Low-density lipoprotein apheresis in a pediatric patient of familial hypercholesterolemia: Primi experientia from a tertiary care center in North India.

Familial hypercholesterolemia (FH) is an autosomal dominant disorder due to mutation of apolipoprotein-B receptor gene causing severe dyslipidemia. Lifestyle modification and medical treatment attenuate the disease progression, but as these fail to control the blood cholesterol levels, low-density lipoprotein (LDL) apheresis comes forth as a treatment option. To the best of our knowledge, the following is the very first case of pediatric FH being treated by LDL-apheresis to be reported from India. A severely malnourished female child presented with yellowish skin lesions over different parts of the body, viz., bilateral Achilles tendon, both knees, elbows, both pinnae, and outer canthus of both eyes. She had a strong family history of borderline hypercholesterolemia and was diagnosed as a case of FH. She was maintained on diet modification. LDL-apheresis was planned as the cholesterol levels were not controlled with the diet modificationt. However, unavailability of an appropriate kit in India for LDL-apheresis led to the use of the modified PL1 kit meant for therapeutic plasma exchange procedures. We conducted two sessions of LDL-apheresis. After the first session, the LDL-cholesterol (LDL-C) level fell by 75.9% and the total cholesterol fell by 73.5%. A second procedure led to a decline in total cholesterol level by 18.6% and LDL-C by 19.46%. Subsequently, she was advised diet modification and statin therapy with regular follow-up after every 6 months. Thus, the cascade filtration technique is a safe and effective treatment option for removing the undesired lipoproteins.

Familial hypercholesterolemia (FH) is caused by the mutation of hepatic cell surface receptor genes for apolipoprotein-B which leads to decreased hepatic low-density lipoprotein (LDL) uptake.[12] This autosomal dominant condition is characterized by severe dyslipidemia and predisposes to premature coronary heart disease.[3] This may be inherited either as homozygous (1 in 1 million) or heterozygous (1 in 500) condition.[14] Treatment plan of such patients dictates lifestyle modification and medical treatment.[2] LDL apheresis comes forth when the aforementioned treatment plan fails to control the blood cholesterol levels or is not tolerated.[3] Although liver transplantation with immunosuppression therapy is the definitive treatment option, it has its own limitations.[5]

Case Report

A 6-year-old severely malnourished female (body mass index = 12.22 kg/m2) child weighing 14 kg, presented with yellowish skin lesions over different parts of the body. The patient was single child born out of nonconsanguineous marriage. She was apparently well till the age of 9 months when her parents noticed multiple small yellowish tuber-like lesions over natal cleft that slowly increased in size and coalesced to form larger lesions. Subsequently, similar lesions were noted over bilateral Achilles tendon, both knees, elbows, over both pinnae, and near the outer canthus of both eyes. She was evaluated in the year 2013 and was diagnosed to be a case of familial hypercholesterolemia. At 3 years of age, she was advised dietary modification as the use of statins were not recommended at this age. There was neither history of chest pain, dyspnea on exertion, palpitation, intermittent claudication, focal neurological deficits or syncope nor history suggestive of any clinical conditions, viz., nephrotic syndrome, cholestasis, hemolysis, overt hypothyroidism, acute intermittent porphyria, any long-term drug intake. The child had a strong family history of borderline hypercholesterolemia as her parents, paternal uncle, paternal grandfather and maternal grandmother were reported to have plasma LDL-C > 130 mg/dL (National Cholesterol Education Program-Adult Treatment Panel III).[6]

Physical examination of the child revealed multiple tuberous xanthomas present in the natal cleft, back of both elbows, knees, dorsum of both hands, and multiple tendon xanthomas over bilateral Achilles tendon and eruptive xanthomas over both the buttocks [Figure 1a-c]. Solitary nodule was present on lateral canthus of both eyes [Figure 1d]. There were no signs of any arcus or xanthelasma. Her hemogram showed hemoglobin of 12.4 g/dL, hematocrit of 34.3%, leukocyte count of 10,300/μL, and platelet count of 380,000/μL. The serum cortisol level, function tests for liver, kidney, thyroid, and urine examination were normal. Other organ systems, on examination, revealed no abnormalities.

Figure 1

Illustrations of lesions of the patient. (a) Lesions at the natal cleft, (b) Lesions at the Achilles tendon, (c) Lesions at the elbows, (d) Lesions at the upper canthi.

Treatment

After being diagnosed with FH, the child was maintained on diet modification. LDL-apheresis was planned as the cholesterol levels were not under control with the diet modification. However, the unavailability of an appropriate kit in the Indian market for LDL-apheresis (P1R, Fresenius Kabi, Hong Kong), led us to use the available PL1 disposable kit (Fresenius Kabi, Hong Kong) used in routine therapeutic plasma exchange (TPE) procedures, after making minor modifications in the circuit. The LDL-apheresis was conducted using COM.TEC (Fresenius Kabi, Hong Kong).

Modification of PL1 kit for low-density lipoprotein apheresis

Before starting the procedure, the PL1 kit was primed with normal saline (0.9% NS) mixed with anticoagulant solution viz. Acid-Citrate-Dextrose-A (ACD-A) solution (Terumo Penpol Ltd., Puliyarakonam, Trivandrum, India). LDL-C was to be extracted from the separated patient's plasma product using a fiber cascade filter (Evaflux Plasma Fractionator, Model: 5A20, Batch No: 140910, Kawasumi Lab Inc., Tokyo, Japan).

