Differential Diagnosis of a Patient With Lysosomal Acid Lipase Deficiency

A Case Report

Ashwin S. Akki, MD, PhD; Sun M. Chung, MD; Bryan J. Rudolph, MD, MPH; Michelle R. Ewart, MD

Disclosures

Lab Med. 2018;49(4):377-384. 

In This Article

Case Report

Clinical History

A 12-year-old boy of Mexican origin and Hispanic ethnicity had first presented for treatment in 2010, at the age of 6 years, when he was admitted to a hospital for exacerbation of asthma. The results of a blood test performed at that time revealed elevated low-density lipoprotein cholesterol (LDL-C) and high transaminase and alkaline phosphatase (ALP) levels (Table 1). The body mass index (BMI) of the boy was 19.7; this value is above the 95th percentile for his age. After initial work-up, common metabolic disorders (ie, Wilson disease, hemochromatosis, and alpha-1 antitrypsin deficiency), as well as viral and autoimmune hepatitis, were excluded. The patient was seen again in March 2012, at which time his BMI was 22 (>95th percentile) and his alanine aminotransferase (ALT), aspartate aminotransferase (AST), and ALP levels remained high. Dietary and lifestyle modifications were recommended; by following them, the patient lost approximately 1.4 kg during the next few months. Subsequently, the patient was followed up by a pediatric gastroenterologist once every 6 months over the next few years, during which time the liver enzymes, LDL-C, and total cholesterol of the patient continued to be elevated (Table 1).

In August 2016, the patient was referred to the Fatty Liver Center at our hospital, The Children's Hospital at Montefiore, Bronx, NY, for additional management. His BMI at this time was 26.9 (>95th percentile), and his liver enzyme, LDL-C, and total cholesterol remained elevated. Physical examination revealed hepatomegaly, and an abdominal ultrasound showed increased hepatic echogenicity, raising concerns for NAFLD. Given the duration and degree of liver-enzyme elevation, a decision was made to proceed with a liver biopsy at that time. Microscopic examination of the biopsy revealed diffuse, microvesicular steatosis involving more than 90% of the liver parenchyma (Images 1A and 1B); minimal (<5%) macrovesicular steatosis was also noted. Also, portal areas contained clusters of foamy histiocytes that were prominently visible on a periodic acid–Schiff diastase (PAS-D) stain (Images 1C and 1D). Occasional acidophilic bodies and scattered lobular inflammation were also observed. Pericellular and/or portal fibrosis were absent on trichrome stain (not shown), as were ballooned hepatocytes, Mallory hyaline, and satellitosis (neutrophils surrounding ballooned hepatocytes).

Image 1.

Diffuse, microvesicular steatosis (A, B and C = H&E staining; original magnification A = 100X, B and C = 200X) in a liver specimen from our patient, a 12-year-old boy of Mexican origin. D, PAS-D stain. Yellow arrow indicate hepatocytes with microvesicular steatosis. Red arrows indicate foamy histiocytes in the portal areas.

Differential Diagnoses

The observed morphology led to a broad differential diagnosis:

  • Medication-induced hepatotoxicity: Medication-induced hepatotoxicity (Reye syndrome, tetracycline or valproic acid toxicity, etc) was ruled out because the patient was asymptomatic and had not taken any hepatotoxic medications.

  • NAFLD with microvesicular steatosis: Mixed microvesicular and macrovesicular steatosis has been reported in approximately 10% of patients with NAFLD. The presence of microvesicular steatosis in NAFLD is generally associated with advanced fibrosis.[6] Liver biopsies from a number of patients with NAFLD in our practice have contained mixed large-droplet, small-droplet, and microvesicular steatosis (Images 2A and 2B); a single case of NAFLD even showed foamy histiocytes in the portal areas (Image 2B) akin to our index case (Image 1). Our patient, however, had more than 90% microvesicular steatosis, with clusters of foamy histiocytes in the lobules and portal areas.

  • Glycogenic hepatopathy: First described in patients with type 1 diabetes who had hepatomegaly and elevated aminotransferase levels, glycogenic hepatopathy is clinically characterized by increased echogenicity on abdominal ultrasound, similar to that observed with fatty liver. A liver biopsy typically reveals pale and swollen hepatocytes, absent fatty change, no or minimal inflammation, and no or minimal lobular necrosis.[12] Abundant cytoplasmic glycogen deposits are typical with a periodic acid–Schiff (PAS) stain (Images 3A–3C; vs control Image 3D), and diastase digestion is able to remove the glycogen. Mechanistically, glycogenic hepatopathy results from excess accumulation of glycogen in hepatocytes after marked or prolonged hyperglycemia is treated with insulin. These changes have also been noted in patients with type 2 diabetes and in those who take steroids.[13,14] The patient described herein did not have diabetes: his hemoglobin A1c values were within the normal range (5.2–5.5), and a PAS stain did not reveal excess glycogen accumulation (data not shown).

