Ace the Case: A 28-Year-Old Man With Hepatomegaly and Dyslipidemia

Clinical Review

Lysosomal acid lipase deficiency (LAL-D) is a rare autosomal recessive disease that is estimated to occur in 1 in 40,000 to 300,000 individuals and varies by population. The later-onset form is more common than the early-onset form, with significant morbidity and early mortality.2 LAL-D results from an autosomal recessive lysosomal storage disorder that is caused by a marked decrease in the activity of the LAL enzyme due to mutations affecting the LIPA gene.2

Significant morbidity and early mortality are often associated with the disease due to the marked decrease of LAL enzyme activity, which results in the accumulation of lipid substrates in various tissues and cell types, primarily in the hepatic, gastrointestinal, and cardiovascular systems.3 There are two forms of the disorder. The rarest and most severe form begins in infancy. The less severe form can begin from childhood to late adulthood.3 Patients with LAL-D often are misdiagnosed because symptoms may be nonspecific, and awareness of the condition may be minimal.3

The two forms were once thought to be separate disorders. However, they both have the same genetic cause and are now considered to be variants of a single condition.3 These names (and others) are sometimes used to distinguish between the forms of LAL-D:3

  • Wolman disease (early-onset LAL deficiency)
  • Cholesteryl ester storage disease or CESD (late-onset LAL deficiency)
  • Acid cholesteryl ester hydrolase deficiency, Type 2
  • Acid lipase disease
  • Cholesteryl ester hydrolase deficiency storage disease
  • LIPA deficiency

Mutations in the LIPA (lipase A) gene, which provides coding for producing lysosomal acid lipase, results in the enzyme’s deficiency.3 This enzyme is located within lysosomes as well as the Kupffer cells and the monocyte macrophage system.4 These enzymes promote the digestion and recycling of cellular materials, metabolizing cholesteryl esters and triglycerides.4 The severity of the condition depends on the availability of the functional enzyme.4 Those with early-onset LAL-D have no normal enzyme activity, while those with the later-onset form have some remaining enzyme activity.4

If LAL activity drops to 5% of normal, the rate of endosomal and lysosomal release of cholesterol decreases to a critical level.5 This decreased lysosomal acid lipase activity results in the accumulation of cholesteryl esters, triglycerides, and other lipids within lysosomes, generating an increase in alternative methods of cholesterol production and elevated total cholesterol and LDL-C.5 The progressive systemic lipid accumulation ultimately results in organ dysfunction and phenotypic manifestations of lysosomal acid lipase deficiency.6

The age at onset and rate of progression vary greatly, which may relate to the nature of the underlying mutations.3 Patients presenting in infancy have the most rapidly progressive disease, developing signs and symptoms in the first weeks of life.7 In this severe, early-onset form of LAL-D, lipids diffusely accumulate, particularly within the liver, resulting in hepatosplenomegaly, hepatic fibrosis, cirrhosis, and jaundice.7 In addition, steatorrhea and malabsorption leads to poor weight gain, weight loss, failure to thrive, and developmental delay.6 Adrenal gland calcifications and iron deficiency anemia may also be demonstrated. Infants eventually develop severe malnutrition and multi-organ failure, generally failing to survive past 1 year.6 The severe form (Wolman disease) has a reported incidence of 1:500,000.7

In the later-onset LAL-D, signs and symptoms vary, usually beginning in mid-childhood, although they can appear anytime up to late adulthood.3 Nearly all affected individuals develop hepatomegaly as was seen in this patient, although splenomegaly may also occur.3 About two-thirds of individuals develop hepatic fibrosis, eventually progressing to cirrhosis.3 Approximately one-third of individuals with the later-onset form have malabsorption, diarrhea, vomiting, and steatorrhea. Individuals with later-onset LAL-D may also demonstrate transaminase elevations and dyslipidemia.3 Elevated low-density lipoprotein cholesterol levels and decreased high-density lipoprotein cholesterol levels are common features, and cardiovascular disease may manifest as early as childhood.3 Many are likely to be referred to lipid clinics before diagnosis.3 Microvesicular hepatosteatosis can be demonstrated on biopsy.3

