Ivan, a 31 year old male is presented to a physician with complaints of sharp retro-sternal chest pain when lifting heavy objects, or when walking up flights of stairs. The chest pain lasts for about 2mins and radiates up to his left jaw. The patient reports that his father and two paternal uncles had heart attacks in their early 30's. Upon careful palpation, the physician detects a thickened Achilles tendon. His symptoms and ECG are consistent with stable angina, the physician prescribes No2 to treat the angina and order a serum lipid panel, as well as urinalysis. (Lange's Biochemistry Vignettes.)
The lipid panel results confirm high levels of LDLc and Total Cholesterol well over the normal range, with LDLC 340mg/dl and TC 360 mg/dl. Additionally, TG levels are 65mg/dl and HDL-C levels are 50 mg/dl, all within the normal parameters. The patient is not diabetic and proteinuria is not present, ruling out proteinuria as a secondary cause of elevated LDLC. Additionally, upon careful questioning, Ivan recalls and describes visible tendon Xanthomas on his father's hands and admits to smoking at least a pack of cigarettes a day. Patient shows no signs of dementia, ataxia or cataract development, ruling out 27-hydroxylase deficiency, but corneal arcus is visible.
The above is a representation in which a patient is diagnosed with Familial Hypercholesterolemia Class IIb. FH is an autosomal dominant inherited disease, which results in elevated levels of plasma cholesterol, and as a result, increased chances of premature Coronary Artery Disease (CAD). For this reason, early detection and preventative care is important in managing the progression of CAD. Heterozygous FH(HeFH) is more common than Homozygouszygous FH. 1/500 persons worldwide are afflicted with HeFH. Homozygous FH rate is 1/1000, 000. In addition, studies have shown that there is an increased rate of incidence some populations, such as African, Christian Lebanese, Finns, French Canadians, due to genetic phenomena referred to as the founder effect (Goldstein et al., 2001)
A further analysis into the epidemiology of FH leads to the varying differences in mortality and morbidity rate of Homozygous FH compared to HeFH. In the case of Homozygous FH there is greater risk of early death because of high accumulation of plaque in major arterial beds and myocardial infractions at a very early age (Richter et al.). Survival beyond the teenage years is not common. Other features of Homozygous FH are valve abnormalities at a young age, aortic stenosis, and xanthomas present in very early childhood, in some cases even at birth. (Goldstein et al. 2001)
Diagnosis for FH is involves simple physical examination and a plasma lipid work up. Severe LDLC elevation with normal levels of TG and HDL is very common in individuals with FH. A diagnosis of HeFH in younger patients can be made if a parent is diagnosed with FH by measuring LDLc levels, and if they measure in the top 90th percentile for LDLc levels for their age group, a positive diagnosis can be presumed. A definitive diagnosis can also be made by gene or receptor analysis. However, gene and receptor analysis are found to be very expensive, and show no significant impact on the treatment of the disorder. Nonetheless a lesion biopsy is an inexpensive method of determining HeFH. Lesions, called Xanthelasmas contain accumulations of cholesterol, where as lesions caused by hypertriglyceridemia contain TG. And if there are elevated levels of HDLc and TG, other lipid disorders may be the cause.
Illustrated in Table 1 is a list of criteria of certainty of familial hypercholesterolemia proposed by the MED PED (Make early diagnosis prevent early death) program of the World Health Organization. In the case of this study by Garcia-Alverez et al 2003, this table was sent to potential subjects as a way of having their physician qualify them for the study. The sum of clinical indications presenting in the patient was taken and the results were the following. Greater than 8 points from the test warranted a definite subject for HeFH, 6-8 points landed the patient in the probable to possible range for HeFH.
In addition, when symptoms are present, this test can also be used in lieu of expensive DNA testing or liver receptor analysis testing, especially where diagnostic tools are not available or testing is not available in the region. (Garcia-Alveraz et al. 2003)
The patho-physiology of FH lies within the defective LDL receptors on hepatocytes, the genes for which are located on the short arm of chromosome 19 (Austin et al., 2004; Kwiterovich, 2008). LDL receptors on hepatocytes recognize two markers on circulating LDL's and bind to them, allowing for the uptake of LDL's. Hepatocytes recognize Apolipoprotein B-100 (ApoB-100) and ApoE via membrane receptors. Since the discovery of the mutation causing FH by Goldstein and Brown, there have been over 700 other mutations identified that have shown to have impact on LDL receptor function, production, and activity.
