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Identifying Lysosomal Acid Lipase Deficiency in Clinical Practice

  • Authors: James A. Underberg, MD, MS; Nirav K. Desai, MD
  • CME Released: 12/22/2014
  • Valid for credit through: 12/22/2015, 11:59 PM EST
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Target Audience and Goal Statement

This activity is intended for pediatricians, gastroenterologists, cardiologists, primary care physicians, hepatologists, and other healthcare professionals who diagnose and manage patients with dyslipidemia.

The goal of this activity is to educate clinicians on and provide clinical guidance for the diagnosis and management of lysosomal acid lipase deficiency (LALD) disorders.

Upon completion of this activity, participants will be able to:

  1. Discuss the pathophysiology, prevalence, and multisystemic impact of LALD
  2. Identify clinical manifestations of LALD in the context of a differential diagnosis


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  • James Underberg, MD MS

    Clinical Assistant Professor of Medicine, NYU School of Medicine; Director, Bellevue Hospital Lipid Clinic, NYU Center for Prevention of Cardiovascular Disease, New York, New York


    Disclosure: James A. Underberg, MD, MS, has disclosed the following relevant financial relationships:
    Served as an advisor or consultant for: Amgen Inc.; Aegerion Pharmaceuticals, Inc.; Lilly USA, LLC; Liposcience Inc.; Novartis Pharmaceuticals Corporation
    Served as a speaker or a member of a speakers bureau for: Amarin Corporation plc; AstraZeneca Pharmaceuticals LP; Genzyme Corporation; GlaxoSmithKline; Kowa Company Ltd; Merck & Co., Inc.; Sanofi
    Received grants for clinical research from: Aegerion Pharmaceuticals, Inc.; Kowa Company Ltd

    Dr Underberg does not intend to discuss off-label uses of drugs, mechanical devices, biologics, or diagnostics approved by the FDA for use in the United States.

    Dr Underberg does not intend to discuss investigational drugs, mechanical devices, biologics, or diagnostics not approved by the FDA for use in the United States.

  • Nirav K. Desai, MD

    Instructor in Pediatrics, Boston Children's Hospital, Boston, Massachusetts


    Disclosure: Nirav K. Desai, MD, has disclosed the following relevant financial relationships:
    Received grants for clinical research from: Synageva BioPharma

    Dr Desai does not intend to discuss off-label uses of drugs, mechanical devices, biologics, or diagnostics approved by the FDA for use in the United States.

    Dr Desai does not intend to discuss investigational drugs, mechanical devices, biologics, or diagnostics not approved by the FDA for use in the United States.


  • Luba Goldin, MS

    Scientific Director, Medscape, LLC


    Disclosure: Luba Goldin, MS, has disclosed no relevant financial relationships.

CME Reviewer(s)

  • Nafeez Zawahir, MD

    CME Clinical Director, Medscape, LLC


    Disclosure: Nafeez Zawahir, MD, has disclosed no relevant financial relationships.

Peer Reviewer

This activity has been peer reviewed and the reviewer has disclosed the following relevant financial relationships:
Received grants for clinical research from: Otsuka Pharmaceutical Co., Ltd.
Served as an advisor or consultant for: Thoratec Corporation; HeartWare International, Inc.

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Identifying Lysosomal Acid Lipase Deficiency in Clinical Practice

Authors: James A. Underberg, MD, MS; Nirav K. Desai, MDFaculty and Disclosures

CME Released: 12/22/2014

Valid for credit through: 12/22/2015, 11:59 PM EST


  • James A. Underberg, MD, MS: Hello. I am Dr James Underberg, clinical assistant professor of medicine at the NYU School of Medicine and the NYU Center for the Prevention of Cardiovascular Disease. I am also the director of the Bellevue Hospital Lipid Clinic in New York City. Welcome to this program titled "Identifying Lysosomal Acid Lipase Deficiency in Clinical Practice."

  • Slide 1.

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  • Joining me today in New York is Dr Nirav Desai. Dr Desai is the medical director of the Adolescent Bariatric Surgery program and attending physician in the Division of Gastroenterology, Hepatology, and Nutrition at Boston Children's Hospital in Boston, Massachusetts. Welcome.

    Nirav K. Desai, MD: Thank you.

    Dr Underberg: The goal of this program is to provide clinical guidance on diagnosing lysosomal acid lipase deficiency in order to better enable early disease management.

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  • I thought what we would do is begin with an overview of lysosomal acid lipase deficiency (LALD). If you could just get us started with a basic understanding, I think that would be a great way to begin.