Given the similarities between the lipid profile observed in patients with LAL-D and that of common genetic hyperlipidemias such as hereditary familial hypercholesterolemia (HeFH) and familial combined hyperlipidemia (FCH), it is important that clinicians remain vigilant to avoid misdiagnosis.3 Given that these clinical manifestations are shared with other cardiovascular, liver, and metabolic diseases, it is not surprising that LAL-D is underrecognized in clinical practice.4

LAL-D is similar to other lysosomal storage disorders such as Gaucher, Fabry, and Pompe.3 LAL-D usually presents with prominent hepatic manifestations, lipid disorders, and cardiovascular involvement.8 The deficiency in LAL predominantly results in cholesteryl ester accumulation, particularly in the liver, spleen, and macrophages throughout the body.3 On liver biopsy, the microvesicular steatosis may be misdiagnosed as nonalcoholic steatohepatitis, nonalcoholic fatty liver disease, or cryptogenic liver disease.3 Definitive diagnosis is key and should include the most sensitive and specific assays and methodologies.9

The histologic diagnosis of LAL-D is facilitated by immunostaining for the lysosomal protein cathepsin D, which is routinely performed in many pathology laboratories.8 Measurement of LAL using dried blood spots (DBS) is made difficult by the presence of other lipases in whole blood.1 Lalistat is a specific inhibitor of LAL that allows the determination of LAL in DBS.1 Results show the method differentiates clearly between normal controls, carriers, and affected cases.1

Molecular genetics tests can also be performed, including:1

  • Sequence analysis of select exons
  • Mutation scanning of the entire coding region
  • Deletion/duplication analysis
  • Targeted variant analysis
  • Sequence analysis of the entire coding region

Current management of LAL-D focuses on lipid control and amelioration of liver complications.3 Supportive treatment has included cholestyramine, statins, and ultimately, liver transplantation.5 Treatment with statins does not reverse the disease manifestations, which lead to liver failure.5 The limited success of statins in treating all aspects of LAL-D means that alternative, disease-specific treatments are needed. The ongoing availability of sebelipase alfa, a recombinant lysosomal acid lipase, offers a disease-specific therapeutic approach that may change the natural course of the disease.10 In patients with LAL-D, sebelipase alfa has been found to be well tolerated, and rapidly decreases serum transaminases.10 These improvements are sustained with long-term dosing and are accompanied by improvements in serum lipid profile.10 In December 2015, sebelipase alfa was approved by the FDA for the treatment of patients of all ages with LAL-D.11 It is administered once a week via intravenous infusion in people with rapidly progressing disease in the first 6 months of life, and every other week with less aggressive disease.11

There is a need for enhanced awareness of LAL-D so that early diagnosis can help limit disease-associated morbidity and mortality. Clinicians are likely to be confronted with LAL-D in clinical practice and should be aware of the hallmarks of the disease. Differential diagnosis is key because a number of other conditions have similar clinical and laboratory presentations. Early recognition and diagnosis of individuals with LAL-D is essential if appropriate care is to be provided. The recent development of a blood test for LAL-D provides physicians with a method for rapid diagnosis.1

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All the following are associated with fatty liver except:
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Correct Answer: A.

Rationale: Fatty liver increases the risk for insulin resistance, hepatocellular carcinoma, type 2 diabetes, and cirrhosis.3 Insulin resistance is thought to underlie the accumulation of fat in the liver, but other factors such as oxidant injury contribute to the fact that some individuals may have isolated steatosis without any liver injury, while others can progress to steatohepatitis or even cirrhosis.3 Acanthosis nigricans is a skin condition characterized by areas of dark, velvety discoloration in body folds and creases that is associated with insulin resistance.3