Building a better understanding of the burden of disease in familial chylomicronemia syndrome

KEYWORDS:

• FCS
• familial chylomicronemia syndrome
• lipoprotein lipase
• lipoprotein lipase deficiency
• type 1 hyperlipoproteinemia

1. Introduction

Familial chylomicronemia syndrome (FCS), also referred to as type 1 hyperlipoproteinemia or lipoprotein lipase deficiency, is a rare genetic lipid disorder characterized by severe elevations in circulating triglycerides [1]. Patients with FCS typically present with plasma triglyceride levels ranging from 10 to 100 times the normal value (1500–15,000 mg per deciliter [17–170 mmol/L]). [2,3], The condition is often characterized by eruptive xanthomas, lipemia retinalis, chronic anemia, and hepatosplenomegaly [2]. Most concerning, severe hypertriglyceridemia (HTG) predisposes to acute pancreatitis (AP), a serious condition often complicated by the systemic inflammatory response syndrome, multiorgan failure, pancreatic necrosis, and mortality rates as high as 20% in adults [4,5] and 7% in children. [6,7], In addition, patients may complain of fatigue, ‘brain fog’ (i.e. cognitive impairment), and various other symptoms that can impact activities of daily living [8].

With regard to diagnosis, limited guidance in the literature on diagnostic criteria exists, although there are certain disease manifestations that may lead to a diagnosis. For example, FCS should be suspected in patients with extreme hypertriglyceridemia but no secondary cause (e.g. uncontrolled diabetes, alcohol use). Diagnosis is often missed until patients see experienced lipid specialists, and many patients are diagnosed only after having several bouts of acute pancreatitis.

FCS is caused by mutations in either the lipoprotein lipase (LPL) gene, which encodes for the enzyme responsible for the catabolism of triglycerides, or in genes related to the function of LPL, including APOC2, APOA5, LMF1, and GPIHBP1 [2]. As a result, patients cannot efficiently clear circulating triglycerides, resulting in plasma chylomicron accumulation.

Currently, no FDA-approved treatment exists for FCS and patients are left trying to manage their condition with an extremely restrictive diet that is burdensome and difficult for adherence (total fat intake ≤15% of calories). The currently available triglyceride-lowering agents – niacin, fibrates, and omega-3 fatty acids – are generally ineffective in this patient population. In addition to significant limitation of dietary fat, patients need to restrict alcohol intake and avoid certain medications that may elevate triglycerides. Plasmapheresis may be necessary for some patients to manage the condition.

2. Understanding the burden of disease in FCS

The burden of disease for FCS patients remains unclear, mostly due to the rarity of the disease and lack of effective treatments. Self-reported data at FCS patient meetings has elucidated the difficulty living with FCS including frequent and intense abdominal pain, cognitive dulling, anxiety, depression, and impaired social interactions [8]. However, more robust, quantitative data is needed to provide clinicians with a better understanding of disease burden. Additionally, efforts to better understand and characterize the burden of disease in FCS could provide important new insights to potentially address these challenges while identifying new benchmarks to support diagnosis and research new treatments.

Certain literature does highlight some of the potential outcomes of severe hypertriglyceridemia, although not necessarily in the FCS population. For example, Rashid et al. reported patient characteristics, treatment patterns, comorbidities, and risk factors associated with development of AP in patients with severe HTG. Their retrospective analysis of 5550 patients found that 5.4% developed AP and concluded that patients with severe HTG are often underdiagnosed, undertreated, and nonadherent to lipid-lowering therapy. The authors called for improvements in treatment options to reduce the incidence of AP and new economic studies to evaluate the burden of AP on health systems [9].

Gardner et al. reported a prospective multicenter study in 2010 that found a profound impact on the ability to work and interpersonal relationships for patients who experienced chronic pancreatitis. Data from their survey of 111 patients found that 74% of patients had their work life altered by CP, 60% reported that it affected their social lives, and 46% reported that it had an effect on relationships with family and friends [10].

