Cholesterol in the Family

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Article from the Summer 2016 Issue of Heart Insight by Jon Caswell
It seems to Bill Linsman of Los Angeles that he always had heart issues, but then so did his father. Bill had his first heart attack at age 38, then bypass surgery at 50. He had another heart attack in 2008, at 63, as stents were being put into his coronary arteries. He didn’t learn the underlying cause of these things until more than 20 years after that first heart attack in 1984.

“I knew I had high cholesterol, but I did not know I had a genetic disorder that put me at higher risk of cholesterol problems,” Bill said. This inherited disorder, called familial hypercholesterolemia (FH), produces high cholesterol earlier in life than it would normally appear.

“FH is an autosomal dominant genetic disease, which means, if you have it, you inherited it from one of your parents,” said Joshua Knowles, assistant professor of cardiovascular medicine at Stanford University. “And if you have it, each of your children has at least a 50 percent chance of inheriting it.” Knowles is chief medical advisor for the FH Foundation.

The situation
If we eat animal products, we take in cholesterol as part of our diets. But even if we don’t, our bodies also make it in the liver and it’s exported to other cells where it is used in making cell membranes, among other uses. “You can think of FH as a defect in the body’s ability to recycle LDL [bad] cholesterol,” Knowles said. Because of that, the LDL cholesterol levels in the blood remain very high — above 190 milligrams per deciliter (mg/dL) of blood in adults with FH. Over time those levels are toxic to blood vessels, and atherosclerotic plaques develop. “Eventually that leads to a very elevated risk of coronary heart disease, much higher than the average population,” Knowles said. Half of men with untreated FH will have a heart attack or angina before age 50, sometimes as early as their 20s — just like Bill Linsman. Thirty percent of untreated women will have one before 60. Cholesterol levels rise in everybody as we age. “People with FH are basically born with high cholesterol and their levels get even higher as they age,” Knowles said.


“We say we never find an individual with FH; we only find families with FH.”




Screen Shot 2016-05-24 at 3.47.06 PMGene Mutations
FH is caused by a mutation in the gene for the LDL receptor, which is involved in LDL recycling. Mutations in other genes that effect the process can cause inherited high cholesterol that, though it isn’t FH, causes the same problems. Those genes include the PCSK9 gene and the gene for Apolipoprotein B.

• The LDL receptor sits on the surface of the liver and binds to the cholesterol-containing lipoproteins and pulls them out of the bloodstream.
• Apolipoprotein B is a little molecule that sits on the outside of the cholesterol particle and binds to the LDL receptor.
• PCSK9 is a naturally occurring enzyme that functions to control how many LDL receptors are on the surface of the liver.

Treatment is usually statin based. Because their cholesterol levels are so high, FH patients often require more than one medication, and sometimes more than two. “If the response to statins is not adequate, additional cholesterol lowering medications like ezetimibe are used,” Knowles said. “People with extremely elevated LDL, like those with the homozygous form, may undergo a dialysis- like procedure, called LDL apheresis, every few weeks to remove cholesterol from their blood.”

Another class of lipid-lowering medications (bile acid sequestrants) like cholestyramine or colesevelam may also be used. They reduce the amount of cholesterol absorbed by the intestines, lowering the amount of cholesterol that makes it into the blood. All these genes are connected with one another. If you inherit a specific type of mutation in any of these three genes, you can develop FH or inherited high cholesterol.

Hetero and Homo
There are two types of FH — heterozygous and homozygous. Heterozygous FH is much more common and occurs when a person inherits one causal mutation from one parent. This occurs in about 1 in 250 people.

Homozygous FH occurs when someone inherits one causal mutation from both parents. “This form is much rarer,” Knowles said. These individuals can have LDL cholesterol levels over 500 and many of them have bypass surgeries or need them before they’re adults. Left untreated, it is rare for these patients to survive into their 20s.

Screen Shot 2016-05-24 at 3.47.21 PMTreatment
Treatment is usually statin based. Because their cholesterol levels are so high, FH patients often require more than one medication, and sometimes more than two. “If the response to statins is not adequate, additional cholesterol lowering medications like ezetimibe are used,” Knowles said. “People with extremely elevated LDL, like those with the homozygous form, may undergo a dialysis- like procedure, called LDL apheresis, every few weeks to remove cholesterol from their blood.”

