Lysosomal Acid Lipase Deficiency Unmasked in Two Children With Nonalcoholic Fatty Liver Disease - Pediatrics
←
→
Page content transcription
If your browser does not render page correctly, please read the page content below
Lysosomal Acid Lipase Deficiency
Unmasked in Two Children With
Nonalcoholic Fatty Liver Disease
Ryan W. Himes, MD,a Sarah E. Barlow, MD, MPH,a Kevin Bove, MD,b Norma M.
Quintanilla, MD,c Rachel Sheridan, MD,b Rohit Kohli, MBBS, MSd
Lysosomal acid lipase deficiency (LAL-D) is a classic lysosomal storage abstract
disorder characterized by accumulation of cholesteryl ester and
triglyceride. Although it is associated with progressive liver injury, fibrosis,
and end-stage liver disease in children and adolescents, LAL-D frequently
presents with nonspecific signs that overlap substantially with other, more
aSection of Gastroenterology and Hepatology, Department
common, chronic conditions like nonalcoholic fatty liver disease (NAFLD), of Pediatrics and cDepartment of Pathology and
metabolic syndrome, and certain inherited dyslipidemias. We present 2 Immunology, Texas Children’s Hospital, Baylor College
of Medicine, Houston, Texas; and bDepartment of
children with NAFLD who achieved clinically significant weight reduction Pathology, Cincinnati Children’s Hospital and dSection
through healthy eating and exercise, but who failed to have the anticipated of Gastroenterology and Hepatology, Department of
improvements in aminotransferases and γ-glutamyl transferase. Liver Pediatrics, University of Cincinnati, Cincinnati, Ohio
biopsies performed for these “treatment failures” demonstrated significant Dr Himes conceptualized the report and drafted the
microvesicular steatosis, prompting consideration of coexisting metabolic initial manuscript; Drs Barlow, Bove, Quintanilla,
and Sheridan reviewed and revised drafts; Dr Kohli
diseases. In both patients, lysosomal acid lipase activity was low and LIPA conceptualized the report and revised the initial
gene testing confirmed LAL-D. We propose that LAL-D should be considered draft; and all authors approved the final manuscript
in the differential diagnosis when liver indices in patients with NAFLD fail as submitted.
to improve in the face of appropriate body weight reduction. DOI: 10.1542/peds.2016-0214
Accepted for publication Jun 7, 2016
Address correspondence to Ryan W. Himes, MD,
Lysosomal acid lipase deficiency low-density lipoprotein cholesterol 6701 Fannin St, Houston, TX 77030. E-mail: himes@
(LDL-c) and depressed high-density bcm.edu
(LAL-D) is an autosomal recessive,
single gene disorder, caused by lipoprotein cholesterol levels. In spite of PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online,
1098-4275).
mutations in LIPA (OMIM #278000) the later presentation in these patients,
resulting in lysosomal accumulation there is evidence of clinically significant Copyright © 2016 by the American Academy of
liver disease and liver-related mortality Pediatrics
of cholesteryl ester and triglyceride
among children and adolescents with FINANCIAL DISCLOSURE: Dr Himes has served on
in hepatocytes, endothelium, and
LAL-D, underscoring the importance an advisory board, speakers’ bureau, and been
myeloid-derived cells. Depending a site investigator for an epidemiology study
on ethnicity and race, prevalence of identifying affected patients.3 on lysosomal acid lipase deficiency, for Alexion
estimates range from 1:40 000 to Pharmaceuticals; Dr Barlow has served as site
The diagnosis of LAL-D, particularly in investigator for an observational database on
1:300 000.1,2 LAL-D may present in
children and adolescents, is hampered lysosomal acid lipase deficiency, for Alexion
early infancy with malabsorption and by the lack of specific clinical findings, Pharmaceuticals; Dr Kohli has served on an
catastrophic liver failure culminating the broad spectrum of disease advisory board and speakers’ bureau for Alexion
in death before 6 months of age, a Pharmaceuticals; and Drs Bove, Quintanilla, and
presentation, and significant overlap
clinical phenotype formerly called Sheridan have indicated they have no financial
with more common diseases. In relationships relevant to this article to disclose.