There are now 5 classes of FH
Class I includes non-functioning alleles (null) that leads to a complete lack of LDL receptor
In this type of FH, there is a defect in the genes in the liver producing LDL receptor at the transcriptional level.
Class II includes defective transport genes for LDL receptor transport within hepatocytes, and result in failure to fold and transport to the cell surface
Class IIa mutations cause a complete blockage of LDL receptor from the hepatocyte Endoplasmic Reticulum to the Golgi.
Class IIb mutations cause a partial blockage of transport
Class III includes defective binding alleles that affect binding of LDL to liver hepatocyte LDL receptor. A defect in production of ApoB-100 or ApoE
Apo-E is acquired from circulating HDL's and ApoB-100 is acquired from packaging of LDL's in the liver (Lipincott's)
Class IV includes defective alleles that are responsible for the clatherin coated pits responsible for increasing hepatocytes affinity for circulating LDLs
Class V includes a defect in alleles responsible for recycling the receptor and ligand after the LDLs have been internalized, resulting in decreased clatherin on hepatocyte cell membranes. (medscape.gov)
Further insight into the patho-physiology and the mechanism of symptoms occurring in patients with FH reveals that the disease manifestation is being accelerated by normal hepatic physiology. Due to the drastic decrease or even a lack of LDL receptors on hepatocytes, there is an already high level of serum cholesterol. However, since the liver hepatocytes are not readily taking up the circulating LDL's, there is no communication, or a misinterpretation of circulating LDL's by the hepatic regulatory system, which in the end results in production of even more VLDL bodies by the liver. VLDL's ultimately form LDL's once the triglyceride (TG) payload has been delivered and mostly cholesterol remains. In patients with Homozygous FH levels of LDLc can be as high as 600 mg/dl and patients with HeFH, figures between 200-400 mg/dl are commonly seen. (medscape)
Due to the high number of circulating LDL's, the LDL clearing is taken up by non-hepatic cells of the body that do not have LDL receptors. Monocytes and Macrophages readily ingest LDL's in high levels, but do not possess the proper enzymes to break them down. Due to the inability of monocytes and macrophages to properly break down LDL, there is accumulation of LDL in these cells as well as foam cell formation. Foam cells are then recruited below the endothelial layer of vascular tissue leading to plaque deposition, a factor in CAD. Additionally, free cholesterol also deposits in skin, causing xanthelasmas and xanthomas, as well as in the cornea, resulting in corneal arcus. (medscape, Austin MA et al. 2004)
Because of the mechanism by which LDL's are increasingly produced in the body, it is important to treat patients that have FH with drugs, rather than diet and exercise alone. Most commonly, FH candidates are treated with intent to lower LDLc by means of Statins, cholesterol absorbers and a diet free of cholesterol. In severe cases of Homozygous FH, when LDLc levels cannot be lowered below 200 mg/dl, despite all treatments, LDL aphaeresis is recommended as treatment (Richter et al.). The goal level for LDLc is less than 100mg/dl in patients with FH and Statin therapy is continuous. Statin drugs are HMG-CoA reductase inhibitors, an enzyme responsible for cholesterol synthesis. Statins are given with a combination of bile acid sequestrants coupled with a high fiber diet, exercise, and low cholesterol and fat diet. (Illingworth et al. 2000)
As for our patient, Ivan has been diagnosed with Familial Hypercholesterolemia Type IIb and will be treated accordingly. Firstly Ivan should be educated about his condition and his increased risk for CAD, and that the impact of smoking is putting him at a higher risk for CAD. Devised treatment plan for Ivan will include setting a 6 week goal of <200mg/dl LDLc. A course of treatment for Ivan will be administration of a strong Statin drug, such as Simvastatin and bile acid sequestrants, such as niacin, along with a low fat and cholesterol diet and exercise. Prognosis of the patient depends on the level of LDLc on the following visit. If the goal is not met, additional Statin drugs and bile acid sequestrants can be administered with no risk of drug interaction. If Ivan collaborates with the doctor's orders accordingly, treatment should be uneventful and reduce his risk for CAD in the near future.
