Hyperlipoproteinemia type 1 is a rare genetic disorder characterized by dysfunction of lipoprotein lipase or determined apolipoproteins. Patients suffering from this disease present with recurrent abdominal pain due to pancreatitis, hepatosplenomegaly as well as eruptive cutaneous xanthomas. Blood sample analysis in these patients reveal severe hypertriglyceridemia.
HLP1 is a genetic disorder and symptom onset occurs early in life. About 25% of affected individuals manifest first symptoms within their first year of life and the vast majority of patients seek medical attention before reaching the age of ten [5]. Recurrent episodes of abdominal pain are the most frequent cause of consultation; its severity may vary from mild to incapacitating. Since abdominal pain originates from an inflamed pancreas, it is generally localized to the mid-epigastric area. However, radiation of pain to adjacent regions may also be reported. Physical examination may further reveal hepatosplenomegaly. Patients may show multiple eruptive xanthomata that indicate disturbances of lipid metabolism and severe hyperlipidemia. These cutaneous lesions may be restricted to determined parts of the body, wherein arms, trunk, and buttocks are most commonly affected. These cutaneous lesions may also develop in a more generalized manner. If an ophthalmological examination is carried out, lipemia retinalis may be detected. Retinal vessels appear to be cream-colored in case of extreme hyperlipidemia [10]. Neuropsychiatric disorders have been related to HLP1 and may possibly be explained by functional impairment of brain LPL [11]. In this context, dementia may be expected in HLP1 patients.
Blood samples taken from HLP1 patients are frequently cloudy, exhibiting a milky haze. Suspicion of hyperlipidemia is confirmed by biochemical analysis, with triglyceride levels being a sensitive but non-specific indicator of HLP1. Due to physiological postprandial increases of triglyceride concentrations, blood samples should be obtained on an empty stomach. The reference range for triglycerides is up to 200 mg/dl. In HLP1 patients, physiological values may be exceeded by more than tenfold. As a rule of thumb, both eruptive xanthoma and lipemia retinalis are indicative of serum triglyceride levels above 1500 mg/dl [5] [10]. If such symptoms are presented by a pediatric patient, primary dyslipidemias should seriously be taken into account. To this end, it is important to acquire a detailed family history and to carry out a target-oriented approach to HLP1 diagnosis:
Detection of gene defects associated with HLP1 are diagnostic of the disease, but such analyses are not generally feasible. Also, minor shares of HLP1 cases cannot be ascribed to a known gene defect despite extensive genetic screens. Nevertheless, the identification of the precise mutation is a requirement for family analysis, genetic counselling, and prenatal testing.
Serum triglyceride levels should be lowered as far as possible. In general, concentrations below 1000 mg/dl should be aimed at, and significant reductions of morbidity and mortality can be expected below 2000 mg/dl [5]. Reduction of dietary fat is the mainstay of treatment. HLP1 patients should be advised not to consume more than 20 g of lipids per day, and ideally, dietary fat mainly consists of medium-chain triglycerides [12]. If dietary adjustments are insufficient to reduce serum triglyceride concentrations, alternative treatment options have to be considered.
In 2012, alipogene tiparvovec has been approved for HLP1 therapy, although evidence of its long-term efficacy is still lacking. Still, delivery of the LPL gene variant LPLS447X in a vector derived from adeno-associated virus serotype 1 has been shown to augment LPL activity and this can decrease serum triglyceride concentrations and the frequency of pancreatitis episodes [13].
Parenteral nutrition is only a short-term solution in reducing hypertryglyceridemia in acute settings, but it does prevent chylomicron formation. Of note, pancreatitis should be treated according to standard procedures. Hepatosplenomegaly generally resolves spontaneously as soon as serum triglyceride levels are reduced.
HLP1 may cause recurrent acute pancreatitis and eventually chronic pancreatitis. About 5% of patients diagnosed with hypertriglyceridemic acute pancreatitis die from this complication [2]. Development of steatorrhea or diabetes mellitus secondary to pancreatitis is rare.
Furthermore, HPL1 patients are at extremely high risk of developing life-threatening cardiovascular diseases associated with chronic hypertriglyceridemia, e.g., atherosclerosis, coronary heart disease, peripheral vascular disease, and stroke. It has been estimated that hypertriglyceridemia increases the individual risk of coronary heart disease by 30% in men and 75% in women [9]. Since being overweight,obesity and diabetes mellitus type 2 are risk factors for cardiovascular disorders, controlling these risk factors comprise both an adequate therapy for HPL1 and a preventive strategy for disease-related complications. Compliance with diet recommendations and regular exercise may largely contribute to an improved outcome.
The hallmark of HLP1 is hypertriglyceridemia, and triglycerides accumulate in affected individuals due to an ineffective breakdown of chylomicrons. The single most important enzyme for this process is LPL, and it is encoded by a gene located on the short arm of chromosome 8. It is mainly expressed by endothelial cells of capillaries. Mutations of this gene may alter the enzyme's functionality, resulting in severely reduced or absent LPL activity. LPL mutations are the most common cause of HLP1.
LPL depends on ApoC-II as a cofactor. Thus, mutations of the gene encoding for ApoC-II similarly interfere with lipid metabolism and lead to hypertriglyceridemia. It is located on the long arm of chromosome 19.
Besides LPL and ApoC-II mutations, other gene defects have recently been related to HLP1, e.g., mutations of genes encoding for apolipoprotein A-V (ApoA-V), lipase maturation factor 1 (LMF1), glycosylphosphatidylinositol-anchored high-density lipoprotein-binding protein 1 (GP1HBP1) and glucokinase regulator (GCKR) [4]. ApoA-V facilitates LPL-mediated hydrolysis of triglycerides, LMF1 is required for folding and assembly of LPL, GP1HBP1 is expressed by endothelial cells and binds LPL, and GCKR induces hepatic lipogenesis.
