Claudia Morozzi

Severe Hypertriglyceridemia-Related Acute Pancreatitis

Acute pancreatitis is a potentially life‐threatening complication of severe hypertriglyceridemia. In some cases, inborn errors of metabolism such as lipoprotein lipase deficiency, apoprotein C‐II deficiency, and familial hypertriglyceridemia have been reported as causes of severe hypertriglyceridemia. More often, severe hypertriglyceridemia describes various clinical conditions characterized by high plasma levels of triglycerides (>1000 mg/dL), chylomicron remnants, or intermediate density lipoprotein like particles, and/or chylomicrons. International guidelines on the management of acute pancreatitis are currently available. Standard therapeutic measures are based on the use of lipid‐lowering agents (fenofibrate, gemfibrozil, niacin, Ω‐3 fatty acids), low molecular weight heparin, and insulin in diabetic patients. However, when standard medical therapies have failed, non‐pharmacological approaches based upon the removal of triglycerides with therapeutic plasma exchange can also provide benefit to patients with severe hypertriglyceridemia and acute pancreatitis. Plasma exchange could be very helpful in reducing triglycerides levels during the acute phase of hyperlipidemic pancreatitis, and in the prevention of recurrence. The current evidence on management of acute pancreatitis and severe hypertriglyceridemia, focusing on symptoms, treatment and potential complications is reviewed herein.

Lipid and low-density-lipoprotein apheresis. Effects on plasma inflammatory profile and on cytokine pattern in patients with severe dyslipidemia

Available evidence on the effects of therapeutic plasmapheresis (TP) techniques and in particular lipid- and LDL-apheresis (LDL-a) on plasmatic inflammatory mediators including cytokines were reviewed. Studies on this issue are not numerous. However, the review of existing evidence clearly suggests an active role of apheresis on the profile of inflammatory molecules and on cytokine pattern in plasma. These non-lipid-lowering effects can be defined to some extent pleiotropic or pleiotropic-equivalent. Although further studies are desirable, the data reported in this review confirm that lipid- and LDL-a not only show acute lipid-lowering and cholesterol-lowering effects, but also efficacy in reducing several proinflammatory peptides, including cytokines. This effect was not related apparently to lipids and lipoproteins reduction. Thus, TP (lipid- and LDL-a), commonly utilized in the treatment of severe genetically determined lipid disorders, unresponsive to hypolipidemic drugs, offers new possibilities of interpretation of its role in the mechanisms leading to the blockade of atherosclerotic lesion development and progression. The ability of TP on short-term to induce such a profound change in the plasmatic metabolic and inflammatory profiles must be kept in mind in the treatment of acute coronary syndromes, before and after interventions of coronary revascularization, and in the acute phase of cerebrovascular ischemia, at least in patients with severe dyslipidemia. Further studies are needed, in particular aimed at assessing if circulating cytokines may be downregulated by TP not only by direct removal, but through indirect effects on both gene translation and transcription perhaps via the cytokine receptor function.

A three month-old infant with severe hyperchylomicronemia: Molecular diagnosis and extracorporeal treatment

OBJECTIVE Chylomicronemia syndrome presenting in childhood is a rare recessive disorder due to mutations of lipoprotein lipase (LPL) and more rarely of APOC2, APOA5, GPIHBP1 or LMF1 genes. It often requires urgent and suitable treatment to avoid acute pancreatitis. The aim of this study was the molecular characterization and treatment of a 3 month-old infant with plasma triglycerides (TG) > 300 mmol/L. METHODS All candidate genes were sequenced. The patient was submitted to one plasma-exchange (PEX) procedure and subsequently to a rigid lipid-lowering diet (milk: Monogen(®)). RESULTS The proband was homozygous for a novel LPL mutation (c.242G > A, p.G81D) which in silico results pathogenic. After PEX, which was well tolerated, TG dropped to 64 mmol/L. During 5-month follow-up there was a clear trend towards lower and stable TG values. CONCLUSION PEX is applicable in subjects with very low body weight when the extreme severity of the clinical picture has no therapeutic alternatives.

New clinical perspectives of hypolipidemic drug therapy in severe hypercholesterolemia.

