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 Table of Contents  
CASE REPORT
Year : 2021  |  Volume : 6  |  Issue : 1  |  Page : 92-95

Role of lipoprotein apheresis in the management of familial hypercholesterolemia


1 Department of Cardiology, Manipal Hospital, Bengaluru, Karnataka, India
2 Department of Transfusion Medicine, Manipal Hospital, Bengaluru, Karnataka, India
3 Department of Biochemistry, Manipal Hospital, Bengaluru, Karnataka, India

Date of Submission04-May-2021
Date of Decision10-May-2021
Date of Acceptance11-May-2021
Date of Web Publication29-May-2021

Correspondence Address:
Dr. Ambuja Kantharaj
Department of Transfusion Medicine, Manipal Hospital, Bengaluru, Karnataka
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/gjtm.gjtm_37_21

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  Abstract 


Familial Hypercholesterolemia (FH) is an autosomal dominant disorder due to a congenital absence of low-density lipoprotein receptor (LDL-R) that transports cholesterol-carrying lipoprotein particles into cells. Absence of these receptors results in increased levels Non-HDL lipoproteins (like LDL, VLDL, Triglycerides, Lipoprotein a) which predisposes to premature atherosclerosis and cardiac complications. Treatment modalities for this condition include use of high intensity statins and diet control. However some of these patients with familial hypercholesterolemia do not respond to diet and drug therapy. Here Lipoprotein apheresis is believed to be a feasible and effective option. Lipoprotein apheresis is a relatively new technique in India used to treat familial hypercholesterolemia. Lipoprotein apheresis using cascade filter is effective in reducing non-HDL lipoprotein levels by 60-75% in a single procedure. However, the disadvantage of the procedure it is expensive and needs to be repeated every 2 weeks for lifetime. This case is being reported for rarity of this condition (1 case per million) and more so the rarity of the use of Lipoprotein apheresis procedure in our country.

Keywords: Cascade filtration, familial hypercholesterolemia, lipoprotein apheresis, management of familial hypercholesterolemia


How to cite this article:
Iyengar SS, Kantharaj A, Shivaram C, Hemantha Kumara D S, Murgod R, Shreedhara G. Role of lipoprotein apheresis in the management of familial hypercholesterolemia. Glob J Transfus Med 2021;6:92-5

How to cite this URL:
Iyengar SS, Kantharaj A, Shivaram C, Hemantha Kumara D S, Murgod R, Shreedhara G. Role of lipoprotein apheresis in the management of familial hypercholesterolemia. Glob J Transfus Med [serial online] 2021 [cited 2021 Jun 25];6:92-5. Available from: https://www.gjtmonline.com/text.asp?2021/6/1/92/317172




  Introduction Top


Lipoproteins play a key role in the absorption and transport of dietary lipids by the small intestine, from the liver to peripheral tissues, and from peripheral tissues to the liver and intestine[1] [Table 1].
Table 1: Properties of few lipoprotieins

Click here to view


Familial Hypercholesterolemia (FH) is an autosomal dominant disorder due to mutations involving the genes of LDL receptor or apolipoprotein B or proprotein convertase subtilisin/kexin type 9 (PCSK9). The commonest cause of FH is an inherited loss of function of low-density lipoprotein receptor (LDL-R) that transports cholesterol-carrying lipoprotein particles into liver cells for degradation. LDL is the main transporter of plasma cholesterol carrying 65-70%. Absence of LDL receptors results in increased levels of plasma LDL cholesterol, pre-disposing to premature atherosclerotic cardiovascular disease and mortality.[2],[3]

Patients with homozygous FH (HoFH) inherit the defective gene (LDL-R gene) from both parents as against heterozygous FH which is characterized by inheritance of a single defective gene from one parent. They are prone to coronary artery disease, myocardial infarction, and sudden death in the second decade of life.[4] Hence, controlling levels of non-HDL lipoproteins (such as LDL, very-LDL [VLDL], triglycerides, and lipoprotein A) is important.