    Dr Desai: That sounds good, Dr Underberg. Lysosomal acid lipase deficiency is a rare autosomal lysosomal storage disease. It is characterized by progressive accumulation of cholesteryl esters and triglycerides in the spleen and other organs. It is underrecognized, with some patients being diagnosed incorrectly. Patients have often been labeled as having heterozygous familial hypercholesterolemia, hyperlipidemia, or other diseases.[1]

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  • Dr Underberg: We are talking about a disease that, at least from my understanding, crosses over into a variety of different areas of medicine, right? Maybe they present to their primary care physician, or, potentially, to their pediatrician, lipidologist, cardiologist, or gastroenterologist. Perhaps if you had a case you could present to us, it might be a great way of getting people to understand the complexities with regard to identifying and diagnosing this particular disorder. From what I understand, you have a good one for us.

    Dr Desai: Yes, I think I have a great case. The patient we saw was 11 years old. She had no significant past medical history. She presented to our lipid clinic at Boston Children's Hospital for hyperlipidemia. She had a typical lipid screening done at her pediatrician's office at her well-child visit. It is interesting to note that when that test was done 3 months before she had come to see us, she was not feeling well. She was having fever, myalgia, and headache, and her pediatrician had actually diagnosed her with Epstein-Barr virus. When she had come to see us 3 months after that initial lipid screen, she said she was "almost 100%," though she still had some fatigue, headaches, myalgia, and fever.

    We performed a diet and lifestyle review. The patient reported to us that she was watching about 3 to 4 hours of screen time per day, she was getting about an hour of physical exercise per day, and that she had the diet of a typical 11-year-old: She was eating pizza, cheeseburgers, and ice cream. She had no significant past medical history. She had a 21-year-old brother whose cholesterol was not checked. Her mother was healthy, with a cholesterol of 168 mg/dL. Her father was from the Ivory Coast and had normal cholesterol levels. Her maternal grandparents were healthy; their cholesterol levels were not known, but her mother thought they were normal. Her paternal grandparents' history was unknown too. We did not know much about her family history, but most of what we knew seemed very reassuring.

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  • When we examined the patient, the only thing of note was that we could palpate a liver edge. Her height and weight were normal. She was not obese or even overweight. There were no skin manifestations.

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  • We reviewed some of her blood tests. The blood tests that were done 3 months before -- the screening tests that were done in her pediatrician's office -- revealed hypercholesterolemia. Her total cholesterol was 395 mg/dL. She had elevated triglycerides. She had low high-density lipoprotein (HDL) cholesterol, as low as 17 mg/dL. Her low-density lipoprotein (LDL) was 334 mg/dL. Interestingly, her liver enzymes were abnormal at that time too. Her aspartate aminotransferase (AST) was 203, and her alanine aminotransferase (ALT) was 187. She had these tests repeated 2 months before her visit with us in the office, and her total cholesterol was still elevated at 398. Her triglycerides were elevated as well. Her LDL was high, and her HDL was low. On the day of her visit to the lipid clinic, her total cholesterol remained elevated, her HDL had come up slightly to about 38 mg/dL, and her LDL was still about 290 mg/dL. We checked her thyroid function tests, which were about normal.

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  • In our minds, we were going through a differential diagnosis.[1] We thought, “Could this all be related to Epstein-Barr virus?” However, it seemed like an atypical lipid presentation. With Epstein-Barr virus, triglycerides are usually elevated and HDL is usually low. Her HDL was low, but her LDL was elevated.[2]

    Dr Underberg: Very high, actually. We might suspect a genetic cholesterol disorder.

    Dr Desai: Exactly. Interestingly, there was nothing in her family history that would suggest that. We did think about familial hypercholesterolemia as well. That day in the office, we had provided diet and lifestyle modification counseling and had recommended that she follow up with us in about 3 months. When she did follow up with us, which was 6 months after her initial lipid examination, her symptoms of Epstein-Barr virus were gone. She was feeling healthy. She had made the changes that we had recommended. She was on a diet low in saturated fat. She had eliminated trans fats and was going to the gym and doing some more exercise. When we repeated the blood tests at this visit, her liver enzymes were still elevated, though down slightly, from when she had first had them done. Her total cholesterol was 358, her triglycerides were 138, and her LDL cholesterol was 297 mg/dL.

    We then thought that it still seemed a little far out to be due to Epstein-Barr virus infection. We did a chronic hepatitis evaluation, evaluating her for diseases such as α1-antitrypsin deficiency, Wilson's disease, or infectious hepatitis. The other thing we thought about was whether these 2 things could be related: her elevated liver enzymes as well as her hypercholesterolemia.

