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Familial Hypertriglyceridemia
Introduction
Familial hypertriglyceridemia (FHTG), also known as type IV familial dyslipidemia, is a genetic disorder characterized by hepatic overproduction of very low-density lipoproteins (VLDL), leading to elevated serum levels of triglycerides and VLDL. This condition typically follows an autosomal dominant inheritance pattern, giving affected individuals a 50% chance of passing the disorder to their offspring. Recent evidence suggests a polygenic basis, with multiple genetic variants contributing to the phenotype.[1]
Type IV familial dyslipidemia falls within the Fredrickson classification system of lipid disorders, also known as the World Health Organization (WHO) classification of hyperlipidemias. Developed by American physician Donald Fredrickson in the 1960s, this system categorizes hyperlipidemias into 5 major types based on the elevation of different lipoproteins.
Clinically, FHTG presents with mild-to-moderate elevations in serum triglyceride concentrations, often accompanied by comorbidities such as obesity, hyperglycemia, and hypertension.[2] Individuals with this disorder frequently have heterozygous inactivating mutations in the lipoprotein lipase (LPL) gene, which alone can significantly raise triglyceride levels. In combination with medications or coexisting conditions, these mutations can further increase serum triglyceride levels and cause acute pancreatitis.[1]
Early identification and intervention are crucial, as individuals with FHTG may be asymptomatic until severe complications arise. Recognizing clinical signs such as xanthomas, hepatomegaly, and lipemia retinalis, along with obtaining a thorough family medical history, aids in the timely diagnosis of this condition. Effective management of FHTG requires a multifaceted approach, integrating lifestyle modifications and pharmacological therapies.
Etiology
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Etiology
FHTG is an autosomal dominant disorder characterized by elevated plasma triglyceride levels due to increased synthesis of VLDL particles by the liver and chylomicrons from the small intestine. While rare monogenic forms of hypertriglyceridemia exist, most cases are polygenic, with the phenotype influenced by the interaction of genetic variants from over 30 genes and environmental factors.[3][4][5] Researchers have identified 6 genes associated with a rare, autosomal recessive form of monogenic hypertriglyceridemia.[6]
A common mutation implicated in the development of FHTG is the heterozygous inactivating mutation of the LPL gene, which encodes for the enzyme LPL. Inactivation of this gene impairs triglyceride hydrolysis within the VLDL core, causing elevated plasma triglyceride levels.[7][8] Additionally, insulin acts as a potent activator of LPL in adipose tissue. Individuals with insulin resistance may exhibit less LPL activity, worsening preexisting FHTG.[9]
Hypertriglyceridemia not only elevates triglyceride levels but also affects other lipid levels and contributes to pathological changes in lipid metabolism and cardiovascular health. For example, elevated triglyceride levels can alter the composition and function of transport lipoproteins, leading to changes in total serum cholesterol and the formation of smaller, denser low-density lipoprotein (LDL) particles, which are more atherogenic than larger LDL particles.[10] The cumulative effect of multiple genetic variants contributes to diverse patient phenotypes and clinical presentations, which can be influenced by secondary factors such as obesity, insulin resistance, diabetes, alcohol consumption, and oral estrogen medication.[11]
Epidemiology
The prevalence of FHTG in the general population is approximately 1%, but it is higher in individuals with obesity, insulin resistance, or a family history of atherosclerotic cardiovascular disease (ASCVD). In families with at least one case of premature ASCVD, the prevalence of FHTG may be as high as 20%.[12]
The frequency of heterozygous carriers of various pathogenic mutations in the LPL gene ranges from 0.06% to 20%, with different mutations causing varying degrees of pathology.[13] The prevalence of FHTG differs across ethnic groups, with Hispanic and East Asian populations showing higher susceptibility than individuals of African or European ancestry.[14]
Pathophysiology
LPL is a key enzyme in metabolizing triglycerides within VLDL particles. Mutations in the LPL gene reduce or eliminate LPL activity, impairing triglyceride metabolism and causing the accumulation of VLDL and triglycerides in the blood. This accumulation leads to the hydrolysis of these particles into free fatty acids (FFAs), which can precipitate acute pancreatitis, the most frequent complication of severe FHTG. The toxic effects of the released FFAs and the induction of pancreatic exocrine enzymes contribute to this condition. Normally, trypsin is activated in the duodenum to aid digestion; however, premature activation within the pancreas leads to autodigestion of pancreatic tissue.