Treatment modalities for this condition include the use of high intensity statins and diet control.

However, some of these patients with “FH” do not respond to diet and drug therapy.[5],[6] Here, lipoprotein apheresis is believed to be a feasible and effective option. The advantage of this procedure is that it is effective in people who do not respond to drug therapy and also helps to bring down the cholesterol levels very rapidly unlike drugs which can take weeks to months. The American Society for Apheresis[7] also recommends LDL apheresis for the management of HoFH (Category 1 Evidence Grade 1a). Various methods are available for lipoprotein apheresis[8] such as therapeutic plasma exchange by plasmapheresis, immunoadsorption cascade filtration, Dextran sulfate LDL adsorption (DSA), and Heparin-induced LDL precipitation(HELP).

Cascade filtration or membrane differential filtration is considered superior to conventional plasmapheresis[9] but is less effective than adsorption or precipitation techniques (DSA/HELP).

Double membrane/cascade filters are used to remove High molecular weight substances (like LDL etc.,) while retaining low-molecular-weight substances such as albumin and HDL, thus reducing requirement for albumin replacement. The secondary membrane in cascade filtration has a cutoff of approximately one million daltons. High-molecular-weight proteins (>1 million Daltons) such as LDL cholesterol and lipoproteins are retained in the hollow fibres of the filter, whereas low-molecular-weight proteins such as HDL pass through the filter and are returned to patient with the plasma.

Sieving co-efficient which is defined as the ratio of the solute concentration in the filtrate to the simultaneous solute concentration in plasma is the highest (0.9) for albumin and lowest (0.03) for LDL in the cascade filter used here, and hence, it can remove LDL selectively and retain albumin and HDL.

Lipoprotein apheresis is a relatively new technique in India used[10] to treat familial hypercholesterolemia. Similar procedure has been reported from a premier institute from the northern part of the country . It was in a 6 years old girl of HoFH, reducing the LDL C by 75.9% in the first session safely.. This case is being reported for rarity of this condition (1 case per million) and more so the rarity of the lipoprotein apheresis procedure.


  Case Report Top


A 16-year-old female was diagnosed with HoFH with LDL-R gene mutation. She was on treatment since the age of 6 years but was refractory to the medical line of management with the following drugs Atorvastatin 80 mg, Cholestyramine and Cholesterol absorption inhibitors like Ezetimibe. Parents gave a history of consanguineous marriage. No significant past history was noted. Parents were on statins, and the younger sibling of the patient was normal.

On examination, the patient had xanthomas on the eyelids and on the left cubital fossa. Echocardiogram showed mild valvular and supravalvular aortic narrowing. The patient was offered LDL apheresis. LDL Apheresis was done by Transfusion Medicine department using Fresenius Comtec Cell separator and Plasmapheresis kit (Fresenius Kabi Pvt Ltd, Bad Homburg, Germany) and Evaflux model 5A20, code: 100205, Cascade double membrane filter (Kawasumi Lab, Inc., Tokyo, Japan).

Procedure

The patient was connected to a cardiac monitor for continuous monitoring of vital signs during the procedure. In view of hypotension, the patient was administered 500 ml normal saline (NS) before the start of procedure.

The patient weighed 50 kg was 165 cm in height. Estimated total blood volume (TBV) was 3.5 l and estimated plasma volume was 2.1 l. The plasmapheresis kit was loaded on Fresenius Comtec cell separator. The Cascade filter was then inserted to the plasma return line using compatible intravenous (IV) tubings so that the plasma is filtered to remove non-HDL proteins before being returned to the patient. The outlet of the filter was connected to the plasma return line of the kit to be mixed with other cellular components and returned to the patient. The waste containing non-HDL proteins was diverted to a waste bag using a port at the bottom of the cascade filter. The filter was then primed with 1 l NS. The circuit was set-up, as shown in [Figure 1]. The right femoral vein was used as access line for the apheresis procedure, and the left ante-cubital vein was used as the return line.
Figure 1: Flow diagram of cascade filtration (CF) with evaflux 5A in combination with centrifugal cell separator

Click here to view


The TBV and plasma volume was calculated to be 3.5 Lit–2.1 L, respectively. Approximately 1.5 times, the plasma volume is processed to get the desired results. Plasma flow rate was set at 40 ml/min to start with and then increased to 50 ml/min.

