Familial hypercholesterolemia (FH) is an autosomal dominant disorder. The pathogenesis of this disorder is the absence or abnormality of LDL receptors on the cell membrane surface, resulting in abnormal LDL metabolism in the body, resulting in elevated plasma total cholesterol (TC) levels and low-density lipoprotein-cholesterol (LDL-C) levels .
FH is divided into heterozygous FH and pure heterozygous FH. In the United States, the prevalence of heterozygous FH is about 1 in 500, with a slightly higher prevalence in specific populations; pure heterozygous FH is very rare, with an incidence of 1 in a million in the United States. The pathophysiology and genetics of heterozygous FH are briefly described in the new European Atherosclerosis Society (EAS) consensus document for the treatment of underdiagnosis and undertreatment of heterozygous familial hypercholesterolemia [8] Nordestgaard stated that the writing group was able to find data on diagnosis rates for only 20 countries and territories; using an acceptable estimate of the incidence of FH (1/500), the actual number of cases diagnosed: 33,000 in the Netherlands (71% FH diagnosis rate), 68,000 in the United States, and 620,000 in Canada, with a diagnosis rate of <1%. A copenhagen study screened 69,000 people from the general population and found a much higher prevalence of definite or probable FH: 1 case for every 200 people screened. Based on this finding, nordestgaard said that the number of undiagnosed cases of fh worldwide is between 13.7 million and 34.3 million. Europe is 1.8 to 4.5 million.
People with FH have a high risk of early onset coronary heart disease (>50% risk for men at age 50 and >30% risk for women at age 60). The onset of coronary symptoms in untreated patients is delayed by 40 years in men and by 10-15 years in women. Evidence from large clinical trials supports that the application of statins to lower low-density lipoprotein cholesterol (LDL-C) levels reduces cardiovascular morbidity and mortality. There are no randomized placebo-controlled endpoint studies on statin use in the FH population (for ethical reasons) given the high levels of LDL-C in patients with FH that contribute to the associated risk of cardiovascular disease; nevertheless, there are observational studies that confirm that statins can modify the clinical course of this disease. Therefore, intensive lipid management in patients with FH of either sex is very important, with the aim of preventing or delaying the progression of coronary atherosclerosis.
I. Screening and diagnosis
(i) The European Atherosclerosis Society (EAS) group decided that children, adults and families should be screened for FH and family members should be screened for FH if one of the following conditions is met
1. cholesterol in plasma > 8 mmol/L (> 310 mg/dL) in adults.
2, children with > 6 mmol/L (> 230 mg/dL) 6 mmol/L of plasma cholesterol.
3, early-onset coronary artery disease.
4, yellow tumors of the tendons.
5. Sudden premature cardiac death.
(ii) Encourage physicians to develop a “family tree” to track age, LDL levels, and the presence or absence of FH, use the offspring of patients with confirmed disease as index cases, and initiate cascade screening.
(iii) The three main popular clinical diagnostic criteria are the British Simon Criteria, the US MEDPED criteria, and the Dutch Clinical Monitoring Guidelines (DLCN). The consensus recommendation for clinical diagnosis is based on the DLCN, with a score of >8 confirming FH, a score of 6-8 most likely FH, a score of 3-5 likely FH, and a score of 0-2 unlikely FH. Only the factor with the highest score in each group can be selected. Genetic testing is recommended for hypercholesterolemic patients with yellow tumors and early onset coronary artery disease with a score >5. Cholesterol levels (mmol/L) LDLC, ≥8.5LDLC, 6.5C8.4LDLC, 5.0C6.4LDLC, 4.0C4.98531 LDL receptor functional gene mutations were determined as positive.
(d) The clinical diagnosis of FH in China is mainly based on the criteria proposed in Clinical Coronary Heart Disease published in 1998: total serum cholesterol >7.8 mmol/L in adults, total cholesterol >6.7 mmol/L in children under 16 years of age or LDL-C >4.4 mmol/L in adults, and patients or relatives with tendon yellow tumors are diagnosed as pure-allele familial hypercholesterolemia, and those who do not meet the pure-allele criteria are diagnosed as heterozygous familial hypercholesterolemia. The diagnosis of heterozygous familial hypercholesterolemia was made in those who did not meet the criteria. There is a lack of molecular biology diagnosis. Therefore, there is an urgent need to conduct our own FH studies and to develop corresponding standardized management strategies.