Toxic FFAs induce free radical damage, inhibit mitochondrial complexes, and cause pathological elevations of intracellular calcium concentrations, leading to pancreatic acinar cellular injury and inflammation. The severity of lipotoxicity depends on both the direct effects of lipid metabolism and the overall level of systemic inflammation. Certain FFAs induce tumor necrosis factor-alpha (TNF-α) production, which promotes white blood cell migration and an inflammatory response that worsens acute pancreatitis episodes. FFAs directly stimulate inflammation by causing mitochondrial vacuolization and releasing intracellular contents, inhibiting mitochondrial complexes I and V, reducing adenosine 5'-triphosphate (ATP) production, and inducing cell death.[15] This process also disrupts the pancreatic microvasculature, leading to ischemia-reperfusion injury.[16][17]
Patient body mass index (BMI) correlates directly with the severity of acute pancreatitis episodes. Intrapancreatic fat serves as a site for pancreatic acinar cell necrosis and is associated with more severe acute pancreatitis, as evidenced by macrophage infiltration. Additionally, increased calcium deposition, indicative of fat necrosis through saponification, may occur in patients with FHTG, who often have elevated BMI or obesity. This increases their risk of acute pancreatitis.[15]
In summary, mutations in the LPL gene impair triglyceride metabolism, leading to elevated serum VLDL and triglycerides. This can precipitate acute pancreatitis due to toxic FFAs and the premature activation of pancreatic enzymes. The severity of acute pancreatitis is influenced by BMI and systemic inflammation, with intrapancreatic fat and increased calcium deposition further exacerbating the condition.
Histopathology
Most patients with FHTG have no signs or symptoms, but severely affected individuals may exhibit eruptive xanthomas on physical examination. Histologically, xanthomas appear as lipid-laden macrophages, known as foam cells, within the dermis. These foam cells are surrounded by a mixed inflammatory infiltrate of lymphocytes, histiocytes, and neutrophils.[18]
History and Physical
Patients with FHTG often have a family history of the disorder; however, many individuals are unaware of their family medical history. Unless the patient has familial combined hyperlipidemia (FCHL), a family history of premature ASCVD is usually absent. During a review of systems, patients may report consuming a diet high in fats and simple carbohydrates and leading a sedentary lifestyle, which can exacerbate their condition.
Their personal medical history is frequently noncontributory unless severe hypertriglyceridemia has led to an episode of acute pancreatitis. They may have coexisting conditions that worsen their lipid profiles, such as obesity, diabetes, or treatment with triglyceride-raising medications. Patients with acute pancreatitis typically complain of abdominal pain, nausea, and vomiting.
Most FHTG patients have no signs or symptoms of the condition. However, patients with marked elevations in triglycerides may develop eruptive xanthomas, which are small (1-5 mm) red-to-yellow papules, mainly on the extensor surfaces of the extremities, buttocks, and back.[19][18] Xanthomas are often the only physical examination findings of severe hypertriglyceridemia and require prompt identification and management to prevent complications such as acute pancreatitis. All patients with hypertriglyceridemia or known associated conditions, such as metabolic syndrome or diabetes, should receive a thorough skin examination to check for the presence of xanthomas.
Individuals with severe hypertriglyceridemia may also develop chylomicronemia syndrome, which includes symptoms such as short-term memory loss, hepatosplenomegaly, pancreatitis, dyspnea, and abdominal pain.[20] Patients with extremely high triglyceride levels, often exceeding 2500 mg/dL, may exhibit lipemia retinalis, characterized by a creamy white discoloration of the retinal vasculature due to lipid accumulation in the blood.
