Hypercholesterolemia in the form of elevated low-density lipoprotein cholesterol (LDL-C) is a major risk factor for the development and progression of coronary artery disease.1

Familial hypercholesterolemia (FH) is a genetic disease of lipoprotein metabolism with autosomal dominant transmission in which affected individuals present very high LDL-C levels, tendon xanthomas and premature coronary artery disease.2

FH is usually due to loss-of-function mutations in the gene encoding the LDL receptor (LDLR), although loss-of-function mutations in the gene encoding apolipoprotein B (ApoB) and gain-of-function mutations in the gene encoding proprotein convertase subtilisin/kexin type 9 (PCSK9) can also cause FH, albeit more rarely.3

Mutations in the LDLR gene lead to absent or reduced production of the protein depending on the type of mutation; mutations in the APOB gene encode mutant ApoB 100 molecules, which have less affinity for LDLR, thus blocking or reducing the binding of ApoB to LDLR, while gain-of-function missense mutations in the PCSK9 gene enhance LDLR catabolism.4–7

Homozygous FH is extremely rare, with a prevalence of 1/1000000. Most cases of homozygosity involve either the same functional mutation in both alleles (true homozygotes) or different functional mutations in each allele (compound heterozygotes).

Another rare condition that presents the same phenotype as homozygous FH is autosomal recessive hypercholesterolemia (ARH), which is caused by mutations in the gene encoding LDLR adaptor protein 1 (LDLRAP1) and the parents do not usually present dyslipidemia.8

There are also rare cases of double heterozygosity, which present a more severe phenotype than patients with heterozygous FH but less severe than those with homozygous FH.9–11

Heterozygous FH is much more frequent than homozygous FH, with a prevalence of 1/300–500 individuals; it is thus one of the most common severe genetic diseases and is recognized as a public health problem by the World Health Organization (WHO),12,13 who estimate that over 10000000 individuals worldwide have FH. However, less than 10% are diagnosed and of these, less than 25% receive lipid-lowering therapy.13

Treatment of dyslipidemia, for both primary and secondary prevention, focuses on reducing LDL-C. Numerous clinical trials have demonstrated the benefits of statin therapy in reducing LDL-C and cardiovascular (CV) morbidity and mortality.1,14

Among the non-pharmacological treatment options for severely hypercholesterolemic patients who are intolerant or refractory to lipid-lowering therapy is LDL apheresis. There are various techniques, all of which lead to significant and acute reduction in plasma LDL-C levels.15 At Hospital Santo António, Porto, we use the technique of direct adsorption of lipoproteins (DALI).

We describe the experience of the multidisciplinary clinic for lipid disorders assessing severely hypercholesterolemic patients refractory to lipid-lowering therapy who underwent DALI LDL apheresis.

Since 1993 the endocrinology department of Hospital Santo António has had a multidisciplinary clinic for lipid disorders, which includes specialists in endocrinology and nutrition and has a joint working protocol with the cardiology, neurology, clinical chemistry and nephrology departments. There is a weekly clinic whose main function is the study and treatment of severe lipid disorders, and DALI LDL apheresis has been available there since 2008.

Similar to reports in the literature, 96.4% of the sessions were uneventful.21 The overall incidence of adverse events was 3.6%, also similar to that reported by other authors, and treatment had to be suspended in only one case.21 No prolonged or irreversible adverse effects were seen in any patient.

Comparing the adverse effects in our patients with those observed by Bosch et al.,21 the most common adverse effect in our population was angina (1.95% vs. 0.09%), followed by hypotension (0.97% vs. 0.97%), clotting of the extracorporeal circuit (0.32% vs. 0.03%) and anaphylactic reaction (0.32% vs. 0%).

There were six episodes of angina during the 308 LDL apheresis sessions, a higher percentage than that reported in the literature.21 These all occurred in the same patient, who had critical aortic valve stenosis, and were reversed by reducing flow rate and administering fluids, oxygen and nitrates. The etiology of the angina was probably multifactorial but we believe the underlying aortic stenosis was the main factor, since following surgical treatment, there were no further episodes of angina.