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  • Dr Underberg: That was a wonderful case. It really gives a great overview of the typical type of patient that one might see with lysosomal acid lipase deficiency. Before we go into the details of the condition, I thought I would give our viewers a brief overview of the role of the enzyme lysosomal acid lipase. It is involved in taking lipids -- essentially cholesterol and triglycerides -- that find their way into the lysosome, first via the LDL receptor, and then the endosome, and breaking them down into free cholesterol and the byproducts of triglycerides. Patients who have a deficiency in lysosomal acid lipase do not accumulate free cholesterol in the hepatocyte normally. They build up the cholesterol and triglycerides in the lysosome, hence, lysosomal storage disease. This leads to the typical hepatic and lipid findings that we see in the condition. I was hoping you could tell us a little more about the condition and what we need to know about it.[3]

  • Slide 8.

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  • Dr Desai: Sure. Historically, lysosomal acid lipase deficiency was described as 2 separate diseases[3]: Wolman's disease and the cholesteryl ester storage disease. Wolman's disease was first described in 1956.[4] Wolman's disease, as it was known, manifested in infants. It was rapidly progressive. The infants had prominent hepatosplenomegaly, diarrhea, vomiting, and failure to thrive, and they quickly developed fibrosis and cirrhosis due to the massive accumulation of triglyceride and cholesteryl esters. The lipid would accumulate in the vascular endothelium, skeletal muscle, intestinal mucosa, and adrenal glands. Fifty percent of these infants would have adrenal calcification, and many of them would die of multiorgan failure within 6 to 12 months.

  • Slide 9.

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  • The cholesteryl ester storage disease was first reported by Frederickson a few years later in a 12-year-old boy who had hypercholesterolemia and hepatomegaly who had cholesteryl ester accumulation on the liver biopsy.[5] We think that this manifests postinfancy, and many of these patients have a shortened lifespan. It is a progressive liver disease with microvesicular steatosis, and there is cardiovascular involvement with premature atherosclerosis.[3]

  • Slide 10.

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  • As we have learned more about these diseases, they really are a continuum.

    Dr Underberg: Right. I think that is the key. For most of us, we remember Wolman's disease from back in medical school. That is how I remember this condition. It is only more recently, as I have learned much more about the spectrum of the condition, that I have learned there can be a variability in expression of this enzyme that I think allows it to present not just in childhood after infancy, but all the way through into adulthood. Correct?

    Dr Desai: That is exactly right, Dr Underberg, which is what makes this disease challenging for pediatricians, gastroenterologists, and lipidologists: the spectrum of its presentation. Historically, lysosomal acid lipase deficiency is autosomal recessive. It is caused by mutations in the lipogene, which you were talking about. The most common defect in it is in axon 8. It is a spliced junction mutation, which is found in about 50% of patients who have lysosomal acid lipase deficiency. In thinking about the prevalence, it is unclear because many of these patients are not even diagnosed yet. We think it could range from 1 in 300,000 to 1 in 400,000. There is a specific population of Jewish infants of Iraqi or Iranian origin who appear to be most at risk, with an estimated incidence of about 1 in 4200.[3,6]

    Dr Underberg: Almost a founder population, like we are seeing in some of the other inherited lipid disorders.

    Dr Desai: Exactly right.

    Dr Underberg: With regard to the genetics, it seems that if you have a child who presents with the condition, both parents might be asymptomatic. Correct?

    Dr Desai: That is exactly right.

  • Slide 11.

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  • Dr Underberg: Let's talk a little more about the phenotype. Can you tell me about the liver manifestations that one might see in an adolescent or an adult?

    Dr Desai: Some of the presentations -- some of the hepatic manifestations -- may be nonspecific. Some may have had hepatomegaly, an elevated AST or ALT. Sometimes the AST is even higher than the ALT. Then there are the lipid manifestations as well.[3]

    Dr Underberg: Exactly. As I was mentioning earlier, because of the lack of accumulation of free cholesterol on the hepatocyte, genes essentially get turned on to make more cholesterol. At the same time, the LDL cholesterol receptor becomes upregulated, bringing more cholesterol back into the liver, which leads to the worsening of the lysosomal storage condition and the worsening of the hepatic condition. It is really fascinating. HDL is also impacted. HDL cholesterol levels go down because of an abnormality in cholesterol efflux, potentially via the ABCA1 transporter gene and LXR. Finally, triglycerides can be elevated, and that is fairly variable.

    What is interesting is that you can also see fatty liver in these patients. Correct?

    Dr Desai: That is exactly right. Typically, it is microvesicular steatosis.

  • Slide 12.

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  • Dr Underberg: How many of these patients out there do you think are being misdiagnosed? They may have fatty liver. They may have elevated cholesterol. They are going to a gastroenterologist, a lipidologist, a cardiologist. No one really knows, right?

    Dr Desai: Exactly, and this is why we are hoping to raise awareness for pediatricians, gastroenterologists, and lipidologists.