Patients with homozygous familial hypercholesterolemia (HoFH) represent the most severe patients within the spectrum of dyslipidemias. Untreated Low-Density Lipoprotein Cholesterol (LDL-C) levels in these patients are usually in the range 500 to 1200 mg/dL. Moreover, these patients exhibit a scarce responsiveness or even non responsiveness to oral lipid lowering agents. Patients with heterozygous familial hypercholesterolemia (HetFH) tend to have untreated LDL-C levels of 250-500 mg/dL. Many of these patients are responsive to 3-hydroxy-3-methylglutaryl-coenzyme A (HMGCoA-reductase) inhibitors (statins) and/or other specific drugs. Unfortunately, a significant subset of these patients (5-10%) have a severe and/or refractory form of HetFH and after current maximal oral therapy, they remain significantly far from treatment goals (The National Cholesterol Education Program (NCEP) ATPIII guidelines). This would be defined as LDL-C levels of ≥ 190 mg/dL - prior Coronary Heart Disease (CHD) or CHD equivalent - or ≥ 250 mg/dL (no prior CHD or CHD risk-equivalent). The only current therapy option for these patients is Low Density Lipoprotein-apheresis (LDL_a). While LDL_a is very effective in reducing LDL-C, many patients do not receive this extracorporeal therapy because of costs and limited availability of LDL_a centers. Recently, new potent lipid-lowering drugs have been developed and are currently under investigation. Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays a critical role controlling the levels of LDL-C. Studies have demonstrated that PCSK9 acts mainly by enhancing degradation of the Low-Density Lipoprotein receptor (LDLR) protein in the liver. Inactivation of PCSK9 in mice reduces plasma cholesterol levels. Since the loss of a functional PCSK9 in human is not associated with apparent deleterious effects, this protease is becoming an attractive target for lowering plasma LDL-C levels either alone or in combination with statins. Mipomersen, an apolipoprotein B (ApoB) synthesis inhibitor, for lowering of LDL-C showed to be an effective therapy to reduce LDL-C concentrations in patients with HoFH who are already receiving lipid-lowering drugs, including high-dose statins. Lomitapide is a potent inhibitor of microsomal triglyceride transfer protein and is highly efficacious in reducing LDL-C and triglycerides (TG). Lomitapide is currently being developed for patients with HoFH at doses up to 60 mg/d. These new powerful lipid-lowering drugs might be possibly superior than available hypolipidemic agents. Their mechanisms of action, effectiveness, safety, and indication in severe, genetically determined dyslipidemias, are reviewed.

Toward an international consensus—Integrating lipoprotein apheresis and new lipid-lowering drugs

BACKGROUND Despite advances in pharmacotherapy of lipid disorders, many dyslipidemic patients do not attain sufficient lipid lowering to mitigate risk of atherosclerotic cardiovascular disease. Several classes of novel lipid-lowering agents are being evaluated to reduce atherosclerotic cardiovascular disease risk. Lipoprotein apheresis (LA) is effective in acutely lowering the plasma concentrations of atherogenic lipoproteins including low-density lipoprotein cholesterol and lipoprotein(a), and novel lipid-lowering drugs may dampen the lipid rebound effect of LA, with the possibility that LA frequency may be decreased, in some cases even be discontinued. SOURCES OF MATERIAL This document builds on current American Society for Apheresis guidelines and, for the first time, makes recommendations from summarized data of the emerging lipid-lowering drug classes (inhibitors of proprotein convertase subtilisin/kexin type 9 or microsomal triglyceride transfer protein, high-density lipoprotein mimetic), including the available evidence on combination therapy with LA with respect to the management of patients with dyslipidemia. ABSTRACT OF FINDINGS Recommendations for different indications are given based on the latest evidence. However, except for lomitapide in homozygous familial hypercholesterolemia and alirocumab/evolocumab in heterozygous familial hypercholesterolemia subjects, limited data are available on the effectiveness and safety of combination therapy. More studies on combining LA with novel lipid-lowering drugs are needed. CONCLUSION Novel lipid-lowering agents have potential to improve the performance of LA, but more evidence is needed. The Multidisciplinary International Group for Hemapheresis TherapY and Metabolic DIsturbances Contrast scientific society aims to establish an international registry of clinical experience on LA combination therapy to expand the evidence on this treatment in individuals at high cardiovascular disease risk.

Apheresis-inducible cytokine pattern change in severe, genetic dyslipidemias

OBJECTIVE The effects of direct adsorption of lipids LDL-apheresis (DALILDL-a) on plasma cytokines in two Homozygous and heterozygous familial hypercholesterolemic (HozFH, HtzFH) and in four HyperLp(a)lipoproteinemic [HyperLp(a)] patients, were evaluated. METHODS Plasma, macrophage inflammatory proteins 1α (MIP-1α), macrophage inflammatory proteins 1β (MIP-1β), monocyte chemoattractant protein-1 (MCP-1), RANTES (Regulated upon Activation, Normal T-cell Expressed, and Secreted), granulocyte-colony stimulating factor (GCSF), granulocyte macrophage-colony stimulating factor (GM-CSF), interleukin-1α (IL-1α), interleukin-1β (IL-1β), interleukin-2 (IL-2), interleukin-6 (IL-6), interferon-γ (IFN-γ), concentrations, were measured before and after LDL-a on three consecutive sessions for each patient. RESULTS MIP-1α was significantly reduced (P=0.05), while MIP-1β was significantly increased (P=0.05). Plasma MCP-1 was reduced, although not significantly, while RANTES was significantly increased (P=0.05). GCSF and GM-CSF were both significantly reduced (GM-CSF: P=0.05, GCSF: P=0.05, respectively). IL-1α level was significantly reduced (P=0.001). IL-1β, IL-6, and IFN-γ levels were significantly reduced in plasma after apheresis (IL-1β: P=0.001, IL-6: T1 P=0.001; T2 P=0.05, respectively, IFN-γ: P=0.001). IL-2 level in plasma was significantly reduced at T0, and T2, (P=0.001). However, IL-2 level showed a statistically significant increase at T1 (P=0.001). A significant correlation between IL-1α and IFN-γ was found: r=0.882 (P=0.001). CONCLUSIONS In this study LDL-a induced profound changes in several circulating cytokines and promoted anti-inflammatory and anti-atherogenic cytokine profile in plasma of patients with severe dyslipidemia, with pre-existing angiographically demonstrated Coronary heart disease (CHD), and aortic valvular disease (#=1) (AVD).

