Lipoprotein X-Induced Hyperlipidemia

Etiology

There are 4 commonly reported etiologies of LpX-induced hyperlipidemia in the literature. They include cholestatic liver dysfunction, deficiency of the lecithin-cholesterol-acyl-transferase enzyme, graft vs host liver disease, and lipid infusion.[3][4] 

Elevated levels of LpX typically occur in cases of liver dysfunction, irrespective of the underlying cause. Enzymes, notably the cholesterol 17 alpha-hydroxylase enzyme, typically facilitate the usual conversion of cholesterol into bile acids, attributing this phenomenon. Cholestasis prevents the normal formation of bile acids, leading to the formation of LpX.

LpX is rich in phospholipid and unesterified cholesterol, with albumin as the primary protein component and apolipoprotein C (apo-C) on the surface.[4]  The reticuloendothelial system and the kidneys clear LpX. Researchers historically linked Lpx with patients who had cholestatic diseases. LpX fails to exert feedback inhibition on cholesterol synthesis, which leads to hypercholesterolemia in obstructive jaundice.[4] Aside from primary biliary cholangitis, LpX elevation has also been seen in patients with cholestasis of pregnancy.

This condition can also be present in patients with mutations in the enzyme that esterifies cholesterol (ie, lecithin–cholesterol acyltransferase [LCAT]). Patients with LCAT deficiency will have a higher formation of LpX because of their inability to convert free cholesterol to cholesterol esters.[5] Total parenteral nutrition has been shown to cause an increase in the accumulation of unesterified cholesterol and phospholipids, which comprise most of the structure of Lp-X.[4]

Of the identified causes, the most frequently noted cause of LpX-induced hyperlipidemia is cholestatic liver disease. Among the identified causes, cholestatic liver disease emerges as the most frequently noted cause of LpX-induced hyperlipidemia. More than 75% of patients diagnosed with primary biliary cholangitis exhibit hypercholesterolemia, characterized by elevated cholesterol levels.[6] Among the identified causes, cholestatic liver disease emerges as the most frequently noted cause of LpX-induced hyperlipidemia. More than 75% of patients diagnosed with primary biliary cholangitis exhibit hypercholesterolemia, characterized by elevated cholesterol levels.[7] Although patients with cholestatic disease exhibit marked derangements in serum lipids and a high frequency of dyslipidemias, the observed risk of cardiovascular events was noted to be similar to that in the general population.[8]

Epidemiology

Hypercholesterolemia due to elevated lipoprotein X level is uncommon. Even among patients with difficult-to-treat hyperlipidemia and identifiable secondary causes, LpX-induced hyperlipidemia is not a common cause.[9] In contrast, dyslipidemia due to secondary causes is common but is usually secondary to excessive alcohol intake or uncontrolled diabetes mellitus.[9] 

Due to the rarity of this disease, epidemiologic data regarding its true incidence and prevalence is scarce. The majority of the data regarding this disorder consists of case reports of patients with severe cholestatic liver diseases. Among patients with liver disease, the prevalence of lipoprotein-X-induced hyperlipidemia is quite remarkable. According to one report, among 97 patients with liver disease, elevated lipoprotein X levels were found in 45% of patients with cholestatic features.[10] However, in patients with liver disease without cholestasis, LpX was not elevated. According to this study, the prevalence of lipoprotein X elevation varied in different cholestatic diseases, with extrahepatic obstruction of recent onset showing elevated lipoprotein X level in 75% of the cases.[10]

Pathophysiology

Lipoprotein X is an abnormal lipoprotein that is rich in free cholesterol and phospholipids and is primarily in patients with cholestatic diseases.[4] Cholestatic diseases disrupt the conversion of cholesterol to bile acids, resulting in an accumulation of bile acids and cholesterol in plasma.[3] As described above, the hypercholesterolemia observed in cholestasis is due to the accumulation of the anomalous LpX.

LpX is a low-density lipoprotein subfraction[11] that forms from a bile lipoprotein after acquiring small quantities of triglycerides, apo-C, and esterified cholesterol in the blood vessels.[3]  The reticuloendothelial system and the kidney mediate Lp-X catabolism, but the exact mechanisms of this process are poorly understood.[3]

This accumulation of LpX leads to severe hypercholesterolemia. However, there is no evidence of increased cardiovascular events or risk with this disease.[7][8] The mechanism behind this "protective" effect is not elucidated and remains under study. Studies suggest that LpX reduces low-density lipoprotein (LDL) atherogenicity by preventing LDL oxidation and provides "protection" for endothelial cells by preserving their integrity in hypercholesterolemia.[11] 

LpX resembles a "lamellar vesicle" with a diameter of 30 to 70 nm,[12] and has a density close to very low-density lipoprotein (VLDL) and LDL, which can alter the results of LDL calculations. Lp-X completely lacks apo-B in its structure.[12] The lipid composition of LpX consists mainly of free cholesterol and phospholipids, with less than 5% comprising cholesterol esters and triglycerides. The surface of the albumin contains small apolipoproteins like apo-A1, apo-E, and apo-C, while its aqueous core dissolves these components.[12] The lack of apo-B provides a long half-life in circulation.[12] LpX is primarily removed from the plasma by the reticuloendothelial system (at the spleen).

History and Physical

Patients typically come to attention when laboratory testing of serum lipids yields grossly abnormal results. Still, history and physical are some of the most important aspects of a patient's evaluation because they give clinicians a clue about the cause of the patient's presentation. Ask patients with hyperlipidemia 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 a single family member with severe hyperlipidemia or premature 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.