Evaluation
The best way to evaluate patients with FHTG involves taking a comprehensive medical history, performing a thorough physical examination, and interpreting specific laboratory tests. FHTG is characterized by elevated VLDL levels, with triglyceride values typically ranging from 200 to 1000 mg/dL. Affected individuals often have low or normal LDL and high-density lipoprotein (HDL) cholesterol levels. They are generally asymptomatic unless severe hypertriglyceridemia develops, with levels greater than 500 mg/dL, which increases the risk of acute pancreatitis.[12]
Clinical practice guidelines from The Endocrine Society emphasize distinguishing FHTG from other hypertriglyceridemia syndromes, such as FCHL, which are associated with a higher risk of premature ASCVD.[21] FCHL often presents with elevated apolipoprotein B (apoB) or LDL cholesterol concentrations, which are not typically seen in FHTG.
After the history and physical examination, obtaining a fasting lipid profile is the next step in diagnosing FHTG. Elevated triglyceride levels without known secondary causes suggest a genetic disorder.[21] According to the Endocrine Society guidelines cited by Berglund et al, the following values determine the severity of triglyceride levels:
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Mild: 150 to 199 mg/dL
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Moderate: 200 to 999 mg/dL
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Severe: 1000 to 1999 mg/dL
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Very severe: ≥2000 mg/dL[21]
Evaluating affected patients includes assessing other potential comorbid conditions that augment disease progression, such as obesity, insulin resistance, diabetes, nephrotic syndrome, hypothyroidism, and cardiovascular disease. Clinicians should obtain hemoglobin A1c, fasting blood glucose, and liver and thyroid function tests when clinically indicated. Patients with FHTG can develop insulin resistance, leading to diabetes, and insulin resistance also exacerbates hyperlipidemia.[22][9] Patients at increased risk of ASCVD should undergo a baseline electrocardiogram (ECG).[23] Clinicians must identify secondary causes of elevated triglycerides, such as alcohol use, obesity, and prescription medications, including estrogens, corticosteroids, beta-blockers, and antiretroviral therapy.[24][25][26]
While not usually necessary, genetic testing can help distinguish FHTG from other genetic lipid disorders. Identifying specific genes and single-nucleotide polymorphisms associated with triglyceride metabolism can aid in a precise diagnosis.[27] Family members of patients should know their fasting lipoprotein profile and receive counseling, but current recommendations do not include routine screening by genetic testing.[6] While such testing can identify specific mutations, it is not essential in most clinical settings as it will not influence the management of FHTG for patients. The primary approach to evaluating all patients with FHTG and their at-risk family members involves a thorough personal and family medical history, careful physical examination, fasting lipoprotein profiles, and assessment of secondary factors exacerbating hypertriglyceridemia.
Treatment / Management
The treatment of FHTG involves a multifaceted approach aimed at reducing triglyceride levels to mitigate the risk of acute pancreatitis and ASCVD. However, conflicting evidence exists regarding the association between elevated triglyceride levels and ASCVD risk if other lipoprotein levels are within normal limits. The American Heart Association (AHA) has stated that the increased prevalence of metabolic syndrome, characterized by insulin resistance, hypertension, and central obesity, in FHTG patients could contribute to a higher ASCVD risk.[12]
The first step in the management of FHTG is lifestyle modification. Patients usually benefit from a low-fat diet, reducing intake of simple carbohydrates and sugars, and avoiding alcohol. Although dietary fat is not a primary source of serum triglycerides, consuming primarily monounsaturated and polyunsaturated fats rather than saturated fats may improve the lipid profile. Depending on triglyceride levels, recommendations include a total fat intake of 10% to 30% of total calories. Eating fatty fish or taking fish oil supplements with omega-3 fatty acids may also help reduce VLDL and triglyceride levels.[28][29][30] Dietary recommendations include consuming high-fiber foods such as whole grains, legumes, fruits, and vegetables. In addition, clinicians should encourage patients to participate in regular, moderate, and high-intensity physical activities to improve triglyceride levels.[31](A1)
When lifestyle interventions fail to sufficiently lower triglyceride levels to reduce the risk of acute pancreatitis and ASCVD, medication becomes the next step in treatment. Pharmacotherapy recommendations are according to the American College of Cardiology (ACC) and the AHA guidelines, as mentioned below.