Wolman disease. On the other hand, primary care practices, as well as
FUNDING: No external funding.
LAL-D may present insidiously specialty clinics, features of LAL-
in children and adolescents with D, like hepatic steatosis, elevated
variable and nonspecific findings like aminotransferases, and dyslipidemia, To cite: Himes RW, Barlow SE, Bove K, et al.
hepatosplenomegaly, hepatic steatosis, are more often seen coexisting with Lysosomal Acid Lipase Deficiency Unmasked
in Two Children With Nonalcoholic Fatty Liver
elevations in aminotransferases, or a conditions like nonalcoholic fatty liver
Disease. Pediatrics. 2016;138(4):e20160214
lipid profile characterized by elevated disease (NAFLD), metabolic syndrome,
Downloaded from www.aappublications.org/news by guest on February 4, 2020
PEDIATRICS Volume 138, number 4, October 2016:e20160214 CASE REPORT
FIGURE 1
Patient 1: A, Initial liver biopsy reveals predominantly microvesicular steatosis. Macrovesicular steatosis is distributed in ~10% of hepatocytes (hematoxylin
and eosin, original magnification, ×400). B, Masson Trichrome stain highlights mild fibrous expansion of portal tracts (×100). C, Follow-up liver biopsy EM
demonstrates numerous membrane-bound lipid vesicles in hepatocytes and Kupffer cells (uranyl acetate and lead citrate).
and certain inherited dyslipidemias. PATIENT 1 After 6 months, the patient was seen
NAFLD, linked tightly to overweight in follow-up; her BMI was stable
and obesity, is estimated to An 8-year-old Hispanic girl (21.1, 93rd percentile); however,
affect 33% of adults4 and 9.6% of presented to her pediatrician after her aminotransferases remained
children5 in the general population, nuchal acanthosis nigricans was elevated (AST, 131 U/L; ALT, 171
identified during a school-wide U/L), so a diagnostic liver biopsy
making it the most common
screening program. Her weight was was performed. The biopsy revealed
chronic liver disease in the United
38.1 kg (89th percentile), height mixed micro and macrovesicular
States. Unfortunately, there are no
134.7 cm (53rd percentile), and steatosis with minimal lobular
laboratory-based diagnostic tests for
BMI 21.1 (94th percentile). Based inflammation and stage 1 lobular
NAFLD, and although routine liver
on her BMI and the presence of and portal fibrosis (Fig 1 A and
imaging such as ultrasound may be
acanthosis nigricans, screening B), interpreted as consistent with
suggestive of hepatic steatosis, its
laboratory tests were performed that NAFLD.
sensitivity is poor until steatosis
revealed the following: aspartate
exceeds 30%.6 Thus, only liver biopsy
aminotransferase (AST), 207 U/L Over the next 3 years, the patient
can discriminate between simple
(normal, 15–40 U/L); alanine participated in structured programs
hepatic steatosis, a nonprogressive
aminotransferase (ALT), 401 U/L for weight management and
or slowly progressive form of NAFLD,
(normal, 7–35 U/L); total cholesterol, ultimately reduced her BMI to the
and the more aggressive nonalcoholic
235 mg/dL (normal,was low, 0.011 nmol/punch/hour,
and confirmatory Sanger sequencing
of LIPA revealed a homozygous
mutation, c.894G>A, which alters a
splice site and leads to skipping exon
8, resulting in ~97% reduction in
enzyme activity.7
PATIENT 2
A 16-year-old white girl presented
to the emergency department with
fever and symptoms suggestive of
a urinary tract infection. She had
severe obesity, her weight was
137 kg (>99th percentile), height
160.5 cm (35th percentile), with
a resultant BMI of 53.18 (>99th
percentile).
