Lipoprotein X-Induced Hyperlipidemia

Etiology

There are four reported etiologies of Lp-X-induced hyperlipidemia. They include liver dysfunction, deficiency of the lecithin-cholesterol-acyl- transferase enzyme, graft vs. host disease in liver transplant patients, and lipid infusion.[2][3] Lp-X is usually found in liver dysfunction regardless of the cause, such as primary biliary cirrhosis or intra or extrahepatic cholestasis. In cholestasis, bile acid synthesis is dysregulated, leading to increased bile acids and cholesterol in circulation.

Cholesterol is normally converted to bile acids by certain enzymes, including the cholesterol 17 alpha-hydroxylase enzyme. Cholestasis prevents the normal formation of bile acids leading to the formation of Lp-X. It can also be present in patients with mutations to the enzyme that esterifies cholesterol lecithin–cholesterol acyltransferase (LCAT).  Patients with LCAT deficiency will have the higher formation of Lp-X because of their inability to convert free cholesterol to cholesterol esters.[4] 

LCAT deficiency patients also have low HDL levels and anemia. Lp-X is formed in patients with lipid infusion, such as seen in patients getting total parenteral nutrition. Total parenteral nutrition has been shown to cause an increase in the accumulation of unesterified cholesterol and phospholipids, which make up most of the structure of Lp-X.[3]

Epidemiology

Currently, there is no report of the incidence or prevalence of Lp-X-induced hyperlipidemia. There is no report on whether it is more prevalent in men vs. women.

Pathophysiology

There are no definite answers to the cause of hyperlipidemia, but many theories have been proposed. In an article by Jankowski and coauthors (2012), the authors explained that the cause of hyperlipidemia in patients with cholestasis is due to the regurgitation of cholesterol and bile salts into the circulation.[5]

In cholestasis, bile acids are unable to be secreted due to obstruction. Bile accumulates in plasma, causing an increase in bile lipoprotein, which is a precursor to Lp-X. Lp-X forms from the combination of bile lipoprotein and albumin.[3] 

Lp-X has a similar density as LDL; however, its metabolism is different from that of LDL. This is because Lp-X cannot be taken up by LDL receptors. One of the possible causes of hyperlipidemia in these patients is the inability of Lp-X to cause negative feedback in cholesterol production.

History and Physical

History and physical are some of the most important aspects of a patient's evaluation. This is because it gives the clinicians a clue of the cause of the patient's presentation. Patients with hyperlipidemia should be asked about current medications, family history of severe hyperlipidemia, or premature cardiovascular disease. Familial hyperlipidemia should be a top differential if the patient has more than one family member with severe hyperlipidemia or pre-mature cardiovascular disease. If not, clinicians need to think about other reasons that could cause severe hyperlipidemia. Such reasons include liver disease, LCAT deficiency, and lipid infusion.

Physical examination findings that could be seen include the presence of jaundice, scleral icterus, right upper quadrant pain, or liver enlargement. Xanthomas could also be present in some of these patients. Xanthomas can be found around the tendon, elbows, and palms. The cause of the xanthomas is a result of the formation of foam cells in macrophages of patients with severe hyperlipidemia.[6]

Evaluation

Lipoprotein-X (LP-X) is a 30-70nm lipid bilayer vesicle that encloses a fluid compartment.[7]  It has been reported to contain 66% phospholipids, 22% cholesterol esters, and 6% albumin.[8]  It is frequently mistaken for LDL on routine lipid panel labs due to having similar densities.[9]  Lipoprotein-X differs distinctly from all other liver-derived atherogenic lipoproteins, including very Large density lipoprotein (VLDL), intermediate-density lipoprotein (IDL), low-density lipoprotein (LDL), and high-density lipoprotein (HDL). This is because it does not have a micellar structure and does not contain apolipoprotein B100 (Apo B100). Apo B100 is one of the apolipoproteins that are present in other lipoproteins. Patients with elevated Lp-X typically have low Apo B-100. In fact, the target level for Apo B100 has been reported to be below 90 mg/dL.[7] This level approximates to true LDL cholesterol of 116 mg/dL.  To distinguish between normal dyslipidemia and dyslipidemia secondary to Lp-X, a decrease in (HDL-c + LDL-c)/TC ratio could be a marker.[8] This ratio is decreased in patients with lipoprotein-induced dyslipidemia.