Severe Hypertriglyceridemia (Triglyceride Levels ≥500 mg/dL)
Fibrates
Fibrates effectively treat FHTG through several mechanisms targeting lipid metabolism and reducing triglyceride levels. They can decrease triglyceride levels by approximately 50% or more. Fibrates activate peroxisome proliferator-activated receptor-alpha (PPAR-α)—a nuclear receptor regulating the transcription of genes involved in lipid metabolism. This action leads to increased LPL expression, which enhances the hydrolysis of triglycerides in VLDL and chylomicrons and reduces plasma triglyceride levels.[32][21] Fibrates also decrease the hepatic production of apolipoprotein C-III (apoC-III), an LPL inhibitor, and increase the synthesis of apolipoproteins A-I and A-II, which are the major components of HDL. (A1)
Fenofibrate is preferred over gemfibrozil due to a lower risk of severe myopathy when combined with statin medications. Patients tend to tolerate fenofibrate better than gemfibrozil; once-daily dosing improves compliance. Fibrates may cause dose-related increases in serum transaminases, so routine monitoring of liver function tests is recommended, especially at baseline and periodically during therapy.[32][21][33][34](A1)
Omega-3 fatty acids
Prescription omega-3 fish oil (2-4 g daily) is recommended to treat severe hypertriglyceridemia, lower triglyceride levels, and reduce the risk of acute pancreatitis. Icosapent ethyl is a highly purified prescription form of eicosapentaenoic acid (EPA) ethyl ester derived from fish oil. Icosapent ethyl reduces hepatic VLDL synthesis and enhances triglyceride clearance, similar to the omega-3 fatty acids found in fish oil. However, the specific formulation of icosapent ethyl is more effective in lowering triglyceride levels and decreasing ASCVD risk than over-the-counter nutritional supplements.[35](B3)
Statins
For patients with severe hypertriglyceridemia and an elevated risk of ASCVD, statins are often prescribed with fibrates, which can reduce VLDL and non-HDL cholesterol levels.
Mild-to-Moderate Hypertriglyceridemia (Triglyceride Levels 150-499 mg/dL)
Statins
For patients with mild-to-moderate hypertriglyceridemia and poorly controlled significant risk factors for ASCVD and a 10-year ASCVD risk (≥7.5%), statin therapy reduces VLDL and the risk of ASCVD.
All patients with FHTG should address modifiable causes contributing to elevated triglyceride levels, including weight loss, smoking cessation if indicated, regular aerobic exercise, a diet low in simple carbohydrates and sugars, and avoiding medications that adversely affect the lipid profile. Previously, niacin was often prescribed for FHTG but is no longer favored due to its lack of additional cardiovascular benefit, significant adverse effects, and the availability of more effective and better-tolerated alternatives such as fibrates and statins. Adverse niacin effects include hepatotoxicity, gastrointestinal distress, cutaneous flushing, and hyperglycemia.[36]
Emerging and investigational therapies for FHTG focus on triglyceride metabolism and include apolipoprotein C-III inhibitors, such as volanesorsen and olezarsen, monoclonal antibodies, fibroblast growth factor analogs, and drugs targeting LPL-modulating proteins. These treatments offer specific interventions to manage FHTG, potentially reducing the risk of acute pancreatitis and cardiovascular events. Ongoing clinical trials are evaluating their long-term efficacy and safety.
Olezarsen, administered as a monthly injection, has recently received a "fast-track" designation from the US Food and Drug Administration (FDA) for treating familial chylomicronemia and has shown promise in managing FHTG. It is a synthetically modified DNA fragment that targets hepatocyte mRNA to inhibit apolipoprotein C-III (APOC3) synthesis, thus enhancing the clearance of triglyceride-rich lipoproteins. Clinical trials have demonstrated a reduction in plasma triglyceride levels by approximately 60% after 6 months.[37][38][39][40]
In summary, clinicians should prescribe medication for patients with FHTG whose triglyceride levels exceed 500 mg/dL to prevent acute pancreatitis and for those with moderate hypertriglyceridemia and elevated ASCVD risk. The ACC and AHA guidelines recommend fibrates, omega-3 fatty acids, and statins as primary pharmacological interventions. Regular monitoring of fasting lipid profiles is essential to assess the effectiveness of therapy.