The filter was connected with a compatible tubing sets (AV set E, Fresenius Medical Care, China), both at the inlet and outlet ports. It was primed with 1 L of 0.9% NS for removing air from the circuit, before being connected to the primary PL1 circuit. Then, the filter was attached to the plasma outlet line so as to divert the separated plasma from the primary separator through the plasma pump to the cascade filter instead of the waste bag directly. The filtrated plasma through the cascade filter outflow was connected to the replacement loop (kept outside the pump) and the flow from the filter to the waste bag was regulated using a pediatric flow regulator (10% of the plasma flow rate, i.e., approximately 70–140 mL/h). The filtered cholesterol and a small amount of plasma were diverted to and collected in the waste bag. All the modifications of the disposable kit with the filter were done aseptically.

The total blood volume of the child was calculated to be ~1.12 L and the plasma volume of ~670 mL. Therefore, the small blood volume of the patient was compensated by preprocedural priming the inlet and outlet lines with 1 unit of group matched and cross-match compatible (B+) packed red blood cell (hematocrit: 58%) to reduce the total extracorporeal blood volume at any time. Approximately 2 L of plasma was processed in ~2 h at an inflow rate of 15–28 mL/min with anticoagulant: Blood ratio of 1:14 through a double lumen femoral central venous access. During these processes, the vital functions of the patient were closely monitored. The entire procedure was completed without any technical difficulties or discomfort to the patient. A unit of commercially available albumin solution (BUMINATE 20%, 100 mL, Baxter, India) was administered after the completion of procedure to compensate for the lost plasma proteins due to malnourished state of the patient. We conducted 2 sessions of LDL-apheresis 7 days apart for this patient. The pre- and post-apheresis lipid profiles of the patient in both the sessions are depicted in Table 1. After the first session, she was advised diet modification (1600 kCal/day; low fat and low cholesterol diet) and was started on Atorvastatin 20 mg once daily after getting baseline transaminases and creatine phosphokinase levels. Following the second procedure, she was prescribed to continue her diet modification and statin therapy with regular follow-up after every 6 months to evaluate the disease progression and development of hepatic/muscle-related adverse effects of statin therapy as well.

Table 1

Pre- and post-apheresis lipid profile of the patient

Discussion

A nonspecific relatively new treatment modality viz. plasma exchange or therapeutic plasmapheresis was introduced in the early 1970s.[7] Conventional plasmapheresis can be modified into cascade or adsorption types based on the types of filter used for selective removal of plasma constituents.[8] In the cascade filtration method, the separated plasma was filtered through the cascade filter of pore size diameter of 15–30 nm that selectively filters out the larger molecules such as the atherogenic Lp-(a), fibrinogen, LDL-cholesterol (LDL-C), total cholesterol, and triglycerides.[9]

As per the ASFA guidelines released in 2013, cascade filtration plasmapheresis is recommended as a Category 1 treatment option for FH (category 1 and Grade 1a).[10]

In the reported case, after the completion of the first LDL-apheresis, the LDL-C level fell by 75.9% and the total cholesterol fell by 73.5%; thus, resulting a significant decline in LDL-C level of the patient. Subsequently, a second procedure was planned, and total cholesterol was declined by 18.6% and LDL-C by 19.46% [Table 1]. Kardas et al. reported reduction in LDL-C by 70.8%, total cholesterol by 57.9%, high-density lipoprotein cholesterol (HDL-C) by 40.7%, triglycerides by 59.2% after 120 apheresis sessions for 3 pediatric patients.[9] Likewise, Bosch et al. reported 69% reduction in LDL-C, 27% reduction in triglycerides, 52% reduction in total cholesterol, and 11% reduction in HDL-C after treating 12 hypercholesterolemic patients with one session of LDL-apheresis by the LDL absorber (DALI, Fresenius, Germany).[11] Coker et al. performed >600 apheresis procedures for 10 patients over 5 years and reported a reduction of 63% in mean plasma LDL-C using the cascade filtration technique.[12]

The differences in the rate of reduction of the cholesterol may be attributed to the difference in the nature of the patient(s), the equipment used, the amount of blood volume processed, the cascade filter used, the progression of disease, and the stage at which the LDL-apheresis was started, the continued drug regimes that the patient was on and other unforeseeable reasons. However, all authors reported successful post LDL-apheresis reductions in the levels of LDL-C and total cholesterol. Although corroborative patient's symptoms, clinical signs, and long run family history implicate either toward a homozygous or a compound heterozygous expression of the said disease process, the zygosity could not be confirmed by genetic studies in this case.

Conclusion

The cascade filtration technique is a safe and effective treatment option for removing the undesired lipoproteins, viz., LDL-C, total cholesterol and triglycerides from plasma. Although it removes the good lipoproteins and is costly, the benefits most certainly outweigh these side-effects. Hence, to conclude, a routine TPE kit, requiring minor modifications is used for conducting cascade filtration and is an effective basic procedure for patients of FH.

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.