Extracorporeal volume was calculated to be 340 ml (160 ml in Plasmapheresis kit, 140 ml in filter and 40 ml in the tubings) which was <15% of TBV. Patient was infused 2 vials of IV calcium gluconate each in 100 ml NS to manage hypocalcaemia due to acid citrate dextrose (ACD). Approximately 1.5 times the plasma volume, i.e. 3 l of plasma was processed during the procedure and 500 ml of plasma was removed.

Patient tolerated the procedure well. Total cholesterol, lipoprotein, triglycerides, C-reactive protein LDL, apoprotein A1, Apoprotein B, hemoglobin, and platelet count were repeated following the completion of the procedure.

The preprocedure and postprocedure values are shown in [Table 2].
Table 2: Pre-and post-procedure values following low-density lipoprotein apheresis 1st sitting

Click here to view


The patient is planned to receive the next LDL apheresis session every 2 weeks for lifetime. The target of LDL apheresis will be to reduce total cholesterol and LDL levels by >50%–60% from baseline.


  Discussion Top


LDL apheresis is a good alternative to treat HoFH patients who are not responding to medical line of management. The success of the procedure in reducing 60%–75% of lipoproteins in just 2–21/2 h goes to show that it is highly effective in reducing non-HDL lipoproteins to a safe level. LDL, VLDL, Lpa and Apob, all non-HDL proteins were reduced significantly in this case. The German LA Registry study of 1,283 patients with elevated LDL C and Lp(a)concluded that lipid apheresis reduced LDL C by 68.6% and Lp(a) by 70.4%. The major adverse cardiovascular events were reduced by 97% in the first year following lipid apheresis therapy[11] The essential difference between cascade filtration with plasmapheresis and therapeutic plasma exchange is that in the former the plasma minus the undesired elements (LDL and VLDL, etc., is returned to the patient, whereas in the latter, the plasma is removed and replaced with donor plasma. More number of plasmapheresis procedures will be needed to replace cascade filtration and this comes with the additional risks associated with of plasma transfusion.

This was the first procedure done on this patient; usually after lipoprotein apheresis, LDL C and Lp(a) levels show a rebound increase over next 8-13 days[12] and hence the procedure requires to be carried out usually once in two weeks for life to lower risk of progression of atherosclerotic and cardiac complications. A new cascade filter and plasmapheresis kit is needed for every procedure. It is possible that with the advent newer lipid lowering drugs, the frequency of apheresis may be decreased or rarely be given up.

Other challenges of this procedure include securing good long-term venous access like a permcath, etc., for repeated procedures, managing adverse effects during procedure like hypocalcaemia and monitoring for cardiac events. In our patient, we were able to complete the procedure using femoral and antecubital veins. Hypokalcemia may be managed either with oral or IV calcium; although at our center we prefer to administer IV calcium for better compliance and control over calcium levels. Vital signs were monitored continuously using a cardiac monitor as our patient had aortic stenosis and such patients often suffer from atherosclerotic changes secondary to increased lipoprotein levels which may lead to coronary events;[4] hence, precautions need to be exercised.

Lipoprotein apheresis has been in use worldwide[13] in the management of HoFH with significantly elevated LDL-cholesterol and lipoprotein (a) not responding to drug therapy.

Limitations for use of procedure

Despite the enormous benefit, this procedure is seldom used in developing countries because of its cost. This is primarily attributed to the high cost of the cascade filter coupled with the plasmapheresis kit, together with availability of apheresis equipment and skilled workforce. Each procedure costs approximately 60,000/-in Indian Rupees on a fortnightly basis for life.

