lipid

Familial hypercholesterolaemia

BMJ11 May 2012
د. حسين محمد جمعه
اختصاصي الامراض الباطنة
البورد العربي
كلية طب الموصل
2012

This is one of a series of occasional articles highlighting conditions that may be more common than many doctors realise or may be missed at
first presentation. The series advisers are Anthony Harnden, university lecturer in general practice, Department of Primary Care Health
Sciences, University of Oxford, and Richard Lehman, general practitioner, Banbury. To suggest a topic for this series, please email us at easilymissed@bmj.com.

his 52 year old father suddenly died of a heart attack. His paternal uncle and grandfather died of heart attacks in their 40s.
On examination he has xanthomas on the extensor tendons of his hands. Laboratory investigations reveal total cholesterol 9.3 mmol/L and low density lipoprotein (LDL) cholesterol 6.6 mmol/L. He is diagnosed with familial hypercholesterolaemia,
given lifestyle advice, started on simvastatin 80 mg, and referred to a specialist for genetic testing and cascade screening of his relatives.


What is familial hypercholesterolaemia?
Familial hypercholesterolaemia is an inherited autosomal dominant genetic disorder characterised by high serum cholesterol concentrations detectable at a young age. It is associated with early cardiovascular disease, and an underlying genetic cause can be identified in about 80% of cases.

Why is familial hypercholesterolaemia missed?

Underdiagnosis is a global challenge, with correct identification ranging from less than 1% in Russia to 20% in the Netherlands and 44% in Iceland. In the UK only 15% of patients with familial hypercholesterolaemia are expected to have been
recognised in general practice.

It is not known why patients with familial hypercholesterolaemia are often missed in primary care, but many seem to be diagnosed in middle age when family members present with coronary heart disease. Although patients diagnosed with familial hypercholesterolaemia are instructed to contact their relatives, several studies have shown that this is not effective in practice.

The low referral rate to specialists for cascade DNA testing, the lack of national screening programmes, and the limited usefulness of clinical evaluation in relatives all probably
contribute. Underdiagnosis is an even greater challenge among children and young adults, in whom clinical signs are rarely present.

Why does this matter?

Patients with familial hypercholesterolaemia have a high risk of mortality as they are exposed to high concentrations of plasma LDL cholesterol from birth. By early adulthood, without treatment they will have a 100-fold greater mortality risk from
coronary disease than other young adults aged 20–39 years.

Half of untreated heterozygous men and 30% of untreated women will have a myocardial infarction by the age of 50 and 60 years respectively. However, the development of effective cholesterol lowering drugs has reduced cardiovascular mortality,
prolonging life by approximately nine years. A long term follow-up study showed that statins can delay atherosclerotic progression in children and young adults with familial hypercholesterolaemia. The risk of coronary heart disease is considerably higher in patients with homozygous familial
hypercholesterolaemia.

How is familial hypercholesterolaemia diagnosed?

There is no individual diagnostic test with sufficient specificity and sensitivity to reliably detect familial
hypercholesterolaemia. Therefore, three international groups have developed diagnostic tools for familial
hypercholesterolaemia based on clinical signs, family history, and cholesterol measurements. The National Institute for Health and Clinical Excellence (NICE) guideline on identification and management of familial hypercholesterolaemia.


Clinical features
Ask about any relatives with early coronary heart disease. Onphysical examination, determine the presence of tendon xanthomas or yellow coloured cholesterol deposits, which are usually hard and non-tender.
The most common sites for the nodules include the dorsum of the hands and the Achilles tendons, while, rarely, nodules can be present on the extensor hallucis longus and triceps tendons.

A study of 133 patients with familial hypercholesterolaemia found they were seven

times more likely to experience Achilles tendon pain lasting more than three days, but this rarely leads to diagnosis. While the overall diagnostic value is difficult to determine, in patients referred to a specialist clinic for suspicion of familial hypercholesterolaemia, family history or presence of tendon xanthoma increased the odds of a relevant mutation being detected by 7.8 and 3.7 times respectively.

However, tendon xanthoma is classically not present until the third decade of life and is therefore not helpful in diagnosis of younger patients.
In two studies of children with familial hypercholesterolaemia, none had tendon xanthoma. Xanthelasma and premature corneal arcus are less useful, but their presence should prompt investigations.

Investigations

Consider familial hypercholesterolaemia in adults with a fasting total cholesterol concentration >7.5 mmol/L and in children aged <16 years with total cholesterol >6.7 mmol/L.
Triglycerides are usually in the normal range. All measurements should be confirmed at least twice because of biological and analytical variability.

Exclude common causes of secondary

hypercholesterolaemia such as hypothyroidism, diabetes, pregnancy, and drugs (such as thiazide diuretics and steroid hormones). NICE does not recommend the use of ultrasonography of the Achilles tendon for diagnosis or detection
of tendon xanthoma.
A 2005 study found physical examination and ultrasound had similar detection rates.

