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 Table of Contents  
Year : 2021  |  Volume : 1  |  Issue : 3  |  Page : 193-195

Fatty liver in a child: Looking beyond nonalcoholic fatty liver disease

1 Department of Gastroenterology, Regency Health, Kanpur, India
2 Department of Pediatrics, Regency Health, Kanpur, India

Date of Submission01-May-2021
Date of Decision22-May-2021
Date of Acceptance09-Aug-2021
Date of Web Publication31-Aug-2021

Correspondence Address:
Dr. Jaya Agarwal
Regency Health, Kanpur
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ipcares.ipcares_133_21

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Background: Cholesteryl ester storage disease (CESD) is a rare genetic condition caused due to deficiency of the enzyme lysosomal acid lipase (LAL). The condition is characterized by poor growth, dyslipidemia, and fatty liver. There is currently no data on the prevalence of this condition in the Indian population. It can easily be confused with nonalcoholic fatty liver disease (NAFLD). Clinical Description: We report the case of 4-year-old boy who presented to a pediatrician with poor growth. He was born to a nonconsanguineous couple with an uneventful perinatal period. The parents felt that the child was not growing well for 2 years. At presentation, he was hemodynamically stable and anthropometrically normal. He had pallor and hepatosplenomegaly. Rest of the examination was within normal limits. Preliminary workup showed persistent transaminitis. Further evaluation revealed dyslipidemia and hepatic steatosis in the liver fibroscan. The workup for other common causes of chronic liver disease was negative, and the clinical features were suggestive of CESD. Enzyme testing is required for the confirmation of this diagnosis, which was not available at our center or any outsourcing labs. Management: The diagnosis of cholesteryl ester storage disease was confirmed by next-generation sequencing (NGS) with multigene panel targeting the condition. At present, this child is in process to get registered for enzyme replacement therapy. Conclusions: LAL deficiency is a rare and difficult to diagnose entity. It should be considered as a differential diagnosis in children presenting with chronic liver disease with dyslipidemia and in lean children with NAFLD. For rare disorders where enzyme testing is not available, NGS can be utilized for diagnosis.

Keywords: Cholesteryl ester storage disease, dyslipidemia, lysosomal acid lipase deficiency, nonalcoholic fatty liver disease

How to cite this article:
Agarwal J, Hasan A, Mehrotra M, Kapoor R. Fatty liver in a child: Looking beyond nonalcoholic fatty liver disease. Indian Pediatr Case Rep 2021;1:193-5

How to cite this URL:
Agarwal J, Hasan A, Mehrotra M, Kapoor R. Fatty liver in a child: Looking beyond nonalcoholic fatty liver disease. Indian Pediatr Case Rep [serial online] 2021 [cited 2021 Sep 26];1:193-5. Available from: http://www.ipcares.org/text.asp?2021/1/3/193/325079

Lysosomal acid lipase (LAL) is an enzyme involved in the metabolism and breakdown of cholesteryl esters and triglycerides. Lack of LAL leads to the accumulation of these substrates in the lysosomes of different tissues.[1] The most commonly affected organs and systems in which intracellular accumulation occurs are the liver, spleen, adrenal glands, hematopoietic system, vascular endothelium, intestines, and lymph nodes.[2] Cholesteryl ester storage disease (CESD) is a progressive metabolic liver disease due to LAL deficiency (LAL-D) caused by biallelic mutations in the lipase A, lysosomal acid type (LIPA) gene located on chromosome 10q23.2-23.3.1.[3] The inheritance is autosomal recessive. Storage of cholesteryl ester and triglycerides in hepatocytes and hepatic macrophages results in hepatomegaly, microvesicular steatosis, cirrhosis, dyslipidemia, and premature atherosclerosis.[4] The clinical phenotype depends on the type of LIPA gene mutation and the severity of enzyme deficiency.

CESD is a rare condition. However, it is also quite likely that many Indian children with fatty liver do not get recognized or are misdiagnosed as nonalcoholic fatty liver disease (NAFLD) or cryptogenic liver disease, since getting the enzymatic assay is a challenging prospect and genetic testing is expensive. We report a child with fatty liver who was eventually diagnosed as CESD. The aim of sharing this case is to sensitize clinicians to think beyond the usual causes of fatty liver.

  Clinical Description Top

A 4-year-old boy presented to our institute's liver clinic with parental concerns regarding poor growth and abdominal distension noticed for 2 years. The child was born to a nonconsanguineous couple at term, with an average birth weight. He had an uneventful perinatal period and was apparently growing well till 2 years of age. Since then, the parents felt that his growth had started faltering. They also noticed that his abdomen had gradually started to appearing increasingly distended. There was no history of abdominal pain, jaundice, swelling of the feet, blood in the vomitus or stools or from any other site, or diarrhea. The history was unremarkable; the child had not received any blood transfusion. Family history of similar illness in any other members or unexplained childhood death was absent. All developmental milestones had been attained appropriately and the child was immunized for age. His diet was adequate and diverse and intake of calories and proteins was age-appropriate. The child had undergone some baseline investigations before presentation and was detected to have persistently elevated transaminases. The diagnosis had not been ascertained which was the cause for referral.

