INTRODUCTION
The 6-month infant presents to the clinic with splenomegaly and lipemic samples at birth . Screening of complete blood count at birth was ordered, but could not be conducted, owing to the lipemic nature of samples. Subsequently, the patient was referred to a pediatric gastroenterologist, who examined the baby to be oversized with weight in 99th percentile, 81st percentile for height and 70th percentile for head circumference, and body mass index (BMI) in the 99th percentile. He exhibited multiple lipomas on one ear lobe, in the right eye, neck and abdomen. Abdominal examination presented a soft, nontender abdomen with splenomegaly about 2 cm under the lower margin .
Biochemical imbalance
While coagulation panel was normal and within reference intervals, the lipoprotein profiling demonstrated high concentrations of triglyceride and total cholesterol and low levels of HDL .
Physiological responses
The patient presented with several xanthomas on various parts of the body like lateral canthus of the eye, ear lobe and abdomen, which are characteristic features of Familial hyperlipidemia . Systemic evaluation reveal splenomegaly .
REVIEW OF LITERATURE
Type IV hyperlipidemia is an autosomal dominant condition that affects about 1 % of the population. This condition is particularly characterized by high serum triglyceride concentrations of 250 – 1000 mg/dl with moderate concentrations of other lipoproteins and cholesterol . The molecular cause of this disease of lipoprotein metabolism is unclear and the metabolic basis is complex. Aberrant catabolism of triglyceride-rich lipoproteins, excessive production of VLDL by the liver and the consequent overburdening of normal catabolic processes and a genetic increase in the concentration of Apo C-III, are some characteristic features of the disease . Exhibition of this disease infrequently occurs prior to 20 years, but children suffering from diabetes mellitus and renal impairment may manifest it earlier. The clinical symptoms include lipemia retinalis, eruptive xanthomas, cardiovascular diseases and hepatosplenomegaly accompanied by abdominal pain . The genetic factors associated with this type of hyperlipidemia are Apo B (binding to LDL receptors), LDLRAP1 and ABCG 8 mutations.
Although mild form of hypertriglyceridemia usually does not manifest any symptoms, a critical primary hypertriglyceridemia (triglyceride concentrations > 10.0 mmol/L) may be correlated with intense clinical features such as (chylomicronemia syndrome), accompanied by abdominal pain, pancreatitis, short-term memory impairment . While the pathophysiology of acute pancreatitis in this condition is ambiguous, it is believed that chylomicrons in the pancreas cause secretion of free fatty acids, which trigger the inflammatory reaction . Plasma obtained from individuals with severe hypertriglyceridemia is visibly milky. On overnight refrigeration, it fractions out into a creamy supernatant and clear lower part of the fluid .
The disease usually occurs in at least one first degree relative and as in the current case the patient’s maternal grandmother was affected with hypertriglyceridemia and hypercholesterolemia with an occurrence of pancreatitis and father exhibited an identical hyperlipidemic profile .
Dietary triglycerides are assimilated by the small intestine, released into the lymph system, and fed into the systemic circulation as chylomicrons through the thoracic duct . Muscle tissue and fat tissue eliminate part of the triglyceride from the chylomicron and the chylomicron residual substance is absorbed by the liver and digested into a cholesterol rich lipoprotein .
The Fredrickson classification technique categorizes these various primary dyslipidemias into a several groups . All dyslipidemias are characterized by high levels of triglycerides, except Fredrickson (familial hypercholesterolemia). In the United States, the most prevalent types of lipidemias are Fredrickson type IIb (familial combined hyperlipidemia) and type IV (familial hypertriglyceridemia), which together contribute to about 85% of familial dyslipidemias. Type IV lipidemia is featured by high levels of total cholesterol and LDL levels are usually moderate, but the triglyceride level is increased usually in the range of 500 and 1000 mg/dL. Patients with type IV disease are very vulnerable to dietary modifications .
In children with heterozygous familial Hyperlipidemia (FH), the immediate risk of clinical incidents is low, and hence, management begins with identification of risk, subsequent dietary modification, and in some high-susceptibility cases, pharmacologic treatment is initiated after puberty . Low level of low-density lipoprotein (LDL) cholesterol above 4.9 mmol/L, a family history of early coronary heart disease and male gender are important contributing factors of risk. Clinical trials have shown that statins effectively decrease LDL cholesterol concentrations. One study demonstrated the effect of statins in restoration of endothelial function, with no clinical side effects. The reaction of statins for longer than 2 years has not been examined till date . The utilization of bile acid (resins) is restricted owing to their adverse reactions. Children detected with homozygous FH entail advanced management with LDL apheresis, administration of high concentrations of effective statins, and cardiologic follow-up examination. Additionally, Ezetimibe, belonging to the new class of cholesterol absorption inhibitors, may be useful in the treatment of FH .
The significance of hyperlipidemia in the pathophysiology of atherosclerosis is well studied, along with pathogenic symptoms manifesting during fetal life . Cardiovascular risk factors presented in childhood have been associated with coronary diseases later in adulthood, which indicates that prior detection of lipid dysfunction and treatment could play a role in decreasing the incidence of adult cardiovascular diseases .
Examination of the coagulation panel demonstrated fibrinogen, uric acid, lipase and thyroid parameters in the normal range. The lipid panel exhibited high concentrations of triglycerides and low levels of cholesterol, indicative of Type IV familial hyperlipidemia. In this study, the patient showed higher than normal serum concentrations of triglyceride (831 mg/dL) and low levels of HDL cholesterol (< 6 mg/dL). The occurence of a predominant pre-beta band of lipoprotein is typical of excessive triglycerides . Also less concentrations of high density lipoproteins and increased concentrations of very low density lipoproteins is also a prominent feature of Type IV .