II. Treatment goals
In terms of treatment goals, once FH is diagnosed, patients must be treated immediately. In line with the ESC/EAS dyslipidemia guidelines, the primary goal of FH treatment recommended by the consensus is to achieve the LDL-C target. < 2.5 mmol/L (< 100 mg/dl) in adult patients and < 1.8 mmol/L (70 mg/dl) or at least a 50% reduction in LDL-C from baseline levels in patients with coronary artery disease or diabetes. the LDL control goal for children with FH (8-10 years) is < 3.5 mmol/L (< 135 mg/dL), which is more "lenient" because of the need to consider normal growth in children. However, this target value is difficult to achieve with the available therapies in either adult FH or pediatric FH patients. Lowering LDL-C significantly reduces the incidence of cardiovascular events and reduces overall mortality. each 1 mmol/L reduction in LDL-C is associated with a 22% reduction in cardiovascular mortality and a 12% reduction in overall mortality over 5 years.
III. Treatment measures
(i) Lifestyle improvement.
Effective dietary modification and appropriate exercise are the preconditions for treating patients with FH. The level of LDL-C reduction by diet and lifestyle improvement is highly variable, depending on the patient’s initial diet, compliance, and genetic responsiveness. LDL-C decreases by 10-15% in most patients [13,14]. A low-fat diet is emphasized and food fat should be limited to about 25-35 g per day and cholesterol <300 mg per day. for pure subtype fh, repeated blood exchanges are now commonly used to reduce serum ldl levels. Clinicians are encouraged to refer fh patients to a registered dietitian or other qualified nutrition specialist for medical nutrition therapy and advice that will allow for the maximum reduction in ldl-c that can be achieved with dietary control. The diet required by the National Cholesterol Education Program (ncep) Third Adult Treatment Recommendations (atp< span="">III) Therapeutic Lifestyle Change (TLC), for patients with FH, is recommended to limit intake of total fat (25% to 35% of energy intake), saturated fatty acids (<7%= of energy intake), and cholesterol (<200 mg/d=. Patients should also be instructed to consume 2 g/d of plant sterols/sterol esters and 10 to 20 g/d of soluble fiber, both of which can reduce cholesterol absorption.
In addition to following TLC dietary recommendations, patients with FH need to achieve and maintain a healthy weight through physical activity and appropriate caloric intake. If the patient is overweight or obese, significant weight loss can improve lipid levels. A reduction in LDL-C concentrations of approximately 0.8 mg/dl per 1 kg of body weight lost is possible, and limiting alcohol consumption and quitting smoking are recommended. Smoking cessation is known to increase high-density lipoprotein cholesterol (HDL-C) levels to reduce the burden of cardiovascular risk factors other than hyperlipidemia in patients with FH.
The role of dietary modification cannot be ignored in patients with FH receiving pharmacologic therapy, as it can complement lipid-lowering medications in directly reducing LDL-C concentrations. The importance of dietary management for the treatment of hypercholesterolemia needs to be emphasized in patients with FH, and the adverse effects of smoking need to be fully explained.
(ii) Pharmacological treatment
Patients with FH often have a lifestyle improvement program, but in general, lifestyle improvement alone is often not sufficient to achieve LDL-C goals. Since some medications may be harmful during pregnancy and lactation. This section of treatment recommendations for FH focuses on women with no contraindications or non-pregnant women.
1. Statins: Once FH is diagnosed (except for secondary factors causing hypercholesterolemia), adult patients with FH need to be initially treated with a high potency statin (like atorvastatin, resevastatin, pitavastatin, simvastatin) to reduce LDL-C by ≥50% from baseline (with pitavastatin and simvastatin less likely to reduce LDL-C by 50% from baseline levels)
In general, low potency statins (like fluvastatin, lovastatin and pravastatin) are not suitable for the initial treatment of FH patients. Statins inhibit HMGCoA reductase, the rate-limiting enzyme for cholesterol synthesis, resulting in reduced hepatic cholesterol synthesis and upregulation of hepatic LDL receptors. increased LDL receptor activity results in lower circulating LDL-C concentrations. Fifty percent of patients with heterozygous FH have functional LDL receptors, so they respond well to statins. There are even some patients with pure heterozygous FH who have mutations in the LDL receptor gene, but their LDL receptor activity is sufficient for them to respond well to statin therapy. Overall, however, it is not sufficient to achieve LDL-C targets. In patients with hypercholesterolemia, statin application to the maximum allowable dose can reduce LDL-C by 50% to 60%.