Italian Multicenter Study on Low‐Density Lipoprotein Apheresis Working Group 2009 Survey

We present results of the second survey of the Italian Multicenter Study on Low‐Density Lipoprotein Apheresis (IMSLDLa‐WG/2). The study involved 18 centers in 2009, treating 66 males and 35 females, mean age 47 ± 18 years. Mean age for initiation of drug treatment before low‐density lipoprotein apheresis (LDLa) was 31 ± 18 years, mean age to the first LDLa was 37 ± 20 years and average duration of treatment was 9 ± 6 years. The techniques used included direct adsorption of lipids, dextran sulfate cellulose adsorption, heparin‐mediated low‐density lipoprotein (LDL) precipitation, cascade filtration, and plasma exchange. The mean treated plasma/blood volumes/session were 3127 ± 518 mL and 8666 ± 1384 mL, respectively. The average plasma volume substituted was 3500 ± 300 mL. Lipid therapy before LDLa included ezetimibe, statins, ω‐3 fatty acids and fenofibrate. Baseline mean LDL cholesterol (LDLC) levels were 386 ± 223 mg/dL. The mean before/after apheresis LDLC level decreased by 67% from 250 ± 108 mg/dL (P = 0.05 vs. baseline) to 83 ± 37 mg/dL (P = 0.001 vs. before). Baseline mean Lipoprotein(a) [Lp(a)] level was 179 ± 136 mg/dL. Mean before/after apheresis Lp(a) level decreased by 71% from 133 ± 120 mg/dL (P = 0.05 vs. baseline) to 39 ± 44 mg/dL (P = 0.001 vs. before). Major and minor side effects occurred in 27 and 62 patients, respectively. Among patients with coronary artery disease (CAD), 62.3% had coronary angiography and 50.4% coronary revascularization before LDLa. Single vessel, double vessel and triple vessel CAD occurred in 19 (30.1%), 15 (23.8%) and 29 (46%) patients, respectively. Both CAD and extra‐CAD occurred in 41.5%, 39% had hypertension, 9.9% were smokers, 9.9% consumed alcohol and 42% were physically active. Ischemic cardiovascular events were not observed in any patient over 9 ± 6 years of treatment. Two centers have also treated 34 patients (females: 17/males 17; no. sessions: 36; average plasma volume treated: 3000 mL) for sudden hearing loss (SHL). Relief of symptoms was obtained, independently of the system used (HELP; cascade‐filtration).

HyperLp(a)lipoproteinaemia: unmet need of diagnosis and treatment?

Lipoprotein(a) (Lp[a]) is a complex of a low-density lipoprotein (LDL)-like particle and apolipoprotein-B100 covalently bound to apolipoprotein (a) (apo[a]). Lp(a) was first described about 50 years ago (1963) by Kare Berg, who found that high serum levels of Lp(a) are inherited and associated with an increased risk of premature cardiovascular disease (CVD)1. Apo(a) is composed of repeated loop-shaped units called kringles, the sequences of which are highly similar to a kringle shape present in the fibrinolytic pro-enzyme plasminogen. Variability in the number of repeated kringle units in the apo(a) molecule gives rise to differently sized Lp(a) isoforms in the population. Based on the similarity of Lp(a) to both LDL and plasminogen, it has been hypothesised that the function of this lipoprotein may represent a link between atherosclerosis and thrombosis. Lp(a) is able to pass through the intima of blood vessels in humans and animals. Accordingly, high plasma levels of Lp(a) may share with LDL atherogenicity, and may stimulate lipid peroxidation and infiltration, smooth muscle cell proliferation and inflammation in the arterial intima in humans.

Severe hypertriglyceridemia-related acute pancreatitis: Myth or reality?

1. Stefanutti C, Labbadia G, Morozzi C. Severe hypertriglyceridemia-related acute pancreatitis. Ther Apher Dial 2013;17: 130–7. 2. Murphy MJ, Sheng X, Macdonald TM, Wei L. Hypertriglyceridemia and acute pancreatitis. JAMA Intern Med 2013;173: 162–4. 3. Third Report of the National Cholesterol Education Program (NCEP). Expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (Adult Treatment Panel III) final report. Circulation 2002;106:3143–421. 4. Lederle FA, Bloomfield HE. Drug treatment of asymptomatic hypertriglyceridemia to prevent pancreatitis: where is the evidence? Ann Intern Med 2012;157:662–4.