Dyslipidemias: Pathology review

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Case Study0:00–0:44

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.

Pathophysiology0:44–3:35

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.

Clinical Manifestations3:35–5:06

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.

Familial Hyperlipidemia5:06–10:31

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! In addition, tendon xanthomas, particularly on the Achilles tendon, and corneal arcus are common in this type.
On the exam, think of this disorder in someone with a family history of myocardial infarction at an early age. Alright, type 3 familial hyperlipidemia is a rare, autosomal recessive disorder also known as familial dysbetalipoproteinemia.
In this disorder, the apolipoprotein E or ApoE is defective. This protein normally assists with the uptake of chylomicron remnants and VLDL by the liver, so they are elevated in this condition.
It’s also characterized by the development of premature atherosclerosis, however unlike type 2 hyperlipidemia, the xanthomas in this condition tend to develop on the palms.
Okay, type 4 familial hyperlipidemia is also known as familial hypertriglyceridemia. In this subtype, for some unknown reason, the liver pumps out large amounts of VLDL.
In addition, lipoprotein lipase activity is decreased, so VLDLs are not broken down. This also applies to chylomicrons which will also be elevated.
The high yield concept here is that since VLDLs and chylomicrons both contain mainly triglyceride, serum triglyceride levels can increase dramatically.
This condition is characterized by premature atherosclerosis and the risk of developing acute pancreatitis. Alright, onto the acquired causes of hyperlipidemia, starting with the most common cause, diabetes mellitus.

Acquired Hyperlipidemia10:31–12:02

Normally, one of the functions of insulin is to increase lipid uptake in adipose tissue. It does this by increasing the activity of lipoprotein lipase to liberate fatty acids from VLDL and chylomicrons.
In both type 1 and type 2 diabetes, insulin levels eventually drop, causing a decrease in lipoprotein lipase activity. So now instead of being broken down and stored, large amounts of VLDL particles just awkwardly sit in the blood, and these eventually get converted to LDL, the culprit in atherosclerosis.
In hypothyroidism, the body’s metabolism slows down. This includes synthesizing LDL receptors.
Without LDL receptors, LDL particles can’t return to the liver, so they lurk in the blood. In nephrotic syndrome, plasma proteins like albumin are lost in the urine.
In attempt to compensate for the decrease in plasma protein, the liver starts making VLDL. Through various mechanisms, certain groups of medications can also cause hyperlipidemia.
These include estrogen-containing oral contraceptives, beta-blockers, and thiazide diuretics. Alright, now let’s look at hypolipidemia and the most common cause that will show up on your exams is abetalipoproteinemia.

Abetalipoproteinemia12:02–14:48

Normally, a protein called microsomal triglyceride transfer protein, or MTP, is responsible for packaging triglycerides into lipoproteins like VLDL and chylomicrons, so that they can be carried in the blood.
In abetalipoproteinemia, an autosomal recessive genetic defect happens to the MTP protein. There’s also a deficiency of ApoB-48 protein which is also made in the small intestine and are found in chylomicrons, and ApoB-100 which is made in the liver and found in VLDL and LDL.
So the result is low levels of VLDL, LDL and chylomicrons and both cholesterol and triglyceride levels will be low. Abetalipoproteinemia presents early in infancy.
A key symptom is malabsorption of fat in the small intestine due to low levels of chylomicrons, so infants don’t grow properly, a condition called failure to thrive.
In addition, the lipids accumulate inside intestinal cells and the intestinal lumen, resulting in diarrhea that contains large amounts of fat, also called steatorrhea.
On the exam, a clue towards steatorrhea would be malodorous stools that float in the toilet bowl and are difficult to flush down.
Over time, individuals develop signs and symptoms of fat-soluble vitamin deficiency, and this is another high yield fact.
This includes osteomalacia from vitamin D deficiency, retinitis pigmentosa from vitamin A deficiency, as well spinocerebellar degeneration and acanthocytosis on peripheral blood smear from vitamin E deficiency.
To confirm the diagnosis, an intestinal biopsy is performed, which shows intestinal cells that contain large amounts of fat.
The treatment of the disease is based on reducing dietary fats, especially long chain saturated fatty acids to reduce gastrointestinal problems.
Vitamin supplements should also be taken, the most important of which are vitamin E to prevent neurological problems, and vitamin A to prevent retinal damage.
Alright, as a quick recap, Lipid disorders cause abnormal changes in the levels of blood lipid components such as triglycerides, cholesterol, and lipoproteins.

Review14:48–16:30

Hyperlipidemia can be divided into primary, or familial, which is usually caused by an inherited genetic defect, or acquired, caused by various systemic disorders and medications.
Familial hyperlipidemias are subclassified into four major types. Type 1, caused by a deficiency of lipoprotein lipase or its cofactor; apolipoprotein C2, results in elevation of chylomicrons.
Type 2 is caused by an absent or defective LDL receptor, resulting in elevation of LDL in type A, and both LDL and VLDL in type B.
Type 3 is caused by defective ApoE, leading to elevation of VLDL and chylomicrons. Type 4 hyperlipidemia is characterized by increased hepatic production of VLDL.
Acquired causes include diabetes, hypothyroidism and medications like thiazide diuretics. Hypolipidemia can be caused by abetalipoproteinemia which is a genetic disorder that affects the MTP protein.
This leads to decreased levels of chylomicrons, VLDLs, and LDLs. The symptoms are caused by malabsorption of fats and fat soluble vitamins.

Summary16:30–17:03

Okay, back to our case. Jamie is presenting with an acute myocardial infarction.
Considering his relatively young age, it’s important to consider familial hyperlipidemias. Tendon xanthomas on examination, combined with elevation of LDL on lab testing all point towards type 2 familial hyperlipidemia, usually caused by a decrease in the number of LDL receptors or ApoB-100 protein in the liver.