2. Non-statin drugs: statin For those patients who cannot use statin, a combination of other LDL-C lowering drugs should be recommended. In those who cannot tolerate the maximum allowable dose of a high-potency statin, the addition of one or more non-statin cholesterol-lowering drugs may also be considered to reduce LDL-C by ≥50%.
(1) Ezetimibe: specifically inhibits the absorption of cholesterol as well as phytol by binding to small intestinal epithelial cells and interfering with the transport of NPC1CL1 steroids. Reduced reabsorption of cholesterol from the intestine to the liver leads to a compensatory increase in hepatic LDL receptors, which increases hepatic uptake of circulating LDL as well as other lipoprotein particles. Ezetimibe can reduce LDL-C by about 15% to 20% when used alone or in combination with a statin, so it can be used in combination with other lipid-lowering drugs in patients with FH who cannot tolerate statins.
(2) Bile acid sequestrants (cauleveram hydrochloride, abciximide cauleenamide, cauletipo): are anion-exchange compounds that block the reabsorption of bile acids in the intestine. They reduce LDL-C concentrations by up to 20% and are used in patients with FH treated with statins who require further LDL-C-lowering combination therapy [39]. They are generally considered safer than other lipid-lowering drugs because they are not systemically absorbed. Severe gastrointestinal adverse effects, especially constipation and multiple drug-drug interactions, can occur with the elimination of bile amines koleleneamine and koletipo. The newest bile acid sequestrant on the market is kolevulan hydrochloride. It has fewer gastrointestinal adverse effects and drug-drug interactions than cholecalciferol and clostebol, and it is effective at lower doses, resulting in better patient compliance in clinical use. It is also approved by the U.S. Food and Drug Administration (FDA) for improving glycemic control in patients with type 2 diabetes. Therefore, colevelam hydrochloride is recommended as a bile acid chelator for the treatment of patients with FH. The combination of colevelam hydrochloride and statin can further reduce LDL-C by up to 20%.
(3) Niacin: Niacin is a water-soluble B vitamin that can lower very low density lipoprotein cholesterol (VLDL-C) as well as LDL-C and raise HDL-C, but there are some adverse effects such as flushing due to its vasodilatation. Niacin is available in three dosage forms: immediate-release, sustained-release, and constant-release. Extended-release products are the most commonly used, and the constant-release formulations are not recommended due to their potential hepatotoxicity. The combination of extended-release niacin (doses up to 2 g/d) with a stable dose of statin is recommended to effectively reduce LDL-C. Although niacin can reduce LDL-c, the results of the HPS2-THRIVE study published in 2013 showed that its addition to statin therapy did not improve prognosis; its incidence of side effects (especially infection and bleeding) was much higher than expected, at 3%; its incidence of myopathy was higher in the Chinese population than in other populations.
(4) Probucol: It is a strong antioxidant, which is beneficial to inhibit the formation and development of AS, and can reduce or subside yellow tumor, and can reduce plasma TC by 25% and LDL-C by 10%-15%, and is more effective when combined with statins. However, there are no clinical studies to confirm its effectiveness in the treatment of familial hypercholesterolemia.
Betablockers (gemfibrozil, fenofibrate, and fenofibrate) lower triglycerides and raise HDL-C, but not LDL-C, and betablockers can increase the risk of statin-induced myopathy [45], so betablockers should be used with caution. However, fenofibrate is an FDA-approved fibrate in combination with a low-dose statin. Trans-omega-3 fatty acid esters can also be applied if elevated triglyceride levels are also present.
(5) New drugs: Among the other drugs that are mainly under development or newly marketed, the following three are able to significantly reduce LDL-c and have been confirmed by more clinical trials: monoclonal antibodies that inhibit the preprotein convertase bacillus subtilis/kexin 9 (PCSK9); Mipomersen, an inhibitor of apolipoprotein B synthesis; and microsomal triglyceride transfer protein (MTP) inhibitors. Antibodies targeting PCSK9 reduce LDL cholesterol levels in statin-intolerant patients; the use of this class of drugs is safe; however, further clinical studies are needed to confirm their improvement of clinical endpoint events.
