Hypoalphalipoproteinemia (HA) is defined by a low level of high-density lipoprotein cholesterol (HDL-C). Recent investigations have described HA as an HDL cholesterol below the 10th percentile of age and gender-matched controls without alteration in other lipoprotein distribution. The US National Cholesterol Education Program (NCEP) Adult Treatment Panel III (ATP III) defines HA as HDL-C level below 40 mg/dL.
Metabolic syndrome is diagnosed with low levels of high-density lipoprotein cholesterol, high levels of triglycerides, wider waist circumference, high blood pressure, and abnormal glucose level. The ATP III criteria for HDL cholesterol levels associated with metabolic syndrome vary by sex: for males it is less than 40 mg/dL then for females it is less than 50 mg/dL.

Familial hypoalphalipoproteinemia is an autosomal dominant disorder. People suffering from this condition have been found to be at high risk of early coronary heart disease and stroke because their alpha-lipoprotein level is very low. The condition characterised with low levels of high-density lipids in the blood is one of the major causes of coronary artery disease, a condition that poses a great threat in as much as its complications are involved including stroke among others or myocardial infarction.

Hyperalphalipoproteinemia is also common in patients with coronary heart disease (CHD). The studies have shown that 58% of patients with CHD have the levels of high-density lipoprotein cholesterol below the 10th percentile among normal individuals.

A study conducted by National Center for Health Statistics (NCHS) data brief shows that the proportion of adults who had low high-density lipoprotein observed to decrease from 21.3 % between 2009 and 2010 to 20 % between 2011 and 2014.

International statistics

Currently, there is no knowledge about the rate of inheritance and the presence of the defect in the familial ailment. Primary and secondary hypoalphalipoproteinemia are quite frequent in general.

Gender, ethnic, or age distribution

Hypoalphalipoproteinemia (HA) has been reported in individuals of different race groups. Regarding race predilection, although there is no specific race preference seen in HA, some studies point towards higher incidence in Asian Indians.

Female patients are likely to have a relatively lower incidence of hypoalphalipoproteinemia than male patients.

Impaired HDL Production: HA may be due to lower production rate of apolipoprotein in the liver and intestines. HDL is synthesized by the packaging of apolipoproteins (for example ApoA-I) and lipids. Abnormalities in the genes involved in these processes can result in low levels of HDL in the blood.

Enhanced HDL Catabolism: Oxidation and other processes that can lead to the increased breakdown of particles within the HDL fraction can contribute to HA. This can occur through increased activity of enzymes like hepatic lipase or endothelial lipase which can break down HDL particles and thereby lowering their concentration in the bloodstream.
Genetic Mutations: Familial HA is related to genetic defects that affect the lipids of HDL in most of the individuals. For example, mutations affecting genes responsible for apolipoproteins (for example, ApoA-I) or genes responsible for formation and remodelling of HDL — cause low levels of HDL.

Dysfunctional HDL Particles: It may also indicate that even if present, these particles are less efficient in the process of cholesterol efflux where HDL particles transport cholesterol from the tissues back to the liver for excretion. This dysfunction can arise due to alteration in apolipoprotein composition or the overall anatomy of HDL.

Genetic Factors: Primary causes include inherited disorders of lipoprotein metabolism as follows: LPL deficiency FHLD, Familial hypoalphalipoproteinemia and Tangier disease caused by mutation in genes involved in HDL metabolism e.g. Apo A-I and ABCA1 genes.
Metabolic Disorders: Factors decreasing the level of HDL include one which includes metabolic syndrome, type 2 diabetes and liver disease.
Secondary Causes: Another cause of low levels of HDL cholesterol include chronic inflammation, medications, unhealthy diet, habits and endocrine diseases, in particular.

Severity of HDL Reduction: Reduced HDL cholesterol is a better indicator of higher risks to cardiovascular diseases. The lower the HDL level, the higher that particular risk is however, greater decreases in HDL can suggest greater risk.

Presence of Associated Conditions: Concurrent diseases such as metabolic syndrome, type 2 diabetes or chronic inflammation lowers the likelihood of cardiovascular events.

Genetic Factors: Different gene polymorphisms, including those linked to ApoA-I or ABCA1, can predict the development of HA and its effects on health. Familial forms are usually considered to be more severe and with higher risk compared to other variants.

Lipid Profile: Other components of lipid profile include high triglycerides or low LDL cholesterol which have implications on cardiovascular health.

Age Group

Children and Adolescents: HA can be diagnosed early in conditions like Tangier disease where patients experience enlarged tonsils or early signs of cardiovascular disease. Familial HA may also manifest during childhood or adolescence; however, signs and symptoms may not be as severe until later in the lifespan.