Patients with definite or possible familial hypercholesterolaemia according to the Simon Broome Register Group definition should have cascade screening of first degree relatives.
Cascade screening is a cost effective way of detecting elevated cholesterol concentrations in family members. Genetic testing for familial hypercholesterolaemia can be helpful in future case identification and in cascade screening, but it probably has only a limited value in the clinical management of the individual.


How is familial hypercholesterolaemia managed?
Do not use risk estimation tools (such as the Framingham risk score) in these patients, as such tools underestimate their increased risk of premature heart disease. Provide lifestyle advice (for example, diet, physical activity, and stopping smoking) and start a high dose statin (such as simvastatin 80 mg or atorvastatin 40 mg) with an aim of reducing LDL cholesterol concentration by >50%.

Additional treatment may be required to achieve this. Monitor for drug side effects,annually reassess cardiovascular risk factors and symptoms,
and attend to these as necessary. Children, adults at very high risk, and those who fail to respond to treatment should be referred to a specialist for consideration of further management options (such as combination drug therapy and lipoprotein apheresis).

How common is familial hypercholesterolaemia?

• Heterozygous familial hypercholesterolaemia affects about 1 in 500 people (about 110 000 people in the UK)
• An average UK general practice with 8000 patients will have about 16 patients with familial hypercholesterolaemia clustered in five to seven families.
• Certain populations have a higher frequency of familial hypercholesterolaemia such as Afrikaners in South Africa (1 in 70) and French Canadians (1 in 200).
• Homozygous familial hypercholesterolaemia occurs with a frequency of 1 in 1 000 000 people.

Simon Broome Register Group definition of familial hypercholesterolaemia

• Definite diagnosis of familial hypercholesterolaemia requires presence of (a) plus (b) below
• Possible familial hypercholesterolaemia requires presence of (a) plus one of (c) or (d)
(a) At least two confirmed measurements of total cholesterol >7.5 mmol/L and LDL cholesterol >4.9 mmol/L in adults (total >6.7 mmol/L and LDL >4.0 mmol/L in children aged <16 years)
(b) Tendon xanthoma in patient or DNA based diagnosis of familial hypercholesterolaemia in first or second degree relative
(c) Family history of myocardial infarction in second degree relative <50 years or in first degree relative aged <60 years
(d) Family history of high cholesterol in first degree relative or concentration >7.5 mmol/L in second degree relative

Key points

• Familial hypercholesterolaemia carries a high risk of premature cardiovascular morbidity and mortality
• Most cases of heterozygous familial hypercholesterolaemia are missed in general practice
• Consider familial hypercholesterolaemia in patients with a fasting total cholesterol >7.5 mmol
• Specific physical findings may occur after the third decade and include tendon xanthoma, corneal arcus, and xanthelasma
• Ensure cascade screening of all first degree relatives
• Early identification and treatment with statins can prolong life by about nine years


FDA Safety Changes: Statin Label Revised With New Warnings
Medscape Education © 2012 Medscape, LLC 03/02/2012

Clinical Context

Statins are a class of prescription drugs intended to lower blood levels of low-density lipoprotein cholesterol, when used together with diet and exercise. Single-ingredient statins include atorvastatin, fluvastatin, lovastatin, lovastatin extended-release, pitavastatin, pravastatin, rosuvastatin, and simvastatin. Also available are combination statins, including lovastatin/niacin extended-release, simvastatin/niacin extended-release, and simvastatin/ezetimibe.

Study Synopsis and Perspective

The US Food and Drug Administration (FDA) has approved class safety labeling changes for statins, including removal of the recommendation for routine monitoring of liver enzymes and the addition of new information about reversible cognitive adverse effects and reports of increased blood glucose and glycosylated hemoglobin (HbA1c) levels.
In addition, the updated safety label for the statin lovastatin now includes new contraindications and dose limitations when the drug is administered concurrently with certain medications that can increase the risk for myopathy and/or rhabdomyolysis.

"We want healthcare professionals and patients to have the most current information on the risks of statins, but also to assure them that these medications continue to provide an important health benefit of lowering cholesterol," said Mary Parks, MD, director for the Division of Metabolism and Endocrinology Products in the Office of Drug Evaluation II in the FDA's Center for Drug Evaluation and Research, in a news release.

Instead of routine monitoring of liver enzymes, the FDA now recommends that clinicians test liver enzymes in their patients before prescribing statin treatment and as clinically indicated thereafter. Statin treatment should be interrupted in patients who develop serious liver injury with clinical symptoms and/or hyperbilirubinemia or jaundice, and the statin should not be restarted unless an alternate cause is found.

AHA Comments on Changes

"The FDA's announcement on the label changes does not question the benefit of statins to lowering cholesterol, but it does provide patients and healthcare providers the most current information about the safe use of statins," said Gordon F. Tomaselli, MD, president of the American Heart Association (AHA), in an AHA comment on the revised safety labeling for statins.

