Do your patients with Zellweger spectrum disorders have liver involvement?

Liver dysfunction is nearly universal in Zellweger spectrum disorders¹

ZELLWEGER SPECTRUM DISORDERS

Zellweger spectrum disorders are characterized by defective peroxisome biogenesis and multiorgan manifestations.¹

LIVER INVOLVEMENT

Regardless of disease severity, liver dysfunction is a common consequence of Zellweger spectrum disorders, but it may be treatable.¹

Are you monitoring the liver function of patients with Zellweger spectrum disorders?

MULTISYSTEMIC COMPLICATIONS OF ZELLWEGER SPECTRUM DISORDERS

Zellweger spectrum disorders are multiorgan diseases that occur in approximately 1 in 50,000 live births. Zellweger spectrum disorders range from severe (Zellweger syndrome), to intermediate (neonatal adrenoleukodystrophy), to least severe (infantile Refsum disease) phenotypes, and can lead to multisystemic complications that vary based on disease severity.¹

HEPATIC

Liver dysfunction is a common consequence of Zellweger spectrum disorders, yet the liver may not be monitored.^1,2 Nearly 80% of patients with Zellweger syndrome develop hepatomegaly with severe fibrosis as the disease progresses.³ In some cases of Zellweger spectrum disorders, liver dysfunction can be less severe or manifest later in life, pointing to the importance of routine liver monitoring.^1,2,4,5

FAILURE TO THRIVE

Bile acids break down fat-soluble vitamins, aiding in their absorption.⁶ When bile acids are deficient, fat-soluble vitamins are not absorbed properly, often resulting in delayed growth.¹

HEARING

Individuals with Zellweger spectrum disorders frequently have hearing loss.¹

VISION

Retinal dystrophy and optic nerve pathology often lead to vision loss.¹

CENTRAL AND PERIPHERAL NERVOUS SYSTEMS

Nervous system involvement can cause dysfunction in cognition, behavior, and motor abilities.¹

SKELETAL AND DENTAL

Bone and dental abnormalities are often present.¹

ADRENAL INSUFFICIENCY

Progressive adrenal insufficiency can occur in Zellweger spectrum disorders.¹

RENAL

Renal dysfunction affects children with Zellweger spectrum disorders.¹

COGNITIVE / INTELLECTUAL DEVELOPMENT

Central nervous system dysfunction can result in intellectual developmental delay.¹

MECHANISM OF DISEASE

The peroxisome is an organelle with diverse metabolic and physiologically critical functions, including the final steps of bile acid synthesis.^7,8 Zellweger spectrum disorders are comprised of a set of autosomal recessive peroxisomal biogenesis disorders, ranging in levels of severity. The hallmark feature of Zellweger spectrum disorders is defective peroxisome biogenesis caused by mutations in PEX gene family members.¹

Absent or deficient peroxisomes prevent the essential final steps of bile acid synthesis from occuring, leading to complications in multiple organ systems—including the liver.^1,8 The resulting bile acid deficiencies and the accumulation of atypical bile acid metabolites can cause chronic liver injury in Zellweger spectrum disorders.^9,10

Peroxisome defects cause hepatotoxic atypical bile acid accumulation⁴

Abbreviations: CDCA, chenodeoxycholic acid; DHCA, dihydroxycholestanoic acid; THCA, trihydroxycholestanoic acid.

DISEASE MANAGEMENT

Zellweger spectrum disorders affect multiple organ systems and vary in severity and rates of disease progression. Clinical evaluations are recommended as soon as a Zellweger spectrum disorder is diagnosed to establish the extent of disease—particularly involvement of the liver—and should be repeated routinely to monitor progression. Current management of disease complications is palliative, outlined in the table below.¹

FOCUS ON THE LIVER

Liver dysfunction is almost universal in Zellweger spectrum disorders and should be evaluated in all patients.¹ Currently, management of the liver, as with other manifestations of Zellweger spectrum disorders, is largely palliative. Vitamin K supplementation is recommended for patients with Zellweger spectrum disorders to help support liver function.¹ Levels of coagulation factors should be monitored as coagulopathy can accompany hepatic dysfunction.^1,11

Historically, ursodeoxycholic acid (UDCA) has been used to treat liver-related symptoms of bile acid metabolism.^1,12 While UDCA can improve bile flow, UDCA is not a farnesoid X receptor (FXR) agonist and the negative feedback signals necessary to regulate primary bile acid synthesis are absent.¹³ Thus, UDCA does not prevent the accumulation of atypical bile acids such as dihydroxycholestanoic acid (DHCA) and trihydroxycholestanoic acid (THCA), which can lead to liver injury in Zellweger spectrum disorders.^5,9,13 Newly approved therapies may help address hepatic management challenges in Zellweger spectrum disorders.¹

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References: 1. Braverman NE, Raymond GV, Rizzo WB, et al. Peroxisome biogenesis disorders in the Zellweger spectrum: an overview of current diagnosis, clinical manifestations, and treatment guidelines. Mol Genet Metab. 2016;117(3):313-321. doi:10.1016/j.ymgme.2015.12.009. 2. Berendse K, Engelen M, Ferdinandusse S, et al. Zellweger spectrum disorders: clinical manifestations in patients surviving into adulthood. J Inherit Metab Dis. 2016;39(1):93-106. doi:10.1007/s10545-015-9880-2. 3. Wanders RJA, Heymans HSA, Schutgens RBH, Barth PG, van den Bosch H, Tager JM. Peroxisomal disorders in neurology. J Neurol Sci. 1988;88:1-39. 4. Baes M, Van Veldhoven PP. Hepatic dysfunction in peroxisomal disorders. Biochim Biophys Acta. 2016;1863(5):956-970. doi:10.1016/j.bbamcr.2015.09.035. 5. Klouwer FCC, Berendse K, Ferdinandusse S, Wanders RJA, Engelen M, Poll-The BT. Zellweger spectrum disorders: clinical overview and management approach. Orphanet J Rare Dis. 2015;10:151. doi:10.1186/s13023-015-0368-9. 6. Clayton PT. Disorders of bile acid synthesis. J Inherit Metab Dis. 2011;34(3):593-604. doi:10.1007/s10545-010-9259-3. 7. Smith JS, Aitchison JD. Peroxisomes take shape. Nat Rev Mol Cell Biol. 2013;14(12):803-817. doi:10.1038/nm3700. 8. Sundaram SS, Bove KE, Lovell MA, Sokol RJ. Mechanisms of disease: inborn errors of bile acid synthesis. Nat Clin Pract Gastroenterol Hepatol. 2008;5(8):456-468. doi:10.1038/ncpgasthep1179. 9. Bove KE, Heubi JE, Balistreri WF, Setchell KDR. Bile acid synthetic defects and liver disease: a comprehensive review. Pediatr Dev Pathol. 2004;7(4):315-334. doi:10.1007/s10024-002-1201-8. 10. Setchell KDR, Heubi JE. Defects in bile acid biosynthesis–diagnosis and treatment. J Pediatr Gastroenterol Nutr. 2006;43(1):S17-S22.

Liver dysfunction is nearly universal in Zellweger spectrum disorders1