Hypotension is reported as the most common complication of LDL apheresis.16,20,21 This may be due to hypovolemia, vasodilation or vasovagal reaction. In the DALI technique, the negatively charged surfaces of the adsorber increase concentrations of factor XII, kallikrein and bradykinin. Bradykinin can cause hypotension, flushing and Quincke's edema. Although it is generated in the adsorber and reinfused into the patient, it is rapidly degraded by angiotensin-converting enzyme (ACE), so levels in the pre-adsorber afferent line are negligible.16,22

The main cause of hypovolemia during DALI apheresis appears to be the initial transfer of blood to the extracorporeal circuit. Like other authors, we replace part of the initial blood volume with saline solution in the contralateral vein while the extracorporeal circuit is filling in order to minimize this effect and prevent hypotension.16

One of the three cases of hypotension was more severe and accompanied by pallor, dyspnea and a feeling of imminent death. This was in a patient who had been prescribed ramipril for the first time and took it inadvertently on the day of the LDL apheresis session. This episode was interpreted as an anaphylactic reaction. The DALI technique can cause severe hypotension in patients taking ACE inhibitors due to decreased bradykinin catabolism through ACE inhibition and the increased bradykinin production associated with the procedure. Drugs that inhibit degradation of bradykinin into inactive metabolites are thus contraindicated in patients undergoing DALI LDL apheresis.21,23

In order to avoid the risk of hypotension in patients undergoing DALI apheresis, ACE inhibitors should be suspended 24 hours before treatment and whenever possible replaced by other antihypertensive drugs, such as angiotensin receptor blockers, that do not inhibit ACE.

Of the three cases of hypotension, two were resolved with intravenous fluid therapy and reduction of flow rate; in the more severe case, LDL apheresis was suspended and oxygen, fluid and intravenous corticosteroid therapy were required.

As described in the literature, 1 ml of ACD-A per 20–40 ml of blood was used to prevent clotting of the extracorporeal circuit, which proved adequate for anticoagulation.20,21 In 308 sessions, there was only one episode of clotting of the extracorporeal circuit (0.32% vs. 0.17%).20

Besides lipoproteins, the DALI column also adsorbs positively charged ions such as calcium and magnesium. We observed no hypocalcemia or hypomagnesemia in our experience, but like other authors we used a priming solution that contains these electrolytes, saturating the column with these cations and thus preventing hypocalcemia and hypomagnesemia during treatment; in addition, an ampoule of calcium gluconate was used prophylactically at the end of each session.24

Iron deficiency, leading to microcytic anemia, has also been reported in patients under chronic LDL apheresis. This may be due to frequent laboratory tests and residual blood loss in the extracorporeal system after each session. No iron deficiency or anemia was observed in our patients.

We used the methodology previously described by us and other authors17,20 to assess the technique's efficacy in terms of lipid parameters.

Mean acute reductions in LDL-C of 63.3% (57.3–69.6%) were obtained, which are similar to those described by other authors and meet the objectives stated in the German clinical guidelines for LDL apheresis.18,21

With regard to long-term reductions in LDL-C, we achieved a mean reduction of 36.0% (25.6–44.2%), slightly lower than reported in the literature21; however, we believe that the difference may be explained by the longer treatment time and larger number of patients, as well as better patient compliance with drug therapy, in these studies.

We obtained a mean acute reduction in non-HDL-C of 62.3% (55.1–68.4%) and a mean long-term reduction of 35.5% (23.9–45.4%), comparable to those seen for LDL-C. We believe that this was due to the characteristics of our patients’ dyslipidemia: hypercholesterolemia but no DM, obesity or metabolic syndrome criteria, and hence no factors that promote the production of VLDL or IDL. On the other hand, it may have been due to TG values of <400, as reflected in a low error rate in calculating LDL-C by the Friedewald formula.25

Acute reductions in HDL-C were similar to those obtained by other authors and are related to low TG levels, which in turn depend heavily on the food ingested prior to treatment sessions. No significant long-term changes in HDL-C were observed, which demonstrates the selectivity of DALI LDL apheresis.

The results reflect the efficacy and selectivity of DALI LDL apheresis and are comparable to those obtained in previous studies of the technique.20,21

In 308 sessions over a 49-month period the technique was shown to be safe, effective and selective for LDL-C, with acute reductions of over 60% and no significant changes in other lipoproteins. The main objective of LDL-C reduction is to prevent the development and progression of atherosclerosis, and the improvement seen in our patients’ lipid profiles was reflected in the absence of disease progression. The selective elimination of LDL-C by DALI apheresis is an important advance in the treatment of hypercholesterolemic patients with high CV risk.26

LDL apheresis in conjunction with lipid-lowering therapy prevented the development of atherosclerosis in patients with severe dyslipidemia and high CV risk.

The low incidence of complications means that LDL apheresis is well tolerated by patients, which is reflected in the high rate of adhesion to the treatment.

DALI LDL apheresis was shown to be a simple, safe and effective treatment in patients with FH refractory to diet modification and pharmacological therapy and should be considered as an adjuvant therapy for hypercholesterolemic patients who are intolerant or refractory to statin therapy and for those with contraindications to drug therapy.

The authors have no conflicts of interest to declare.