Few studies, however, focus on the burden of disease specifically in FCS patients. Results of a survey of 84 lipidologists found that FCS patients are at greater risk of developing recurrent AP, and death from pancreatitis-related complications is not uncommon [11]. A separate review involving perspectives from 11 FCS patients and nine caregivers showed throughout their disease, individual patients experienced a significant number of pancreatitis attacks (median = 34, range 6–60) and hospitalizations (median = 17, range 2–40). Patients also reported an increased risk of fatty liver disease, cholecystectomy, and diabetes [12]. Collectively, the limited data currently available reinforces the higher risk of medical and psychosocial challenges affecting the physical and emotional health of FCS patients.

A need still remains for additional studies to better understand and measure disease burden from the patient’s perspective. The current paucity of data limits clinician, patient, and caregiver abilities to accurately assess the impact of FCS as well as the effectiveness of treatment modalities. New insights and quantifiable assessments will play a vital role in the development of more effective disease management strategies.

3. Launch of FCS patient-focused research study

An FCS disease state online survey was released in June 2016 to further understand the multidimensional impact of the disease from the perspective of patients. Through this study, called the Investigation of Findings and Observations Captured in Burden of Illness Survey in FCS Patients (IN-FOCUS), people affected by FCS are invited to share a range of details about their experience living with FCS and the impact it has on their physical and emotional health as well as their personal, social and professional lives.

This web-based research (www.fcsinfocus.com) initiative will seek to produce quantifiable findings on burden of disease in multiple areas that are critical to building a better understanding of FCS, including the following:

• Path to a diagnosis: Information on the factors that led to a diagnosis of FCS or HTG, age at time of diagnosis, history of symptoms, profiles of physicians diagnosing FCS, number of physicians patients saw prior to diagnosis, and experience with misdiagnosis.

• Initial perceptions of FCS and treatment: Details on patient’s response to diagnosis, familiarity with FCS at time of diagnosis, guidance provided by physicians at time of diagnosis, and initial impressions of how FCS would impact their life.

• Symptoms: Identification of types of symptoms, frequency, severity and impact of symptoms, acute episodes, or other related medical problems.

• Satisfaction with management of FCS: Review of patient satisfaction with quality of care and ability to manage FCS, including assessments of treatment and benefits of diet modification as an interventional strategy.

• Impact of disease on personal, social, and professional life: Highlight impact of FCS in multiple areas including employment, household/personal activities, relationships and social life, emotional well-being, and impact on family building.

4. Conclusions and perspectives

Without more robust information on quality of life and burden of disease in patients living with FCS, clinicians will continue to lack many essential insights related to the patient experience that can be used to understand disease severity and impact patient care. Concurrently, patients and caregivers will continue to lack many benchmarks against which to measure the frequency and severity of symptoms and their correlating influences on their physical and emotional health, ability to work and live independently, relationships, socialization, and other factors.

Ongoing research such as the IN-FOCUS patient survey and ongoing pipeline development of new molecules that may prove to manage these patients are key contributors to finding solutions to the patient’s burden of illness as well as their clinical parameters. The long-term goal of an effective treatment solution for these patients would address education to the health-care providers in diagnosis, the burden of illness and diet limitations these patients live with, and a comprehensive platform and support program that may be addressed in possible new therapies.

Declaration of interest

Z Ahmad has received honoraria for educational talks: Genzyme, Sanofi, Amgen. Speaker bureau: Amgen & Consultant/Advisory Board: Regeneron, Genzyme. R Halter and M Stevenson are employees of Akcea Therapeutics. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. Writing assistance was utilized in the production of this manuscript and performed by Bill Berry and Sara Zelkovic of Berry and Company and funded by Akcea Therapeutics.

Additional information

Funding

A small stipend was provided by Akcea Therapeutics to Berry and Company to draft an outline of this manuscript.