At presentation, he was hemodynamically stable and alert. His height was 102 cm (Z score - 0.32) and weight was 14 kg (Z score - 1.23). There was no icterus or stigmata of chronic liver disease on general physical examination. The abdomen was uniformly distended. The liver was firm and palpable 4 cm below the costal margin in the midclavicular line. The spleen was firm and enlarged 2 cm below the left costal margin. There were no ascites. The rest of the systemic examination was normal. The clinical features in the setting of persistently elevated transaminases were suggestive of a chronic liver disorder (chronic persistent hepatitis). The differential diagnoses that were considered included Wilson's disease, viral hepatitis, and the possibility of storage disorders with hepatosplenomegaly, normal development, and onset in early childhood, such as nonneuronopathic Gaucher's disease, glycogen storage disorders, or LAL deficiency.

The salient laboratory investigations indicating liver involvement were elevated serum alanine transaminase (114 U/L) and aspartate transaminase (186 U/L). The lipid profile was deranged; raised serum triglyceride levels (515 mg/dl) and very low-density lipoprotein (83 mg/dl), normal total cholesterol (188 mg/dl) and low-density lipoprotein (74 mg/dl) levels and low high-density lipoprotein levels (30 mg/dl). Blood sugar levels, creatinine phosphokinase, and serum uric acid were normal. The absence of this biochemical triad and the presence of splenomegaly ruled out glycogen storage disorder. An abdominal ultrasound showed an enlarged liver (131 mm span) with increased echogenicity, splenomegaly, and a normal portal vein diameter of 6 mm. Thus, portal hypertension was also excluded. Common causes of chronic liver disease such as Wilson's disease, autoimmune hepatitis, and viral hepatitis were ruled out by the absence of abnormal serum ceruloplasmin, elevated autoimmune markers, and positive viral hepatitis markers, respectively. A Fibroscan (liver elastography) ruled out cirrhosis by detecting normal liver stiffness (4.5 kPa). However, the controlled attenuation parameter of 255 dB/m was suggestive of hepatic steatosis. The clinical phenotype of hepatosplenomegaly, dyslipidemia, and a fatty liver was indicative of a lipid storage disorder, and the possibility of CESD was considered. Confirming our suspicions was a challenge. The LAL enzyme assay is unavailable in India, and there were logistic issues in arranging transport of the sample abroad. A liver biopsy could have provided supportive evidence if lipid deposition had been detected, however, we were unable to convince the parents to give consent for a liver biopsy. Therefore, we decided to proceed with genetic testing.

  Management and Outcome Top

Next-generation sequencing (NGS)-based multigene panel testing for the CESD-related genes was conducted. Targeted gene capture using a custom capture kit was followed by sequencing performed by the Illumina sequencing platform (Illumina Inc., San Diego, California, US). A homozygous silent variation in exon 8 of the LIPA gene (chr10:G.90982268C>T) was detected. These results in the synonymous amino acid change of glutamine at codon 298 proximal to the donor splice site (p.Gln298[=]). This observed variant lies in the alpha/beta hydrolase fold domain of the LIPA protein and has been previously reported in multiple patients affected with CESD[5],[6] in the ClinVar database, 1000 Genomes, and Exome Aggregation Consortium databases. The in silico prediction of the variant is damaging by Mutation Taster 2. On confirmation of the diagnosis of CESD, the parents were counseled and supportive management started. At present, the child is in the process of getting registered for enzyme replacement therapy (ERT) with commercially available sebelipase alfa.

  Discussion Top

LAL-D causes progressive liver disease. However, it is often mistaken for NAFLD due to the lipid deposition in the liver and the difficulties in establishing diagnosis due to lack of awareness among clinicians, coupled with the challenges of confirming diagnosis. The age of presentation is highly variable; some patients are diagnosed in childhood, while others remain undiagnosed until adulthood. LAL-D can have a wide spectrum of clinical presentations. The most severe form is Wolman disease which has LIPA activity <1%. Its clinical manifestations include infantile acute liver failure (usually presenting under 4 months of age), hepatosplenomegaly, failure to thrive, and ascites. Investigations reveal microvesicular steatosis and adrenal calcification.[7]