Future directions

There is a need for active research to develop indigenous cost-effective cascade filters. Till such time, such young patients with hyperlipidemias will continue to lose their life unless helped by the government and philanthropic organizations.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Feingold KR. Introduction to Lipids and Lipoproteins. In: Feingold KR, Anawalt B, Boyce A, et al., editors. Endotext. South Dartmouth (MA): MDText.com Inc; 2000.  Back to cited text no. 1
    
2.
Goldstein JL, Hobbs HH, Brown MS. Familial hypercholesterolemia. In: Scriver CR., Beaudet AL, Sly WS, Valle B, editors. The Metabolic Basis of Inherited Disease. 7th ed. NewYork: McGraw-Hill; 1995. p. 1980-2030.  Back to cited text no. 2
    
3.
Marais AD. Familial hypercholesterolaemia. Clin Biochem Rev 2004;25:49-68.  Back to cited text no. 3
    
4.
Sanna C, Stéphenne X, Revencu N, Smets F, Sassolas A, Di Filippo M, et al. Homozygous familial hypercholesterolemia in childhood: Genotype-phenotype description, established therapies and perspectives. Atherosclerosis 2016;247:97-104.  Back to cited text no. 4
    
5.
Wiegman A, Gidding SS, Watts GF, Chapman MJ, Ginsberg HN, Cuchel M, et al. Familial hypercholesterolaemia in children and adolescents: Gaining decades of life by optimizing detection and treatment. Eur Heart J 2015;36:2425-37.  Back to cited text no. 5
    
6.
Lambert CT, Sandesara P, Isiadinso I, Gongora MC, Eapen D, Bhatia N, et al. Current treatment of familial hypercholesterolaemia. Eur Cardiol 2014;9:76-81.  Back to cited text no. 6
    
7.
Schwartz J, Padmanabhan A, Aqui N, Balogun RA, Connelly-Smith L, Delaney M, et al. Guidelines on the use of therapeutic apheresis in clinical practice-evidence-based approach from the Writing Committee of the American Society for Apheresis: The seventh special issue. J Clin Apher 2016;31:149-62.  Back to cited text no. 7
    
8.
Bambauer R, Bambauer C, Lehmann B, Latza R, Schiel R. LDL-apheresis: technical and clinical aspects. ScientificWorldJournal 2012;2012:314283. Available from: https://pubmed.ncbi.nlm.nih.gov/22654591/.  Back to cited text no. 8
    
9.
Kardaş F, Cetin A, Solmaz M, Büyükoğlan R, Kaynar L, Kendirci M, et al. Successful treatment of homozygous familial hypercholesterolemia using cascade filtration plasmapheresis. Turk J Haematol 2012;29:334-41.  Back to cited text no. 9
    
10.
Dogra K, Goyal A, Khadgawat R, Gupta Y, Rout D, Fulzele PP, et al. Low-density lipoprotein apheresis in a pediatric patient of familial hypercholesterolemia: Primi experientia from a tertiary care center in North India. Asian J Transfus Sci 2017;11:58-61.  Back to cited text no. 10
[PUBMED]  [Full text]  
11.
Schettler VJ, Neumann CL, Peter C, Zimmermann T, Julius U, Roeseler E, et al. Scientific Board aof GLAR for the German Apheresis Working Group. Current insights into the German Lipoprotein Apheresis Registry (GLAR) - Almost 5 years on. Atheroscler Suppl 2017;30: 50-5.  Back to cited text no. 11
    
12.
Moriarty PM, Hemphill L. Lipoprotein apheresis. Endocrinol Metab Clin North Am. 2016;45:39-54.  Back to cited text no. 12
    
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Thompson G, Parhofer KG. Current role of lipoprotein apheresis. Curr Atheroscler Rep 2019;21:26.  Back to cited text no. 13
    


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    Tables

  [Table 1], [Table 2]



 

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