Differential Diagnosis
When evaluating a patient for FHTG, clinicians must rule out other conditions that cause elevated triglyceride levels to distinguish primary hypertriglyceridemia from secondary causes such as uncontrolled diabetes mellitus, obesity, hypothyroidism, renal disease, heavy alcohol use, and the effects of medications like corticosteroids, beta-blockers, estrogens, and antiretroviral therapy. Genetic lipid disorders, such as FCHL and type III hyperlipoproteinemia, can present with similar lipid profiles as FHTG and should be considered in the differential diagnosis.[22][24][25]
Laboratory assessments, including fasting lipid panels, liver, kidney, and thyroid function tests, as well as specialized genetic testing, can help distinguish FHTG from secondary causes and other genetic conditions. These include FCHL, familial dysbetalipoproteinemia, familial chylomicronemia syndrome, and familial hypoalphalipoproteinemia. Accurate diagnosis relies on a thorough medical history, physical examination, and specific laboratory tests to investigate and exclude other etiologies of hypertriglyceridemia.[26][41][42]
Toxicity and Adverse Effect Management
Drug toxicity and the management of adverse effects are crucial considerations when treating patients with FHTG. The primary therapeutic agents, including fibrates, statins, omega-3 fatty acids, and niacin, have unique adverse effect profiles and management strategies.
When combined with statins, fibrates—particularly gemfibrozil more than fenofibrate—can increase the risk of statin-induced myopathy and rhabdomyolysis. When combined with statins, fibrates, especially gemfibrozil, can increase the risk of statin-induced myopathy and rhabdomyolysis more than fenofibrate. Clinicians should inquire about muscle pain, tenderness, or weakness in patients on combined therapy and adjust doses as needed. Fibrates may also precipitate gallstones, particularly in individuals with a history of cholelithiasis or those already at risk for gallstone formation. Patients may experience gastrointestinal discomfort, which often improves over time or when the medication is taken with food.[43][44][45]
Statins can independently cause myopathy and hepatotoxicity. Clinicians should regularly monitor patients for muscle symptoms and perform routine liver enzyme testing. Adjustments to the dosage and consideration of alternative lipid-lowering therapies may be necessary to manage these adverse effects.
Omega-3 fatty acids frequently cause dyspepsia and a fishy aftertaste. They are also associated with an increased risk of bleeding, particularly in patients on anticoagulants or antiplatelet therapy, who should be monitored regularly for bleeding complications. Advising patients to take omega-3 fatty acid preparations with meals can help reduce gastrointestinal symptoms, and considering alternative formulations if intolerance persists may minimize adverse effects.[46]
Niacin can have significant adverse effects, including cutaneous flushing, hepatotoxicity, and hyperglycemia. Flushing is the most common adverse effect and can be minimized by taking the medication after meals and pretreating with aspirin. Niacin may also cause hyperuricemia and increase the risk of developing gout, potentially necessitating discontinuation of the medication and treatment for gout. Due to these adverse effects and the lack of additional ASCVD benefits when added to statin therapy, niacin's use in FHTG is limited.[21][29] In summary, managing FHTG with fibrates, omega-3 fatty acids, statins, and niacin requires careful selection of agents, appropriate dosing, and regular monitoring to minimize adverse effects and optimize therapeutic outcomes.
Prognosis
The prognosis for patients with FHTG is generally favorable, as it is not typically associated with an increased risk of premature ASCVD if the lipid profile is otherwise within normal limits. However, individuals with FHTG are at an elevated risk for developing acute pancreatitis and chylomicronemia syndrome, particularly in the presence of secondary factors that exacerbate hypertriglyceridemia.[21]
Treatment focuses on lifestyle interventions and pharmacotherapy to reduce triglyceride levels and prevent complications. Patients with FHTG who effectively manage this chronic condition can expect to lead a healthy life.
