the lysosomal-mitochondrial liaisons underlie the secondary accumulation of specific lipids, such as cholesterol in mitochondria, resulting in mitochondrial dysfunction and defective antioxidant defense, which contribute to disease progression. Thus, a better understanding of the lysosomal and mitochondrial interactions and trafficking may identify novel targets for the treatment of Niemann-Pick disease.

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“…The hepatomegaly that develops as a result of longstanding ASMD is a significant cause of morbidity and mortality leading to cirrhosis, liver failure, and death. 2 , 3 SM accumulation occurs within the lysosomes of both macrophage-derived Kupffer cells (foam cells) and in hepatocytes where it cocrystalizes in lamellar structures with cholesterol. 3 The liver is a major organ involved in lipoprotein biogenesis, metabolism, and lipid homeostasis.…”

mentioning

confidence: 99%

“… 2 , 3 SM accumulation occurs within the lysosomes of both macrophage-derived Kupffer cells (foam cells) and in hepatocytes where it cocrystalizes in lamellar structures with cholesterol. 3 The liver is a major organ involved in lipoprotein biogenesis, metabolism, and lipid homeostasis. 4 , 5 Therefore, massive hepatocellular accumulation of SM 6 is likely to perturb normal cell function and lead to derangements in lipid homeostasis.…”

mentioning

confidence: 99%

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Clearance of Hepatic Sphingomyelin by Olipudase Alfa Is Associated With Improvement in Lipid Profiles in Acid Sphingomyelinase Deficiency

Thurberg

Wasserstein²,

Jones

et al. 2016

American Journal of Surgical Pathology

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Acid sphingomyelinase deficiency (ASMD; Niemann-Pick disease type A and B) is a lysosomal storage disorder characterized by abnormal intracellular sphingomyelin (SM) accumulation. Prominent liver involvement results in hepatomegaly, fibrosis/cirrhosis, abnormal liver chemistries, and a proatherogenic lipid profile. Olipudase alfa (recombinant human ASM) is in clinical development as an investigational enzyme replacement therapy for the non-neurological manifestations of ASMD. In a phase 1b study conducted to evaluate the safety and tolerability of within-patient dose escalation with olipudase alfa, measurement of SM levels in liver biopsies was used as a pharmacodynamic biomarker of substrate burden. Five adult patients with non neuronopathic ASMD received escalating doses of olipudase alfa every 2 weeks for 26 weeks. Liver biopsies obtained at baseline and 26 weeks after treatment were evaluated for SM storage by histomorphometric analysis, biochemistry, and electron microscopy. Biopsies were also assessed for inflammation and fibrosis, and for the association of SM levels with liver volume, liver function tests, and lipid profiles. At baseline, SM storage present in Kupffer cells and hepatocytes ranged from 9.8% to 53.8% of the microscopic field. After 26 weeks of treatment, statistically significant reductions in SM (P<0.0001) measured by morphometry were seen in 4 patients with evaluable liver biopsies. The 26-week biopsy of the fifth patient was insufficient for morphometric quantitation. Posttreatment SM levels ranged from 1.2% to 9.5% of the microscopic field, corresponding to an 84% to 92% relative reduction from baseline. Improvements in liver volume, liver function tests, and lipid profiles were also observed. This study illustrates the utility of SM assessment by liver biopsy as a pharmacodynamic biomarker of disease burden in these patients.

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Cirrhosis and Liver Failure: Expanding Phenotype of Acid Sphingomyelinase-Deficient Niemann-Pick Disease in Adulthood

Abstract: Acid sphingomyelinase-deficient Niemann-Pick disease (ASMD) includes the severe neuronopathic type A, the non-neuronopathic type B, and rare intermediate cases.

Cited by 13 publications

References 17 publications

Disease manifestations and burden of illness in patients with acid sphingomyelinase deficiency (ASMD)

Disease manifestations and burden of illness in patients with acid sphingomyelinase deficiency (ASMD)

Lysosomal and Mitochondrial Liaisons in Niemann-Pick Disease

Clearance of Hepatic Sphingomyelin by Olipudase Alfa Is Associated With Improvement in Lipid Profiles in Acid Sphingomyelinase Deficiency

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