Adults: Patients with HA may have some manifestations related to cardiovascular diseases, for example, earlier onset of coronary atherosclerosis in case of HA associated with metabolic syndrome.

Low high-density lipoprotein (HDL) syndromes are generally asymptomatic in normal population; no signs and symptoms to suggest abnormalities in lipid profile. However, if atherosclerosis is present, the physical examination may reveal symptoms related to the affected arterial regions, which can include:

Tendon xanthomas

Cutaneous xanthomas

Some of the features include ischemic coronary heart disease and peripheral vascular disease.

An S4 gallop which is suggestive of Ischemic left ventricular dysfunction
manifestation include jugular venous pressure over 5 cm with prompt arterial pulsation as well as crackles on listening at the lung bases, peripheral oedema, and hepatomegaly in cases of congestive heart failure.
Arrhythmias

Metabolic Syndrome: HA may co-occur with other symptoms that are characteristic for metabolic syndrome including obesity, high blood pressure, and high triglyceride levels.

Type 2 Diabetes: HA is common in patients with T2DM, and it plays a part in the cardiovascular risk.

Chronic Inflammatory Diseases: Some diseases like rheumatoid arthritis or systemic lupus erythematosus have been reported to relate to the development of HA.

Chronic Presentation: HA is a relatively long-standing disease, and consequences like having a higher cardiovascular risk start to appear in the long run.

Acute Complications: HA related acute events that may arise when the condition is complicated with cardiovascular disease include myocardial infarction or stroke. These events are more likely in patient with severe HA and other cardiovascular risk factors.

Lifestyle Modifications

Diet: Maintain a diet with a focus on fruits, vegetables and whole grain products, appropriate fats (nuts and olive oil among others). Consuming healthier fats and oils and avoiding fried and greasy products are useful in raising the HDL levels.

          Exercise: Aerobic exercise is also known to raise the levels of the ‘good’ high density lipoprotein cholesterol. Take a minimum of 150-minutes moderate intensity exercise per week.

          Weight Management: Adherence to the principles of balanced diet and/ or weight management will benefit the move towards a healthier; accession, hence boosting of the HDL and general form of lipids.
          Smoking Cessation: Smoking cessation is critical since it can aid in gaining an increased level of HDL cholesterol.

Pharmacological Interventions

          Statins: Another advantage of using statins as a drug is that it has shown, albeit a little impact in raising the levels of HDL cholesterol. They are also helpful in decreasing chances of heart diseases.

          Niacin (Vitamin B3): Niacin plays a role in increasing the levels of HDL cholesterol, although its application is problematic due to side effects, such as flushing and hepatotoxicity.

          Fibrates: These drugs mainly reduce triglycerides but may also have an upwards effect on the density lipoprotein cholesterol. They are often recommended for use when other targets namely triglycerides and low levels of HDL are high.

          PCSK9 Inhibitors: Though their main function is to decrease the LDL cholesterol, they have a potential to raise the HDL levels in some instances.

Treatment of Underlying Conditions

          Metabolic Syndrome: High-density lipoprotein can be raised through use of pro-healthy substances, reduction of elements with metabolic syndrome such as elevated blood pressure, high triglycerides, and insulin resistance among others.

          Type 2 Diabetes: Lifestyle management strategies like proper glycemic control in diabetes and use of lipid modifying agents can also lead to improving levels of HDL cholesterol.

          Hypothyroidism: Optimal dose of thyroid hormone for management of thyroid disorder plays a role in altering the HDL cholesterol levels.

Genetic Disorders

          Tangier Disease and Other Genetic Conditions: Management might require specific interventions like gene therapy if the defect can be corrected and addressing cardiovascular risk factors.

Monitoring and Follow-Up

          Regular Monitoring: Lipid profile checks, cardiovascular response, and compliance with a particular treatment course should be monitored frequently.
          Risk Assessment: It is crucial to re-assess cardiovascular risk from time to time to make changes in management approaches and avoid adverse outcomes.

Endocrinology, Metabolism

Dietary Changes: Consume more polyunsaturated (avocado, nuts) and monounsaturated fats (omega-3 fatty acid sources such as fatty fish), and less saturated and trans fats.

Regular Exercise: Aerobic activity and strength training exercise for a minimum of 150 minutes within the week.

Weight Management: Being overweight and obesity is a result of poor dietary practices and lack of physical activity, so to treat it one must adopt healthy dietary practices and incorporate regular exercise.

Smoking Cessation: Avoid smoking to raise levels of high-density lipoprotein cholesterol.

Moderate Alcohol Intake: Take alcoholic beverages in moderation or avoid them altogether.