Complications
FHTG and its treatments are associated with several known complications, including acute pancreatitis, cutaneous xanthomas, lipemia retinalis, an increased risk of ASCVD, and gallstones. Elevated serum triglyceride levels directly correlate with the risk of pancreatitis, particularly when levels exceed 500 mg/dL. When triglyceride levels exceed 1000 mg/dL, the risk of pancreatitis is about 5%, which increases to 10% when levels surpass 2000 mg/dL. The incidence of acute pancreatitis is higher in patients with a history of pancreatitis in the previous year. Treatment involves intravenous fluid resuscitation, pain management, insulin, and potentially total plasma exchange to reduce serum triglyceride levels.[47][48][49]
Patients with FHTG generally have a relatively low increased risk of ASCVD, in contrast to individuals with FCHL, which is associated with premature ASCVD. However, some studies suggest that elevated baseline triglyceride levels in FHTG could be related to an increased incidence of ASCVD mortality in patients and their family members, indicating that hypertriglyceridemia itself might be a significant risk factor for ASCVD.[50] Complications of FHTG are managed and prevented through lifestyle modifications, lipid-lowering medications, regular monitoring, control of coexisting conditions, and prompt treatment of elevated triglyceride levels and associated issues to achieve optimal patient outcomes.
Deterrence and Patient Education
Patient education about familial FHTG is crucial for effective management and prevention of complications. Patients should be informed that FHTG is an inherited condition characterized by elevated triglyceride levels in the blood, which increases the risk of acute pancreatitis and ASCVD. Understanding the importance of lifelong dietary modifications, including a heart-healthy diet low in saturated fats and sugars, regular physical activity, and maintaining a healthy weight, is crucial for patients.
Clinicians should advise patients to take their prescribed medications as directed to control lipid levels and reduce the risk of complications. Regular follow-up visits and sequential fasting lipid profiles are necessary to monitor progress. Patient education should include information about the genetics of FHTG and its potential impact on family members who may need screening. Additionally, patients must understand the importance of managing secondary factors that exacerbate hypertriglyceridemia, such as diabetes and obesity. By empowering individuals with FHTG with knowledge and practical strategies, clinicians can enhance their ability to effectively manage the condition and lead healthy lives.
Enhancing Healthcare Team Outcomes
Effective management of FHTG necessitates an interprofessional approach that emphasizes skills, strategy, ethics, responsibilities, communication, and care coordination among the healthcare team. Physicians, advanced practitioners, nurses, pharmacists, and other healthcare professionals must collaborate to deliver patient-centered care, ensure patient safety, and improve clinical outcomes.
Primary care physicians and advanced practitioners lead the healthcare team by diagnosing patients and prescribing appropriate therapies. They use their expertise in lipid metabolism, genetic conditions, and treatment options to tailor individualized treatment plans. Cardiologists, endocrinologists, diabetes specialists, and geneticists offer additional insights for the optimal evaluation and treatment of patients with coexisting or rare conditions. Emergency physicians and gastroenterologists are essential for managing acute pancreatitis in patients with FHTG.
Nurses play a crucial role in educating patients and their families, reinforcing lifestyle changes, monitoring adherence to treatment plans, and providing ongoing support. Registered dietitians, clinical nutritionists, and medical nutrition specialists offer guidance on dietary interventions to improve lipid profiles, manage diabetes, and control weight. Pharmacists oversee medication regimens, monitor drug interactions, and advise patients on medication adherence strategies and potential adverse effects.
Interprofessional communication is vital to ensure all healthcare team members are informed about the patient's status, treatment plan, and any changes in their condition. Regular team meetings and shared electronic health records facilitate effective information exchange and coordinated care. Each healthcare professional has clearly defined responsibilities and must understand their specific role in the management of FHTG. Effective care coordination addresses every aspect of a patient's health, from accurate screening and diagnosis to psychological support for chronic condition management. By fostering a collaborative environment and leveraging each team member's expertise, healthcare teams can improve patient-centered care, optimize clinical outcomes, and enhance overall performance in managing FHTG.
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