(6) Others: In addition to phytosterols (stigmasterol) and soluble fiber, which are used as adjuncts to the TLC diet, other non-drug lipid-regulating substances like soy, red yeast, and green tea are helpful for some patients with hypercholesterolemia. However, these substances need to be used with caution in patients with FH who are already receiving multiple medications: soy (with an FDA-approved indication for cholesterol lowering, but recent studies suggest a very weak effect); black currant (some products contain lovastatin as the active ingredient, so they should be used as such and not in combination with other statins); and green tea (only epidemiological data suggest a cholesterol-lowering effect, but no clinical trial data confirm it). (and lack of clinical trial data to confirm).
3. Combination therapy: Another important factor to consider when choosing combination therapy is the potential drug-drug interactions. Drug-drug interactions of statins are related to cytochrome P450 metabolism, drug transporters, and acidification. Therefore, caution is needed when combining statins with the following drugs: fibrates (mainly gemfibrozil), antifungal drugs (except terbinafine, which can be combined with statins), macrolides, antiarrhythmic drugs, cyclosporine, and protease inhibitors. Caution is also needed when taking statins in patients who regularly consume grapefruit juice. Because risuvastatin, unlike atorvastatin and simvastatin, is not metabolized by the cytochrome P450 3A4 pathway, it is less likely to interact with other drugs. Bile acid sequestrants, especially abbreviated bile amine kolelene amine and koletipo, can reduce the absorption of other drugs. Ezetimibe inhibits the absorption of cholesterol by a specific mechanism of action and therefore does not interfere with the absorption of other drugs.
Other major factors to consider when choosing combination therapy include abnormalities in other components of lipids and comorbidities, especially hypertension, diabetes (type 1 or 2), and obesity, which can increase the risk of coronary heart disease. In addition to treating hypercholesterolemia, the prognosis of patients with FH depends largely on the degree of LDL-C reduction, but treatment of other modifiable risk factors such as hypertension, diabetes, and smoking can further reduce the risk of heart disease.
4. Eluting therapy: For patients who cannot achieve LDL reduction through diet and maximal dose of medication (after 6 months), as well as those who cannot tolerate medication or have contraindications, an LDL-eluting regimen can be considered and is recommended for patients with: pure-compound FH with LDL-C ≥ 300 mg/dl (or non-HDL-C ≥ 330 mg/dl); heterozygous FH patients with LDL-C ≥ 300 mg/dl (or non-HDL-C ≥ 330 mg/dl) combined with 0 to 1 risk factor; heterozygous FH patients with LDL-C ≥ 200 mg/dl (or non-HDL-C ≥ 230 mg/dl) and high-risk features such as ≥ 2 combined risk factors or lipoprotein(a) ≥ 50 mg/dl; ④ heterozygous LDL-C ≥ 160 mg /dl (or non-HDL-C ≥190 mg/dl) and combined very high-risk features (diagnosed coronary artery disease, other cardiovascular disease, or diabetes). Elution of LDL is an FDA-approved method for selective removal of ApoB particles from the circulation by in vitro precipitation with the application of dextrose fibrin sulfate or heparin. This procedure needs to be repeated every 1 to 2 weeks. In a single operation, elution of LDL typically removes at least 60% of the lipoproteins contained in ApoB. The higher the baseline lipid level, the better the response to eluting LDL treatment. Given the cyclic nature of ApoB synthesis and circulation, hypercholesterolemia usually recurs at approximately 12 to 13 days. Concurrent statin application enhances the effect of eluting LDL. Long-term treatment can reduce LDL-C by 20% to 40%.
It can improve endothelial function, dilate coronary arteries, and improve microcirculation as well as myocardial perfusion. LDL elution can also contribute to the regression of lipoflavinomas and improve markers associated with vascular disease, including lipoproteins (a) LDL elution is the only treatment option that can cause a sustained decrease in lipoproteins; (b) by more than 50%. Although LDL elution is effective in halting the progression of atherosclerosis and is the only treatment option available for pure-sibling FH, it is time-consuming (taking more than 3 hours every 1 to 2 weeks) and very expensive.