She underwent a renal ultrasound
that confirmed pyelonephritis FIGURE 2
but also incidentally revealed Patient 2: A and B, Liver biopsy reveals predominantly microvesicular steatosis distributed in ~30%
splenomegaly. Her blood counts of the hepatocytes. Patches of macrovesicular lipid were uncommon (hematoxylin and eosin, original
magnification, ×200 and ×400). C, Masson Trichrome stain demonstrates the severe nonuniform,
suggested hypersplenism with
dense periportal, and bridging fibrosis (×20). D, EM reveals numerous membrane-bound, empty-
low platelet (78 000/μL) and appearing, lipid vesicles (lysosomes) in hepatocytes, consistent with LAL-D. The mitochondria
leukocyte (3100/μL) counts. Based are universally contracted with marked dilatation of the inner crystal spaces. This diffuse
on these initial observations, the mitochondriopathic change is not typical of LAL-D and is likely a secondary stress change related to
concomitant NAFLD (uranyl acetate and lead citrate, ×12 000).
treating inpatient service requested
laboratory tests and consulted
gastroenterology. Relevant initial
An abdominal ultrasound revealed microvesicular steatosis, minimal
test results included the following:
normal hepatic echogenicity and no lobular inflammation, and stage 3
AST, 57 U/L (normal, 15–45 U/L);
organomegaly. An abdominal MRI to 4 fibrosis (Fig 2 A, B, and C). EM
ALT, 87 U/L (normal, 7–35 U/L);
with liver elastography demonstrated revealed prevalent membrane-bound
γ-glutamyl transferase (GGT),
splenomegaly, but also reported lipid droplets, as well as diffuse
108 U/L (normal, 7–32 U/L);
a nodular liver with an increased mitochondrial abnormalities typical
LDL-c, 102 mg/dL (normal,
liver stiffness value of 7 kPa; a of metabolic stress in obese patients
45 mg/dL); and
of significant liver fibrosis.8 The of steatosis and the EM findings, the
triglycerides, 83 mg/dL (normal,
child was discharged with advice to differential diagnosis was broadened
A
obesity. This included normal her liver indices, though improved, (p.A307D) and c.1055_1057delACG
results for α-1 antitrypsin PI-type, remained elevated despite significant (p.D352del). Each has a population
antismooth muscle antibody, weight loss: AST, 33 U/L; ALT, 58 frequency ofDISCUSSION treatable; Wilson disease and LAL-D, whether for closer medical
We report 2 children with LAL-D, autoimmune hepatitis are examples supervision or for consideration of
who were initially diagnosed and of conditions routinely tested for treatment. Encouraging results from
treated for NAFLD. Their diagnoses in this context. LAL-D, which can clinical trials12–14 of recombinant
were established only after liver be ruled out with a blood-based lysosomal acid lipase, now approved
biopsies, performed 1 or more enzyme analysis, has not, up to this for use in the United States, may
years into follow-up, demonstrated point, been part of this diagnostic portend a viable therapy for this
findings atypical for NAFLD. Both evaluation in most centers. This is group of patients. We conclude,
were consistent with predominantly in spite of clinical guidelines from given the accessibility of clinical
microvesicular steatosis, suggesting Europe9 and the United States10 that laboratory-based testing for LAL-
the possibility of a competing or endorse consideration of monogenic D, availability of potential curative
coexisting diagnosis. Indeed, we causes of steatosis and utilization treatments, and the data from
believe that these patients had of noninvasive testing initially in our report, there is a supportive
both NAFLD and LAL-D, the latter children, before they undergo liver rationale for testing for LAL-D among
coming to attention only after biopsy. patients with suspected NAFLD who
additional studies were performed, do not respond to routine lifestyle
It is now recognized that LAL-D interventions.