Dr. Tomaselli also stated that the change to perform liver enzyme tests at baseline and for symptoms is "not surprising."
"This will change practice although I will remain vigilant in people with prior history of liver disease, people who drink or who are taking multiple drugs metabolized by the liver. Also, the contraindications of use of in particular anti-HIV drugs with Mevacor (lovastatin) are important to reemphasize as is the known but infrequent increase in blood sugar in patients taking statins."

Additional Safety Information

Rare postmarketing reports have documented mild, generally reversible symptoms of cognitive impairment associated with statin use. These symptoms may include memory loss, forgetfulness, amnesia, memory impairment, and/or confusion. Times to symptom onset vary from 1 day to years, and resolution of symptoms on statin discontinuation also varies, with a median of 3 weeks.


Statin use has also been linked to increases in levels of HbA1c and fasting serum glucose.
The updated lovastatin label indicates that the following drugs are contraindicated with lovastatin: itraconazole, ketoconazole, posaconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, and nefazodone.

Cyclosporine and gemfibrozil should be avoided in patients taking lovastatin, as should grapefruit juice exceeding 1 quart daily. A daily dose of 20 mg of lovastatin should not be exceeded with danazol, diltiazem, or verapamil, and 40 mg of lovastatin daily should not be exceeded with amiodarone.

Clinical Evidence

The National Lipid Association's Liver Expert Panel and Statin Safety Task Force stated that the available scientific evidence does not support routine liver function test monitoring in asymptomatic patients receiving statins. Irreversible liver damage resulting from statins is exceptionally rare and is likely idiosyncratic, and no data exist showing that routine periodic monitoring of liver biochemistries will identify the very rare individual who may develop significant liver injury.

Routine periodic monitoring could actually identify patients with isolated increased aminotransferase levels, resulting in changes in or discontinuation of statin treatment that could increase the risk for cardiovascular events.

Several FDA postmarketing reviews of its Adverse Event Reporting System (AERS) database between the years 2000 and 2009 showed that reporting of statin- associated serious liver injury to the AERS database was extremely low (reporting rate of ≤ 2 per 1 million patient-years). Among 75 identified cases of severe liver injury, defined as a 4 (severe liver injury) or a 5 (death or liver transplant) using the Drug Induced Liver Injury.

Network liver injury severity scale, none were determined to be highly likely or definitely associated with statin therapy. The FDA concluded that, despite increasing use of statins since the late 1990s, no detectable increase in the annual rates of fatal or severe liver injury cases possibly or probably causally associated with statin use have occurred.

To assess the effect of statins on cognition, the FDA reviewed the AERS database, the published medical literature, and randomized clinical trials. Postmarketing adverse event reports generally were of persons older than 50 years who had noticeable, poorly defined memory loss or impairment that was reversible when statins were discontinued. These cases did not appear to be associated with Alzheimer's disease or other fixed or progressive dementia, nor was there an association between the adverse event and the specific statin, the age of the individual, the statin dose, or concomitant medication use.

In the Justification for the Use of Statins in Primary Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) trial, there was a 27% increase in investigator-reported diabetes mellitus in rosuvastatin-treated patients vs placebo-treated patients. High-dose atorvastatin was also associated with worsening glycemic control in the Pravastatin or Atorvastatin Evaluation and Infection Therapy–Thrombolysis In Myocardial Infarction 22 (PROVE-IT TIMI 22) substudy.
Meta-analyses also showed that statin therapy was associated with a 9% to 13% increased risk for incident diabetes.

New label information regarding drug-drug interactions and contraindications and dose limitations for lovastatin, which is a sensitive in vivo cytochrome P450 3A4 substrate, was based on a literature review. Strong cytochrome P450 3A4 inhibitors are predicted to significantly increase lovastatin exposure.


Healthcare professionals and patients should report any adverse effects associated with statin use to the FDA MedWatch Safety Information and Adverse Event Reporting Program at www.fda.gov/MedWatch/report.htm. They can also download a reporting form at http://www.fda.gov/safety/MedWatch/default.htm or call 1-800-332-1088 to request a reporting form, then complete and return to the address on the preaddressed form, or submit by fax to 1-800-FDA-0178.

Clinical Implications

The FDA now recommends that clinicians test liver enzymes in their patients before prescribing statin treatment and as clinically indicated thereafter, rather than routinely monitoring liver enzymes as was recommended previously. Statin treatment should be interrupted in patients who develop serious liver injury with clinical symptoms and/or hyperbilirubinemia or jaundice, and drug therapy should not resume unless an alternate cause is found for the hepatic dysfunction.

Statin use may rarely be associated with mild, generally reversible symptoms of cognitive impairment, with variable time to symptom onset and resolution of symptoms on statin discontinuation. Statin use has also been associated with increases in levels of fasting serum glucose and HbA1c.
The updated safety label for lovastatin now includes new contraindications and dose limitations when the drug is given concurrently with certain medications that can increase the risk for myopathy and/or rhabdomyolysis.