Dyslipidemias: Pathology review
Biochemistry and nutrition
AssessmentsDyslipidemias: Pathology review
USMLE® Step 1 style questions USMLE
A 26-year-old man is evaluated in the emergency department for epigastric pain that began an hour ago. He reports that the pain radiates to the back and is 9 out of 10 in severity. The patient consumes a diet rich in fresh fruits and vegetables. He drinks 2-3 glasses of wine per week on social occasions. Family history is notable for recurrent episodes of pancreatitis in his father and paternal uncle. His temperature is 37.7°C (99.9°F), blood pressure is 125/83 mmHg, and pulse is 96/min. Physical examination is notable for tenderness on light palpation of the epigastric region. Abdominal exam also reveals hepatosplenomegaly and the following finding:
Reproduced from: Wikimedia Commons
Xanthomas are found on the patient’s bilateral elbows. Which of the following set of laboratory findings would be most likely expected in this patient?
Content Reviewers:Yifan Xiao, MD
Contributors:Kaia Chessen, MScBMC, Salma Ladhani, MD, Rachel Yancey
Jamie is a 24-year-old male presenting to the emergency department complaining of sudden onset chest pain and shortness of breath when playing soccer.
On further evaluation, his ECG showed ST-segment elevation and laboratory evaluation showed elevated troponin I levels.
After instituting treatment, Jamie and his family inquire about the odd early onset of his disease.
The physical examination of the skin showed numerous xanthomas.
A lipid panel is ordered and shows marked elevation of LDL.
Jamie had a myocardial infarction which was caused by an underlying lipid disorder.
Lipid disorders include both hyper and hypolipidemia.
Hyperlipidemia can manifest as a high level of cholesterol, a high level of triglycerides, or a combination of both.
Hypolipidemia is the opposite where there’s a low level of these lipids.
So let’s do a quick overview of the physiology of lipid metabolism.
After eating a fatty meal, cholesterol and fatty acids enter the intestinal cells.
The fatty acids are assembled into triglycerides, and then they, along with a small amount of cholesterol, are packaged together with lipoproteins to form chylomicrons.
Chylomicrons move into the lymphatic vessels and eventually end up getting emptied into the left and right subclavian veins where they enter into the blood.
Now an enzyme in capillaries called lipoprotein lipase breaks down the chylomicrons to free the triglycerides, and then it also breaks the triglycerides down into fatty acids.
These can be taken up by nearby tissues to generate energy, like in the muscle cells, or for storage, like in adipocytes.
The remains of the chylomicrons will contain lipoproteins and a small amount of triglyceride and cholesterol, so these chylomicron remnants head to the liver to deposit the leftover lipid molecules.
The Liver is also synthesizing fatty acids and cholesterol and it will combine these with the ones from the chylomicron remnants and package them together.
But instead of chylomicrons, they are packaged into very low density lipoproteins, or VLDLs.
Compared to chylomicrons, these are made of different lipoproteins and contain a bit more cholesterol.
VLDLs are released from the liver and enter into the blood where lipoprotein lipase in the capillaries break them down again to release triglycerides for nearby tissue to use.
As more and more triglycerides leave the VLDL, it becomes an IDL or intermediate density lipoprotein, and when there’s more cholesterol left than triglyceride, it becomes an LDL.
LDLs then travel around in the blood, where they are endocytosed by cells with LDL receptors.
This can happen when they go back to the liver, or in peripheral tissues that need cholesterol to function.
Alright, the causes of hyperlipidemia can be broadly classified into primary hyperlipidemias, which are the familial, inherited hyperlipidemias, and secondary, or acquired hyperlipidemias, which are caused by various other diseases and medications.
Depending on the type and severity, hyperlipidemia can result in various clinical manifestations, or it can be completely asymptomatic.
Beginning from the outside, skin manifestations include xanthomas, which are deposits of fat under the skin and in the tendons.
These occur when extremely high levels of lipoproteins or triglycerides in the blood leak out of the blood vessels.
When these deposits occur around the eyelid, it gets a special name; xanthelasma.
Speaking of the eyes, lipids can deposit around the cornea, creating a brown ring of fat called a corneal arcus. Lipid deposition in the liver can cause fatty liver disease, also called hepatic steatosis.
Now, the most worrisome complication of hyperlipidemias is atherosclerotic cardiovascular disease, including coronary artery disease, stroke, peripheral vascular disease and carotid artery stenosis.
Okay, so let’s look at the primary, or Familial hyperlipidemias, which are inherited in either an autosomal dominant or recessive manner.
Although there are many, the most high yield ones often tested on exams are types 1 through 4.
Type 1 hyperlipidemia is an autosomal recessive disorder characterized by elevation of chylomicrons in the blood, so it’s also referred to as hyperchylomicronemia.
This occurs secondary to a deficiency in lipoprotein lipase.
This enzyme also normally requires a cofactor called apolipoprotein C2, so deficiency of this cofactor can also lead to type 1 hyperlipidemia.
This condition is characterized by the rapid development of many xanthomas on the back and buttocks that can be itchy.
Due to the rapid nature of their development, they’re referred to as eruptive xanthomas.
In addition, the high concentration of triglycerides in chylomicrons can often lead to the development of acute pancreatitis.
This occurs because when the pancreatic cells encounter triglycerides, they release the enzyme lipase, which breaks them down into free fatty acids.
Too many free fatty acids can be toxic to the pancreatic cells, leading to acute pancreatitis.
Another unique feature of type 1 hyperlipidemia is that atherosclerotic cardiovascular disease is not a complication.
That’s because the development of an atherosclerotic plaque is usually related to the elevation of other lipoproteins like low-density lipoprotein, or LDL, and not related to the elevation of chylomicrons.
Finally, people with this condition can develop hepatosplenomegaly.
An important clue that might appear on your exams is that when fasting serum is chilled, the chylomicrons will form a creamy layer at the top of the test tube.
Alright, type 2 familial hyperlipidemia is an autosomal dominant condition also known as familial hypercholesterolemia.
It’s characterized by the elevation of LDL cholesterol if it’s type “A,” and both LDL and VLDL if it’s type B.
Okay, so normally, the liver can decrease cholesterol levels by recycling LDL in the blood.
LDL attaches to its own LDL receptor on the surface of liver cells, and with the help of a protein called apolipoprotein B-100, or ApoB-100, it enters the liver cells.
So in this condition, either the LDL receptor or ApoB-100 are absent or defective, causing LDL levels go up.
Because the liver cells aren’t getting any LDL back, they begin to “think” that cholesterol is actually low in the blood, and so they start making even more cholesterol, and sending them out in VLDL.
As you can imagine, this would worsen the problem.
Unlike type 1, type 2 hyperlipidemia will increase the risk of developing atherosclerosis, and this is high yield.
In fact, individuals may present with coronary artery disease as early as 20 years old!
- "Fundamentals of Pathology" H.A. Sattar (2017)
- "Hyperlipidemia: diagnostic and therapeutic perspectives" J Clin Endocrinol Metab (2000)
- "Lecture Notes: Cardiology" Wiley-Blackwell (2008)
- "Pathophysiology of Heart Disease" Wolters Kluwer Health (2015)
- "Familial hypobetalipoproteinemia: genetics and metabolism" Cell Mol Life Sci. (2005)