  • MCAD and LCAD deficiency: MCAD and LCAD deficiencies are types of fatty-acid oxidation disorders that classically present with nonhypoketotic hypoglycemia.[15] Clinically, these patients often express phenotypic variability but may have lethargy, emesis, encephalopathy, respiratory arrest, or seizures.[15] In contrast, the clinical presentation of our index patient was reasonably indolent. Liver biopsy in patients with MCAD/LCAD deficiency often reveal prominent microvesicular steatosis,[16,17] as observed with our patient. However, diagnosis is confirmed by measuring serum MCAD/LCAD activity that is low and genetic testing that reveals respective mutations.

  • Niemann-Pick disease: Several lysosomal storage disorders present with microvesicular steatosis, including Niemann-Pick disease and LAL-D. Niemann-Pick disease is an autosomal recessive disorder characterized by acid sphingomyelinase (ASM) deficiency.[18] Patients with Niemann-Pick type A or C have an absolute ASM deficiency, which results in severe neurological manifestations. Conversely, patients with type B Niemann-Pick disease have only partial ASM deficiency. These patients do not have major neurological issues but instead present with significant interstitial lung disease and skin changes (nodular xanthoma) due to sphingomyelin accumulation in the viscera.[19] A liver biopsy, if performed, may show collections of foamy Kupffer cells or foamy Kupffer cells with adjacent foamy hepatocytes (Images 4A and 4B).[19] Our index patient did not have any neurological or skin changes.

  • LAL-D: Classically, LAL-D has been described by 2 distinct phenotypes: Wolman disease and cholesterol ester storage disease (CESD). Wolman disease is characterized by little to no lysosomal acid lipase (LAL) activity (less than 1%) and usually results in death within the first year of life.[20] Infants with Wolman disease are critically ill, typically with hepatic dysfunction, failure to thrive, and significant serum cholesterol changes (high low-density lipoprotein [LDL] values). Alternately, CESD manifests in older children or adults and is believed to occur in patients with 1% to 12% LAL activity.[20] Most of these patients are believed to be asymptomatic until the development of cirrhosis, other than the characteristic biochemical profile: elevated LDL-C, low HDL-C, and elevated ALT values. Microvesicular steatosis is a hallmark of lysosomal lipid accumulation, with little difference between areas of the hepatic lobule. Individual foamy macrophages are also commonly present, with fibrosis being more common and extensive in older patients.[21] The time from initial onset of clinical/biochemical abnormalities to diagnosis is variable but can be substantial. In one study, 77% of patients were diagnosed within 5 years of the first reported abnormalities, but nearly 15% had to wait more than 10 years to receive the correct diagnosis.[22]

Image 2.

Liver biopsy results from various patients with nonalcoholic fatty liver disease (NAFLD). A, Specimen from patient A showing mixed large-droplet, small-droplet, and microvesicular steatosis (H&E staining; original magnification ×200). B, Specimen from patient B showing mixed large-droplet, small-droplet, and microvesicular steatosis, as well as foamy histiocytes in the portal areas (H&E staining; original magnification ×200).

Image 3.

Liver biopsy from a patient with glycogenic hepatopathy (AC). A, H&E section showing diffuse hepatocyte swelling with cleared-out cytoplasm, prominent cell membranes and minimal to absent fatty changes. B, Abundant cytoplasmic glycogen deposits demonstrated by a Periodic acid–Schiff stain (vs. D). C, Diastase digestion removes the glycogen. D, Control patient without glycogenic hepatopathy.

Image 4.

Liver biopsies from 2 patients with Niemann-Pick disease type B (H&E stain, 600X). Biopsies show foamy Kupffer cells (A) and/or microvesicular steatosis with foamy Kupffer cells and foamy hepatocytes (B). Reproduced with permission from Dr. Beth Thurberg.

Follow-up

Given his clinical presentation and constellation of histopathologic findings on biopsy, we suspected LAL-D in our patient. Serum LAL testing (Lysosomal Acid Lipase–Blood, Fluorometric Enzyme Assay, Mayo Medical Laboratories) was subsequently performed; the results demonstrated undetectable enzyme activity (0 nmol/hour/mL; reference values ≥21.0 nmol/hour/mL). Confirmatory DNA sequencing demonstrated the presence of homozygous exon 8 splice junction mutation (E8SJM) in the LIPA gene. Testing performed in 2 of the siblings of the patient revealed that the twin sister and younger sister had absent LAL enzyme activity on dried-blood-spot testing, typical cholesterol abnormalities, and elevated ALT levels. These findings were diagnostic for LAL-D. An older brother was also tested for LAL-D but had normal enzyme-activity, LDL-C, HDL-C, and ALT levels.

Comments

3090D553-9492-4563-8681-AD288FA52ACE

processing....