To evaluate patients with lipoprotein X-induced dyslipidemia, CBC, CMP, liver function test including bilirubin, lipid panel, Lp-X, and Apo B100 should be checked. Not all laboratories are equipped with measuring serum Lp-X levels. Methods that have been used to get serum Lp-X levels include electrophoresis using agarose gel, ultracentrifugation, and magnetic spectroscopy.[3]

Images such as computed tomography scans of the abdomen and magnetic resonance cholangiopancreatography (MRCP) could also be done to evaluate for common bile duct dilation, which is a sign of cholestasis. Patients with liver disease like cholestasis usually present with elevated levels of liver function tests, including alanine aminotransferase, aspartate aminotransferase, total bilirubin levels, and also very high levels of total cholesterol, LDL, triglycerides, and low levels of HDL.

Treatment / Management

The definitive therapy for Lp-X induced dyslipidemia is to treat the underlying cause.  For instance, endoscopic retrograde cholangiopancreatography (ERCP) can be used for treating obstructive cholestasis. Cholesterol-lowering medications, such as statins and ezetimibe, are unnecessary when Apo B100 is below 90mg/dL because this suggests that dyslipidemia is caused by Lp-X formation. In fact, statins are not effective because Lp-X does not undergo LDL receptor-mediated hepatic clearance.[7]

Cholestasis also could lead to the accumulation of toxic levels of statins because bile excretion is affected. Ezetimibe is also not effective because of how the medication functions. It works by helping to reduce intestinal cholesterol absorption.[7] However, in cholestasis, there is poor micellar formation leading to poor cholesterol absorption. Suppose the Apo B100 level is <90 mg/dL, most likely it is Lp-x induced and there is no indication for lipid-lowering therapy, however, if it is > 90 mg/dl, which corresponds with LDL cholesterol of >116 mg/dL, then we consider lipid-lowering agents like statin and ezetimibe. In severe cases where Lp-X causes severe hypercholesterolemia, hyperviscosity could occur, and the patient might need to undergo plasmapheresis for rapid reduction in the cholesterol levels.[10](B3)

Differential Diagnosis

The differential diagnoses of major lipid disorders include familial hypercholesterolemia, familial defective Apo B100, familial combined hyperlipidemia, and type III hypolipoproteinemia. We also need to rule out the possibility of hypothyroidism, nephrotic syndrome, and poorly controlled diabetes mellitus.

Prognosis

There are no documented reports about the prognosis of Lp-X induced hypercholesterolemia. In general, patients who have this type of hyperlipidemia get normal LDL -c levels after treatment of the underlying condition. In a case report by Patel AM et al. (2016), it was discussed that a patient with primary sclerosing cholangitis who developed hypercholesterolemia due to Lp-X had normal levels of lipid profile after treatment with steroid and azathioprine.[11] 

Palmer xanthomas found in some patients with cholestasis on physical examination also regress months after the Lp-X levels reduce.[9] Xanthomas are formed due to the Lp-X formation of foam cells in macrophages.[6] In other words, patients with Lp-X-induced hypercholesterolemia usually do well after the underlying cause is treated.

Complications

Apart from leading to hyperlipidemia, Lp-X formation has also been reported to cause electrolyte abnormalities such as pseudo hyponatremia, hypokalemia, and hypochloremia.[3] Lipoprotein X-induced hyperlipidemia patients do not have an increased risk of atherosclerosis because Lp-X has low atherogenicity caused by the absence of Apo B100 in Lp-X.[3]