    Dr Underberg: I was thinking about this before we sat down to talk. When you think about the differential diagnosis from the cholesterol side of things, certainly familial hypercholesterolemia comes into play, familial combined hypercholesterolemia, dysbetalipoproteinemia -- all of these can be suspected as well as other potential conditions. In addition, people can have more than one disease: diabetes or insulin resistance with fatty liver. You were saying that often these patients are not really insulin resistant, correct?

    Dr Desai: That is exactly right. We think that most of these patients are not obese. They may be overweight. They may have normal weight. Again, we are still trying to characterize this disease better.[3,7]

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  • Dr Underberg: Let's talk about treatment now. What obviously happens with many of these patients before they are diagnosed is that they are being treated for their underlying condition, which in many cases is high cholesterol. They probably are put on statins, correct?

    Dr Desai: That is exactly it. Many of these patients are put on statins, and it does help their LDL cholesterol. In fact, in many of the patients, their LDL cholesterol improves. However, in studies that have looked at what happens to the liver, progressive liver disease is seen in these patients. The statins can be helping to decrease their LDL cholesterol, but their liver disease continues to progress.

    Dr Underberg: You might see that in any intervention that upregulates expression of the LDL receptor, right?

    Dr Desai: Right.

    Dr Underberg: We have several, obviously, other than just statins. What about from the hepatic side? How would you manage that?

    Dr Desai: Liver transplant has been investigated in a small series of studies. We do not have long-term data on this. There are about 9 patients in the literature ranging from the ages of 5 to 14 years. Again, this is a multiorgan disease, so we do not think that a liver transplant only is going to be very beneficial.[3,7]

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  • Dr Underberg: From the cardiovascular side with high cholesterol, one of the issues is certainly risk for atherosclerosis. There does seem to be an increased risk of cardiovascular events and atherosclerotic disease in patients with LAL D. What are the end results of the liver disease? Do they go on to fulminant hepatic failure?

    Dr Desai: Absolutely.

    Dr Underberg: Obviously, cardiovascular manifestations, vascular manifestations, issues with responding to typical medications that we have out there leads us to first, wanting to know how do we find these patients and then what can we do for them. Who would you suspect LAL D in?

    Dr Desai: That is a great question. When I think about patients who may have LAL D, I think about patients with a BMI in less than the 95th percentile. We are talking about children here, people who may have elevated liver enzymes, unexplained hepatomegaly. If they have a liver biopsy, it is predominantly microvesicular steatosis or even a mixed micro- and macrovesicular steatosis, elevated LDL -- so an LDL over 160 mg/dL -- and low HDL cholesterol, for males probably less than 40 mg/dL and for females less than 50 mg/dL. We also think about patients who we presume have familial hypercholesterolemia without an identified mutation.[3]

  • Slide 15.

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  • Dr Underberg: How would you test someone once you suspected they had the condition?

    Dr Desai: Historically, lysosomal acid lipase deficiency was confirmed biochemically by measuring the enzyme activity in cultured fibroblasts, peripheral leukocytes, or liver tissue.

    Dr Underberg: People are not doing that in their office though.

    Dr Desai: Not anymore. Exactly. Now there is a dried bloodspot test, and LAL activity can be directly measured. There is an enzyme, Lalistat 2, that is a specific inhibitor for lysosomal acid lipase. You can measure all the lipase activity and then use the Lalistat. The difference between the total activity and the lipase activity with the Lalistat tells you exactly how much lysosomal acid lipase you have.[3]

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  • Dr Underberg: Say someone actually thinks about this, suspects it, gets the testing done, and makes the diagnosis understanding that current treatment right now does not seem to help these patients or may potentially worsen their hepatic disease, what is on the horizon with regards to treatment for these patients? Why should we be looking forward to for them?

    Dr Desai: That is a great question. There are medications in development. Specifically, there is a recombinant lysosomal acid lipase to treat these patients.[8-10]

    Dr Underberg: Great. In the future that might be available to us. Right now, clinical trials might be the way to go. I think understanding the disease and making the correct diagnosis is key, so we do not make these patients worse in the process of trying to make them better.

    Dr Desai: Exactly.

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  • Dr Underberg: In summary, do you want to just say a couple of brief parting words?

    Dr Desai: Sure. Lysosomal acid lipase deficiency has a variable age of onset and is often underrecognized. They symptoms can include hepatomegaly, elevated liver enzymes, and dyslipidemia. We can make the diagnosis based on the lysosomal acid lipase activity or the lipomutation analysis, and enzyme replacement therapy is currently being investigated.

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  • Dr Underberg: Dr Desai, I want to thank you very much for a wonderful overview of this interesting condition. I am sure our audience learned a lot, and I know I did too. To our audience, click on the earn CME credit link to take the CME posttest and evaluation.

    This transcript has been edited for style and clarity.

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