when clinically meaningful weight may be both underdiagnosed2
reduction failed to achieve expected and associated with significant
improvements of laboratory morbidity and mortality, even among ABBREVIATIONS
parameters. In case 2, the severity pediatric and adolescent patients.
of hepatic fibrosis at such an ALT: alanine aminotransferase
In a literature review, Bernstein
early age would not be expected AST: aspartate aminotransferase
et al3 identified 135 patients with
in NASH alone. Moreover, diffuse EM: electron microscopy
LAL-D presenting after infancy; 4
mitochondrial stress changes are GGT: γ-glutamyl transferase
of 8 liver-related deaths occurred
not a component of LAL-D, but are Ig: immunoglobulin
in patients under 21 years of age
frequently observed in NASH. These LAL-D: lysosomal acid lipase
and children aged 5 to 14 years old
phenotypically similar diseases are deficiency
accounted for all 9 liver transplants
not necessarily mutually exclusive. LDL-c: low-density lipoprotein
reported. Burton et al11 presented
cholesterol
In a practical sense, the diagnostic a similar rate of pediatric liver
NAFLD: nonalcoholic fatty liver
evaluation of suspected NAFLD transplantation, 8.1%, among a group
disease
should, at a minimum, address of 49 patients with LAL-D. On this
NASH: nonalcoholic steatohep-
conditions that are potentially background, there appears to be
atitis
life-threatening or those that are value in identifying individuals with
POTENTIAL CONFLICT OF INTEREST: Dr Himes has served on an advisory board, speakers’ bureau, and been a site investigator for an epidemiology study on
lysosomal acid lipase deficiency, for Alexion Pharmaceuticals; Dr Barlow has served as site investigator for an observational database on lysosomal acid lipase
deficiency, for Alexion Pharmaceuticals; Dr Kohli has served on an advisory board and speakers’ bureau for Alexion Pharmaceuticals; and Drs Bove, Quintanilla,
and Sheridan have indicated they have no potential conflicts of interest to disclose.
REFERENCES
1. Reiner Ž, Guardamagna O, Nair D, disease: review of the findings Prevalence of fatty liver in children
et al. Lysosomal acid lipase deficiency- in 135 reported patients with an and adolescents. Pediatrics.
-an under-recognized cause of underdiagnosed disease. J Hepatol. 2006;118(4):1388–1393
dyslipidaemia and liver dysfunction. 2013;58(6):1230–1243
Atherosclerosis. 2014;235(1):21–30 6. Saadeh S, Younossi ZM, Remer EM, et
4. Szczepaniak LS, Nurenberg P, al. The utility of radiological imaging
2. Scott SA, Liu B, Nazarenko I, et al. Leonard D, et al. Magnetic resonance in nonalcoholic fatty liver disease.
Frequency of the cholesteryl ester spectroscopy to measure hepatic Gastroenterology. 2002;123(3):745–750
storage disease common LIPA E8SJM triglyceride content: prevalence
mutation (c.894G>A) in various racial of hepatic steatosis in the general 7. Aslanidis C, Ries S, Fehringer P, Büchler
and ethnic groups. Hepatology. population. Am J Physiol Endocrinol C, Klima H, Schmitz G. Genetic and
2013;58(3):958–965 Metab. 2005;288(2):E462–E468 biochemical evidence that CESD and
Wolman disease are distinguished by
3. Bernstein DL, Hülkova H, Bialer MG, 5. Schwimmer JB, Deutsch R, Kahen residual lysosomal acid lipase activity.
Desnick RJ. Cholesteryl ester storage T, Lavine JE, Stanley C, Behling C. Genomics. 1996;33(1):85–93
Downloaded from www.aappublications.org/news by guest on February 4, 2020
e4 HIMES et al8. Xanthakos SA, Podberesky DJ, Serai The diagnosis and management of lipase in patients with cholesteryl
SD, et al. Use of magnetic resonance non-alcoholic fatty liver disease: ester storage disease. Hepatology.
elastography to assess hepatic fibrosis practice guideline by the American 2013;58(3):950–957
in children with chronic liver disease. Gastroenterological Association, 13. Burton BK, Balwani M, Feillet F, et al.