Still, some cases of HLP1 cannot be ascribed to either of those gene defects and presumably result from as-of-yet unknown mutations.
Of note, all known forms of HLP1 are inherited with an autosomal recessive trait. Although heterozygous carriers do not develop HLP1, they may manifest with mild dyslipidemia.
Although hyperlipoproteinemia is a common condition, few cases correspond to HLP1. In most parts of the world, prevalence of HLP1 is about 1 in 1,000,000 persons [5]. Interestingly, the disease has been reported to affect 1 in 6,000 inhabitants in a geographically isolated region of Quebec, Canada, with about 2% of the population being carriers of LPL mutations [6]. Most likely, this is due to a founder effect. Similarly increased prevalence rates are to be expected in ethnic groups of higher consanguinity.
Despite known racial and gender differences in lipid metabolism [7] [8]., predilection of the corresponding groups of patients has not been described for HLP1.
After digestion of dietary fat, fatty acids, monoglycerides, and diglycerides are absorbed by the mucous membrane of the small intestine. Here, they serve as substrates for triglyceride biosynthesis, and these lipids are eventually combined with cholesterol and apolipoproteins B-48, A-I, A-II and A-IV to form chylomicrons. Chylomicrons are then released into lymphatic vessels, are transported within those vessels up to the thoracic duct and finally reach the cardiovascular system. In a maturation process, the composition of chylomicrons changes. They release determined apolipoproteins and bind others. ApoC-II is among those new constituents of chylomicrons, and it is required for triglyceride breakdown upon delivery of lipids to end organs like the heart, muscles and adipose tissue. Endothelial cells lining the capillaries of those organs express LPL and are thus able to digest the arriving nutrients and to use them for energy supply.
In HLP1 patients, the previously mentioned chain of events is interrupted at the point of delivery to end organs. Due to functional deficits in ApoC-II or LPL, chylomicrons cannot be metabolized. On the one hand, this condition causes an abnormal accumulation of chylomicron constituents in the patient's circulation; on the other hand, cardiac, muscular and adipose tissues are deprived of their main energy supply. In the long term, the former poses a much higher risk since it predisposes for life-threatening cardiovascular disease.
HLP1 is a genetic disorder and corresponding gene defects are inherited in an autosomal recessive manner. If the precise mutation underlying an individual case of HLP1 is known, family members at risk may be tested to identify carriers. Moreover, genetic counselling and prenatal screens may be offered to affected families if patients wish to procreate.
Hyperlipoproteinemia type 1 (HLP1) is a rare metabolic disease triggered by diverse gene defects. The disease may also be referred to as familial lipoprotein lipase (LPL) deficiency or hyperchylomicronemia syndrome, and those terms comprise both the cause and the main symptom of the disease. HLP1 patients show reduced LPL activity, either due to mutations of the gene encoding for that enzyme or because of functional deficiencies of cofactors and associated molecules [1]., and because LPL is responsible for the breakdown of chylomicrons, these substances accumulate in the patient's circulation. Chylomicrons are mainly composed of triglycerides and lipoproteins, which explains the designation HLP1.
Hypertriglyceridemia is the hallmark of HLP1; it is also the cause of acute pancreatitis and hepatosplenomegaly. Pancreatitis accounts for acute mortality rates of approximately 5% [2]., but considerable morbidity and mortality is also associated with long-term sequelae of this lipid disorder. HLP1 patients are at high risk of disabling and life-threatening cardiovascular diseases. In order to prevent conditions like coronary heart disease and stroke, a multidisciplinary approach is required. Accordingly, treatment consists in lowering serum levels of triglycerides by means of dietary adjustments, and in educating about additional risk factors that complicate hyperlipidemia [3].
Hyperlipoproteinemia type 1 (HLP1) is a rare metabolic disease associated with severely increased levels of serum lipids. Large parts of serum lipids originate from dietary fats. Consumed fat is digested in the gastrointestinal tract, metabolites are absorbed by the small intestine and are converted to lipid-rich molecules called chylomicrons. Chylomicrons are subsequently released into the circulation. Chylomicrons constitute assemblies of lipoproteins and lipids that are "ready to dispatch". Their recipients are endothelial cells lining the capillaries of heart, muscle and adipose tissue. These cells dispose of an enzyme, namely lipoprotein lipase (LPL), that allows for the degradation of chylomicrons and the utilization of lipids as a source of energy. However, lipoprotein lipase activity is significantly reduced or even undetectable in HLP1 patients. Thus, chylomicrons cannot be degraded and instead it accumulates in the patient's blood.
Symptom onset often occurs during the first year of life, and in the vast majority of HLP1 patients, takes place before they reach ten years old. Because the main component of chylomicrons are triglycerides, HLP1 patients are initially diagnosed with hypertriglyceridemia. This condition may trigger episodes of abdominal pain and pancreatitis as well as cutaneous lesions referred to as eruptive xanthomas. Moreover, in the long-term, HLP1 and hypertriglyceridemia may have detrimental consequences for the cardiovascular system. HLP1 patients are at high risks of atherosclerosis, coronary heart disease, peripheral vascular disease, and stroke. In order to relieve both acute and chronic symptoms caused by high serum concentrations of lipids, dietary adjustments are recommended. Patients are advised to restrict their daily fat intake and to preferentially use fat consisting of medium-chain fatty acids. In most cases, such measures combined with an overall healthy lifestyle may contribute to decrease trigylceride levels in the blood.