Another class of lipid-lowering medications (bile acid sequestrants) like cholestyramine or colesevelam may also be used. They reduce the amount of cholesterol absorbed by the intestines, lowering the amount of cholesterol that makes it into the blood.

PCSK9 inhibitors are newly developed injectable antibodies that lower cholesterol levels. They target the PCSK9 protein and block it so that more of the receptors on the liver are available to get rid of LDL cholesterol from the blood.

Bill’s experience matches this outline of treatment options. Although he was diagnosed with FH seven years ago, he started on statin therapy in 1985, but over time he became intolerant to them, developing side effects that prevented him from being able to take the medication. “The only alternative at the time was LDL apheresis at our local hospital,” he said. “It was very time consuming — four hours per session — and a substantial nuisance, interrupting the work day, and a bit painful as well. Now I am taking a PCSK9 inhibitor as part of a clinical study.”

Knowles is emphatic that FH cannot be treated by diet and exercise alone. Diet and exercise will lower your LDL some, “but when you’re talking about needing to lower cholesterol levels by 50 percent or 75 percent, diet and exercise is not enough,” Knowles said.


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Family
“We say we never find an individual with FH; we only find families with FH,” Knowles said. “If you identify FH in a family you’re obligated to look at the rest of the family because people are ticking time bombs if they haven’t been identified.

“It’s very cost-effective if you can identify it early enough and treat it,” Knowles said. “So if you find one individual in a family with FH, you really need to check all first degree relatives — parents, siblings, children and then cascade from there — to see if they also have it.” Knowles believes that the children of people with FH should be evaluated. It may be helpful for children to be evaluated as early as age 6. “Oftentimes, kids are started on medication as early as age 8 or 10 if their cholesterol is high enough or if the family history is bad enough,” Knowles said. “If we do not see any evidence of FH, if the LDL levels are stone cold normal as a teenager, we would not expect FH to manifest later.”

Bill has told his three daughters about their propensity for FH, and so far none of them or any of his grandchildren have been diagnosed with FH.

Prognosis
According to Knowles, if the patient is identified early enough and treated aggressively enough, the prognosis is excellent. “They generally do quite well. Their quality of life is pretty good. Some of them do worry about their hearts. They worry about their relatives,” Knowles said.

That was Bill Linsman’s experience: “My wife used to worry about me terribly, and I knew that I was weary of the apheresis — not to mention the scar tissue getting larger in my arms every visit,” he said. “The self- administered PCSK9 inhibitor injections, once every two weeks, are so much easier. The injections provide a terrific freedom that makes us both much more comfortable with how my FH is managed.”

Two PCSK9 inhibitors are approved by the FDA, but it’s important to note that they are still a new treatment, their use is limited and they are costly.

Screen Shot 2016-05-24 at 3.47.45 PMFAMILIAL HYPERCHOLESTEROLEMIA FOUNDATION
The FH Foundationâ„¢ is a patient-centered nonprofit organization dedicated to education, advocacy and research of family high cholesterol. Its mission is to raise awareness of FH and increase the rate of early diagnosis and proactive treatment. Through the Foundation, patients and healthcare practitioners have joined together to change the status quo for FH.

The CASCADE FH Registry
The CASCADE FH Registry™ (CAscade SCreening for Awareness and DEtection of Familial Hypercholesterolemia) is a database where patients with FH can register to help researchers collect data on diagnosed individuals such as disease patterns, trends and gaps in care. It helps patients contribute to ongoing research as well as helping them track their own health, including medications. They can also view reports on how their own cholesterol levels and therapies are changing. It’s free for patients to register, confidential and secure (HIPAA-compliant and HITRUST certified).

FIND FH®
The FIND FH® (Find, Identify, Network,and Deliver for Familial Hypercholesterolemia) initiative uses advanced machine learning, natural language processing and data mining techniques to generate results on a heat map that shows the national geographic distribution of individuals with probable FH at the healthcare provider level. This initiative is allowing healthcare providers in areas with concentrations of individuals with probable FH the opportunity to learn about patients with probable FH in their practice.

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