J Pediatr. 2014;164(1):186–188 American Association for the Study of A Phase 3 Trial of Sebelipase Alfa in
9. Vajro P, Lenta S, Socha P, et al. Liver Diseases, and American College Lysosomal Acid Lipase Deficiency.
Diagnosis of nonalcoholic fatty liver of Gastroenterology. Gastroenterology. N Engl J Med. 2015;373(11):
disease in children and adolescents: 2012;142(7):1592–1609 1010–1020
position paper of the ESPGHAN 11. Burton BK, Deegan PB, Enns GM, et 14. Valayannopoulos V, Malinova V, Honzík
Hepatology Committee. J Pediatr al. Clinical features of lysosomal T, et al. Sebelipase alfa over 52 weeks
Gastroenterol Nutr. 2012;54(5):700–713 acid lipase deficiency. J Pediatr reduces serum transaminases,
10. Chalasani N, Younossi Z, Lavine JE, Gastroenterol Nutr. 2015;61(6):619–625 liver volume and improves serum
et al; American Gastroenterological 12. Balwani M, Breen C, Enns GM, et al. lipids in patients with lysosomal
Association; American Association Clinical effect and safety profile of acid lipase deficiency. J Hepatol.
for the Study of Liver Diseases. recombinant human lysosomal acid 2014;61(5):1135–1142
Downloaded from www.aappublications.org/news by guest on February 4, 2020
PEDIATRICS Volume 138, number 4, October 2016 e5Lysosomal Acid Lipase Deficiency Unmasked in Two Children With
Nonalcoholic Fatty Liver Disease
Ryan W. Himes, Sarah E. Barlow, Kevin Bove, Norma M. Quintanilla, Rachel
Sheridan and Rohit Kohli
Pediatrics 2016;138;
DOI: 10.1542/peds.2016-0214 originally published online September 13, 2016;
Updated Information & including high resolution figures, can be found at:
Services http://pediatrics.aappublications.org/content/138/4/e20160214
References This article cites 14 articles, 1 of which you can access for free at:
http://pediatrics.aappublications.org/content/138/4/e20160214#BIBL
Subspecialty Collections This article, along with others on similar topics, appears in the
following collection(s):
Gastroenterology
http://www.aappublications.org/cgi/collection/gastroenterology_sub
Hepatology
http://www.aappublications.org/cgi/collection/hepatology_sub
Permissions & Licensing Information about reproducing this article in parts (figures, tables) or
in its entirety can be found online at:
http://www.aappublications.org/site/misc/Permissions.xhtml
Reprints Information about ordering reprints can be found online:
http://www.aappublications.org/site/misc/reprints.xhtml
Downloaded from www.aappublications.org/news by guest on February 4, 2020Lysosomal Acid Lipase Deficiency Unmasked in Two Children With
Nonalcoholic Fatty Liver Disease
Ryan W. Himes, Sarah E. Barlow, Kevin Bove, Norma M. Quintanilla, Rachel
Sheridan and Rohit Kohli
Pediatrics 2016;138;
DOI: 10.1542/peds.2016-0214 originally published online September 13, 2016;
The online version of this article, along with updated information and services, is
located on the World Wide Web at:
http://pediatrics.aappublications.org/content/138/4/e20160214
Pediatrics is the official journal of the American Academy of Pediatrics. A monthly publication, it
has been published continuously since 1948. Pediatrics is owned, published, and trademarked by
the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk Grove Village, Illinois,
60007. Copyright © 2016 by the American Academy of Pediatrics. All rights reserved. Print ISSN:
1073-0397.
Downloaded from www.aappublications.org/news by guest on February 4, 2020You can also read