Stress Reduction: Eat a healthy diet, engage in physical activity, and practice good communication with others.

Endocrinology, Metabolism

Niacin: It is also known as nicotinic acid, which is involved in the process of tissue respiration, lipid metabolism, as well as glycogenolysis. It is known for its lipid-lowering properties, whereas its derivatives, nicotinamide and niacinamide, do not possess the same properties.

Gemfibrozil: It is a fibric acid derivative that works through the regulation of the liver’s synthesis of lipids, and is used in the management of elevated serum triglycerides (TGs) and in the optimization of lipoprotein profiles. It is not clearly known how it works, but it is believed to suppress lipolysis, decrease VLDL production, and decrease fatty acid uptake by the liver.

Fenofibrate: It is another fibric acid derivative, however has the potential to be more effective than older fibrates including such as clofibrate or gemfibrozil in the reduction of LDL cholesterol levels. It is mainly employed for the purpose of lowering the TG levels and treating mixed dyslipidemia. The mechanisms by which fenofibrate reduces TG levels include increasing LPL activity and decreasing the synthesis of apo C-III in the liver through PPAR activation. It also enhances oxidation of fatty acids by stimulating acetyl Co A and other enzymes, while suppressing the formation of TG through the inhibition of acetyl Co A carboxylase and fatty acid synthase. The clinical profile of fenofibrate includes the decrease in plasma TGs and VLDL levels and the increase in the levels of HDL cholesterol.

Endocrinology, Metabolism

Atorvastatin: It achieves this by selectively and competitively interacting with HMG-CoA reductase thereby decreasing the synthesis of cholesterol and increasing its degradation. This results in decreased total cholesterol, LDL cholesterol, and triglyceride values and a slight increase in HDL cholesterol.

Simvastatin: It actively competes for HMG-CoA reductase which is involved in cholesterol synthesis hence enhancing cholesterol metabolism and indeed low cholesterol levels in the blood.

Pravastatin: This enzyme competes perfectly and interferes with the reduction of HMG-CoA, an enzyme that is very crucial in the synthesis of cholesterol. It is advised that for patients diagnosed with elevated cholesterol levels, they adopt low cholesterol diet for 3- 6 months prior to using the medication and while on the medication.

Lovastatin: That belongs to the class of agents that work to decrease cholesterol synthesis through inhibiting the enzyme HMG-CoA reductase. The advice also given with pravastatin is that the patient should begin with a cholesterol-lowering diet prior to treatment and should continue the diet throughout the course of therapy.

Fluvastatin: The active agent is a synthetic HMG-CoA reductase inhibitor, like both lovastatin and simvastatin in terms of mechanism of action and having some structural and pharmacokinetic differences such as lack of active metabolites, high protein binding, and very low CSF penetration.

Rosuvastatin: It competitively inhibits HMG-CoA reductase meaning that cholesterol synthesis is lowered, and cholesterol is broken down to reduce total blood cholesterol level.

Pitavastatin: The effectiveness of rosuvastatin has been compared with other statins such as atorvastatin and simvastatin; however, they are more potent at higher doses.

Endocrinology, Metabolism

Angioplasty: In situations where hypoalphalipoproteinemia is complicated by meaningful CAD, it may become necessary to perform percutaneous coronary intervention (PCI), involving angioplasty with stenting to restore blood flow in the arteries supplying the heart.
Coronary Artery Bypass Grafting (CABG): In patients with low levels of HDL cholesterol, atherosclerosis is severe, and CABG is done to bypass the affected arteries and enhance blood circulation to the heart muscles.
Lipid Apheresis: In rare and severe cases such as genetic forms of hypoalphalipoproteinemia (for example Tangier disease) lipid apheresis may be warranted. This procedure is the elimination of lipids from blood such as LDL and VLDL particles to reduce cardiovascular risk.
Liver Transplantation: In cases of genetic lipid metabolism disorders like severe familial hypoalphalipoproteinemia in which the patient has developed advanced liver or cardiovascular diseases then, liver transplantation could be suggested as a final stage.

Endocrinology, Metabolism

Pharmacological management of hypoalphalipoproteinemia is normally done in a step-by-step manner. First, the patient and his/her physician focus on diet, exercise, weight loss/gain, and smoking as the powerful interventions to raise levels of healthy HDL and lower cardiovascular risk. In a second, if these are inadequate, pharmacologic treatment includes statins, fibrates or niacin for lipid disorders. Third, intermittent and severe cases involving critical cardiovascular disorder may require interventional measures such as angioplasty and coronary artery by-pass graft and lipid apheresis. Among these, the evaluation and the supervision are active during each of the stages to measure the response to the treatment.