(iii) Pregnant women
Statins, ezetimibe, and niacin should not be used in women who are pregnant or breastfeeding; women with FH should discontinue statins, ezetimibe, and niacin for at least 4 weeks prior to pregnancy advice or withdrawal of contraception and should not take these medications during pregnancy or breastfeeding. Women who are pregnant are advised to take other lipid-lowering medications as recommended by their physician. For women with FH who are unintentionally pregnant, statin, ezetimibe, and niacin therapy should be discontinued immediately and consult a physician as soon as possible.
Treatment options during pregnancy: LDL-C concentrations may increase during pregnancy due to hormonal changes. Since cholesterol is necessary for the development of the embryo and fetal nervous system, such changes are considered beneficial in non-FH patients. However, in female patients with FH, hormone-induced increases in cholesterol and discontinuation of statins (Class X), ezetimibe (Class C) and niacin (Class C) to prevent birth defects can lead to increased cardiovascular risk in patients. Ciclesviram hydrochloride is a class B lipid-lowering agent in pregnancy and thus can be used when the indication is proven. However, controlled trials cannot be performed during pregnancy. Eluting LDL therapy may be considered during pregnancy if definite atherosclerotic disease is present or if there is a pure-compound FH. Although not explicitly recommended, case-based studies have provided evidence regarding the safety of eluting LDL therapy during pregnancy in female patients with FH.
(iv) Difficult to manage patients
Among patients with hypercholesterolemia, there is a subset of patients whose LDL-C does not meet the NCEP ATP III target values. Many of them are FH patients and those who do not want to receive lipid-lowering therapy. For these difficult-to-manage patients, especially pure-sibling FH, LDL-C targets cannot be achieved with currently available medications, thus requiring a change in treatment to lower cholesterol. For those who cannot tolerate medication or an eluting LDL approach, other treatment options include partial ileal bypass and liver transplantation. Liver transplantation usually results in a significant reduction in LDL levels because it provides a normal LDL receptor, but is rarely used due to the high risk of transplantation. Partial ileal bypass is also rarely used to treat FH, and gene therapy is another treatment option that is still under investigation due to potential adverse effects and long-term safety.
(v) Psychotherapy: FH often develops in children, and the development of atherosclerosis and coronary artery disease is short and harmful, which easily causes great psychological burden to patients in the following aspects: (i) being labeled as a disease (psychological depression); (ii) lack of security in life and work; (iii) moral reproach from immediate family members; and (iv) concern for offspring. Therefore, the necessary psychological counseling for FH patients and their family members also has an important role to play.
(vi) Gene therapy: For heterozygous FH, the expression of LDLR can be stimulated by drugs to make LDL level decrease. However, for pure heterozygous FH, it is difficult to achieve the purpose of treatment by drug therapy alone. In recent years, with the completion of molecular cloning, the Human Genome Project and the development of gene transfer technology, gene therapy for hereditary diseases has made great progress. Gene therapy is the fundamental treatment for FHC. Within a few years, scientists have established animal models of FHC gene therapy: WHH rabbits [82] (Watanbe heritable hyperlipidemic rabbits) and LDLR knockout rats. The efficacy of WHH rabbits in reducing plasma cholesterol levels was investigated using a modified method of in vivo gene transfer to the liver. The murine leukemia virus-acquired retrovirus (containing LDLR-cDNA) was repeatedly injected into the portal vein and treated with ganciclovir (9-1;3-dihydroxy-2-propoxymethylguanine) after partial (10%) hepatectomy and plasmid/liposome mediated thymidine kinase gene transfer to stimulate hepatocyte proliferation. stimulate hepatocyte proliferation. After 2 to 3 months of treatment, plasma LDL levels decreased by a maximum of 35%, and still 20% of WHH rabbits showed a sustained decrease in LDL levels during the subsequent 52-week follow-up period, and 50% of them also showed a decrease in triglycerides. The safety of this gene therapy has been demonstrated on the basis of the animal studies described above, and its clinical application was initiated by Grossman et al. as early as 1992. The procedure is approximately the same and involves excision of a portion of the liver, isolation of hepatocytes and culture of the hepatocytes and, after at least one cycle of cytokinesis, infection of the hepatocytes with a recombinant retrovirus containing LDL receptor cDNA. The next day, the transfected hepatocytes are injected through a catheter into the inferior mesenteric vein and the liver is removed at the same time. However, there are limitations to this treatment, such as the need for surgical removal of the liver and the need to culture a large number of hepatocytes in vitro, and it is difficult to quantify the transplanted hepatocytes.