CESD presents in infancy, childhood, or adulthood, depending on the residual in vitro LAL activity, which typically ranges from 1% to 12% of normal. The progressive accumulation of lysosomal cholesteryl ester and triglyceride leads to the characteristic liver pathology, fibrosis, micronodular cirrhosis, and ultimately to liver failure.[8] Affected individuals usually present with a more indolent course, poor growth (what was interesting to note in this case was that though one of the presenting complaints was the parent's perception that the child was growing poorly, his anthropometry was normal), unexplained hepatosplenomegaly, elevated transaminases, fatty liver, progressive, and/or unexplained chronic liver disease. The characteristic lipid profile is elevated serum LDL-cholesterol and triglycerides, with normal to low HDL-cholesterol concentrations. The causes of premature mortality are liver failure and/or accelerated atherosclerotic disease secondary to chronic hyperlipidemia. These phenotypic features (hepatic enlargement, transaminitis, and deranged lipid profile) of LAL-D are nonspecific and also observed in NAFLD, explaining the numbers of cases that are misdiagnosed or underdiagnosed. Liver histopathology is characterized by enlarged lipid-laden hepatocytes and vacuolated Kupffer cells, typical of microvesicular steatosis, which may also be mistaken for nonalcoholic steatohepatitis. The combination of fatty liver, elevated transaminases, and dyslipidemia can also mimic metabolic syndrome. We did not consider this as a differential in our patient as he was neither obese nor in the appropriate age range.

Confirmation of CESD is established by an enzyme-based biochemical blood test that demonstrates low or absent levels of LAL. This is available as a dried blood spot test in some countries, but not in India. NGS-based multigene panel testing identifies mutations in CESD-related genes. The most commonly inherited defect is the E8SJM (c.894G > A) mutation, which is found in more than 50% of affected children and adults with LAL-D, as in our case.[9] Although genotype/phenotype correlations are limited, E8SJM homozygotes typically have early-onset, slowly progressive disease. No therapeutic options were available until as recent as late 2015, when sebelipase alfa, a recombinant human LAL protein was approved as ERT for LAL-D.[1],[10] Supportive treatment includes cholestyramine, statins, and ultimately, liver transplantation.

There is a paucity of community-based prevalence data on CESD from India and it is possible that cases are being missed. The diagnosis of CESD requires a high index of clinical suspicion. Given that there is overlap of clinical picture with NAFLD and metabolic syndrome, ERT with sebelipase alpha is now available, investigation for LAL-D should be included in second-line investigations more proactively. Awareness about this entity in Indian context combined with availability of efficient diagnostic tools should facilitate the correct diagnosis and institution of early therapy.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

  References Top

Balwani M, Breen C, Enns GM, et al. Clinical effect and safety profile of recombinant human lysosomal acid lipase in patients with cholesteryl ester storage disease. Hepatology 2013;58:950-7.  Back to cited text no. 1
Grabowski G, Charnas L, Du H. Acid lipase deficiency: Wolman disease and cholesteryl ester storage disease. In: Beaudet A, Vogelstein B, Kinzler K, Antonarakis S, Ballabio A, editors. The Metabolic and Molecular Basis of Inherited Metabolic Disease. 8th ed. New York: McGraw-Hill; 2012.  Back to cited text no. 2
Valayannopoulos V, Mengel E, Brassier A, et al. Lysoso-mal acid lipase deficiency: Expanding differential diagnosis. Mol Genet Metab. 2017;120:62-6.  Back to cited text no. 3
Bernstein DL, Hülkova H, Bialer MG, et al. Cholesteryl ester storage disease: Review of the findings in 135 reported patients with an underdiagnosed disease. J Hepatol 2013;58:1230-43.  Back to cited text no. 4
Fasano T, Pisciotta L, Bocchi L, et al. Lysosomal lipase deficiency: Molecular characterization of eleven patients with Wolman or cholesteryl ester storage disease. Mol Genet Metab 2012;105:450-6.  Back to cited text no. 5
National Center for Biotechnology Information. Available from: https://www.ncbi.nlm.nih.gov/clinvar/variation/VCV000203361.14. [Last accessed on 2021 May 01].  Back to cited text no. 6
Aslanidis C, Ries S, Fehringer P, et al. Genetic and biochemical evidence that CESD and Wolman disease are distinguished by residual lysosomal acid lipase activity. Genomics 1996;33:85-93.  Back to cited text no. 7
Carter A, Brackley SM, Gao J, et al. The global prevalence and genetic spectrum of lysosomal acid lipase deficiency: A rare condition that mimics NAFLD. J Hepatol 2019;70:142-50.  Back to cited text no. 8
Muntoni S, Wiebusch H, Jansen-Rust M, et al. Prevalence of cholesteryl ester storage disease. Arterioscler Thromb Vasc Biol 2007;27:1866-8.  Back to cited text no. 9
Jones SA, Rojas-Caro S, Quinn AG, et al. Survival in infants treated with sebelipase Alfa for lysosomal acid lipase deficiency: An open-label, multicenter, dose-escalation study. Orphanet J Rare Dis 2017;12:25.  Back to cited text no. 10


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