Chylomicrons have been reported to accumulate in certain cases of hyperlipemia, and appear in the paper electrophoresis if the fat ingestion is excessive. This build up may be attributable to the error in clearance of ingested fat .
ANALYSIS
Differential Diagnosis
Familial combined hyperlipidemia is the most prevalent form of hyperlipidemia occurring in about 1 in 150 adults, wherein triglyceride concentrations are between 2-5 mmol/L . Familial disbetalipoproteinemia (Type III hyperlipidemia) may be ruled out since the cholesterol levels are increased to almost triglyceride concentrations and HDL levels are normal . Usually, patients with Type IV lipidemia are prone to familial chyomicronemia syndrome (FCS), which is a lipid dysfunctioning caused due to deficiency of enzyme lipoprotein lipase . In these individuals, the ability to appropriately break down fatty acids is impaired. This results in build-up of chylomicrons in the blood. Infants with this syndrome often show clinical symptoms of colic pain and inability to survive . Although chylomicrons detected in the patient’s blood, it was in the normal reference range. Also, although the infant exhibited splenomegaly. Additionally, in FCS, the triglyceride concentrations are elevated to an extremely high level of over 1000 mg/dl . The lipase enzyme concentrations were also normal and the infant did not exhibit any clinical symptoms, which rules out this syndrome.
Thus, based on pathological symptoms and examinations, other types of hyperlipidemia and chylomicronemia may be excluded.
DISCUSSION
Familial Hyperlipidemia (Type IV) or isolated triglyceridemia is usually asymptomatic and incidentally detected in infants without any notable symptoms, as in case of the infant in this case study and it has a very low incidence of early coronary heart disease . Although, VLDL could not be tested in this study, due to highly lipemic plasma, total cholesterol was higher than normal.
This is an autosomal dominant condition and a positive family history of a first degree relative with hypertriglyceridemia, entails further investigation. Physical examinations revealed that the infant was oversized with weight and BMI in almost in the 99th percentile at 7 months. Childhood obesity has been considered as an important risk determinant for lipidemia.
Hyperlipidemia in this condition may be accompanied by a chylomicron build-up, but is usually insignificant compared to the increase in pre-beta lipoprotein and is indicative of a delay in elimination of the ingested fat .
Patients of familial hyperlipidemia typically exhibit less serum HDL cholesterol levels and their Apo-B concentrations are usually not elevated (as observed in this case), reducing the vulnerability to coronary artery disease. Apo-B is a hepatically obtained protein linked to VLDL. Apo-B levels enable distinguishing familial combined hypertriglyceridemia, which has a relatively more atherogenic tendency, from familial combined hypertriglyceridemia, which has less atherogenic capacity.
Treatment and Management
Children are, generally treated, sufficiently with weight control and utilization of step one diet, which includes fat, not more than 30% of total calories consumed daily and 100 mg cholesterol/ 1000 calories . Intense hypertriglyceridemia may be treated by administration of Omega-3 fatty acids (fish oils) to reduce VLDL production . Patients usually derive benefits from omega-3 fatty acids (docosapentanoic acid and eicosapentanoic acid) obtained from supplements of fish oil. Omega-3 fatty acids decrease VLDL formation and consequently lead to decreased serum triglyceride levels. Salmon oil may be found over the counter in 1-g capsules. The initial dose is 1 g two times a day and may be raised to 3 g three times a day .
Drug therapy with fibrates and nicotinic acid (to lower VLDL level and increase HDL level) or oxandrolone is rarely indicated. Although, drug therapy, is rarely recommended, there is some evidence of use of drug therapy with fibrates and nicotinic acid (to decrease VLDL level and increase HDL) . Weight control and dietary management are safest and efficient modes of treatment of this disorder. The regulations for pharmacologic treatment of hyperlipidemia in children have been established by National Cholesterol Education Program (NCEP) and the American Heart Association (AHA) . These guidelines recommend that drug treatment should be administered to children only older than 10 years of age, who despite of dietary alterations for 6 to 12 months of age, present high LDL cholesterol of 4.9 mmol/L in the absence of any other associated risks or an LDL cholesterol level over 4.1 mmol/L and a family history cardiovascular risk factors or disease. Excessive control of fats in the diet should be avoided .
The patient in the case study was examined to be overweight at the time of investigation (7-months). Adiposity-associated hypertriglyceridemia has been found to be linked to triglyceride concentrations as high as those detected in patients with primary hypertriglyceridemia, which indicates that lifestyle and diet may be regarded as important determinants of triglyceride levels. Modification of lifestyle is the primary therapeutic strategy in management of pediatric hyperglyceridemia . Treatment of such patients should focus on lifestyle interventions and weight management prior to initiating any pharmacologic therapy. Obesity is considered as a significant secondary cause of hypertriglyceridemia, which has been associated with several obesity markers, including increased waist circumference, and insulin resistance in a group of obese children. Researchers have also found a correlation between BMI scores and increased triglyceride levels for patients with adiposity-linked hypertriglyceridemia . The infant in this study also exhibited a higher than normal BMI. Evidence also suggests that about 10% to 20% of obese children present abnormally high triglyceride levels . While, the contribution of genetic factors in this case study cannot be neglected, considering the family history of hypertriglyceridemia, an obesity-related secondary cause for the consequent increase in triglyceride and cholesterol levels and the associated symptoms of splenomegaly and lipomas cannot be overruled.
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