Visual physical examination findings 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 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.[13]

In graft versus host disease, LpX-induced hypercholesterolemia presents with hypercholesterolemia on laboratory testing with xanthelasmas and cholesterolomas.[4] Patients with LCAT deficiency present with low concentrations of high-density lipoprotein (HDL), as well as anemia, corneal opacities, proteinuria, and chronic kidney disease.[4] 

Pseudohyponatremia is also a prominent feature of this disease. Consider the presence of LpX in all patients withj pseudo-hyponatremia associated with cholestasis.[4]

LpX accumulation can also result in hyperviscosity syndrome. Patients may have rare presentations such as a central retinal vein thrombosis presenting with vision loss.[14]

Evaluation

As stated above, most patients come to light when they have grossly abnormal lipid testing results with the presence of xanthomas. The serum cholesterol level usually exceeds 1000 mg/dL in patients with xanthomas.[15]

Lipoprotein X (LPX) is a 30 to 70 nm lipid bilayer vesicle that encloses a fluid compartment.[16] It has been reported to contain 66% phospholipids, 22% cholesterol esters, and 6% albumin.[17] It is frequently mistaken for LDL on routine lipid panel labs due to similar densities.[18] 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-B). 

Patients suspected to have LpX-induced hyperlipidemia should have a serum metabolic panel, liver function testing, serum lipid measurement, and apo-B measured. However, care must be taken to account for the "errors" in measurement that can result from the presence of LpX. The presence of LpX interferes not only with the LDL calculation from the Friedewald formula but also interferes with direct LDL assays.[14] LpX can also interfere with the measurements of apolipoprotein E phenotype analysis, total protein, and serum electrolytes if indirect ion-selective electrodes are used.[14] 

Direct measures of LpX are not widely available.[14] Available methods for the detection of LpX include electrophoresis using agarose gel, ultracentrifugation, and magnetic spectroscopy.[4] The latter two are available only in specialized laboratories and are infrequently used in routine diagnosis. Agarose electrophoresis is more readily available but is not foolproof. One case report stated that a commercially available agarose electrophoresis set failed to clearly demonstrate the presence of LpX in their patient.[14] Reviewing the results of other case reports, the authors concluded that the presence of LpX manifests in different ways in electrophoresis and varies by patient, raising caution for the interpretation of agarose electrophoresis.[14] Detection of LpX using agarose gel electrophoresis utilizes the separation of lipoproteins according to their surface charge.[12] After running the specimen on non-denaturing agarose gels, they are fixed with 55% ethanol and stained with a lipophilic dye (such as Sudan Black).[12] LPX, however, is difficult to detect using Sudan Black, which adheres to neutral lipids, because LPX particles are deficient in neutral lipids (such as cholesterol esters and triglycerides).[19] Filipin, a fluorescent polyene antibiotic, has been suggested as a novel alternative for the detection of LpX as it binds specifically to free cholesterol that is abundantly present in LpX.[19]

Indirect measures of LpX utilize the absence of apo-B in this structure by measuring the total cholesterol to apo-B ratio or the discrepancy in calculated vs. measured LDL levels in a serum sample. The total cholesterol to apo-B ratio is usually significantly increased in patients with LpX-induced hypercholesterolemia.[14] Some patients, however, may have only a slight increase in this ratio due to the co-existence of LpX elevation with LDL elevation. In these patients, the apo-B level is increased, lowering the total cholesterol to apo-B ratio.[14] In such cases, a discrepancy of measured vs. calculated LDL may be used to demonstrate the presence of LpX. One case study reported total cholesterol of 982 mg/dL, triglycerides of 115 mg/dL, and HDL cholesterol of 32 mg/dL, for a calculated LDL of 927 mg/dL. In the same sample, the directly measured LDL cholesterol was 499 mg/dL.[12] This difference can be used as an indirect measure of LpX as it is strongly suggestive of hypercholesterolemia secondary to LpX. 

Treatment / Management

The definitive therapy for LpX-induced dyslipidemia is to treat the underlying cause. Statins are ineffective in lowering cholesterol in LpX-related hypercholesterolemia because LpX does not undergo LDL receptor-mediated hepatic clearance.[16] As bile excretion is affected, cholestasis also could lead to the accumulation of toxic levels of statins, most of which is excreted in bile.[16]  Ezetimibe is also not effective because it works by helping to reduce intestinal cholesterol absorption. However, in cholestasis, there is poor micellar formation, leading to poor cholesterol absorption.[16]

In patients with cholestatic diseases, ursodeoxycholic acid and obeticholic acid (OCA) can reduce lipid levels. Ursodeoxycholic acid can decrease total cholesterol and low-density lipoprotein (LDL) cholesterol in patients with primary biliary cholangitis (PBC).[20] Obeticholic acid can decrease total cholesterol and high-density lipoprotein (HDL) cholesterol in patients with PBC and respond poorly to ursodeoxycholic acid (UDCA).[21] (A1)

It is important to note that OCA is contraindicated in patients with advanced cirrhosis.[22] The American Association for the Study of Liver Diseases defines advanced cirrhosis in this scenario as current or prior evidence of liver decompensation (eg, encephalopathy, coagulopathy) or portal hypertension (eg, ascites, gastroesophageal varices, or persistent thrombocytopenia). 

Combining fibrate therapy with UDCA may be an option for patients who respond poorly to UDCA. Adding fenofibrate therapy to UDCA in patients with PBC who had an incomplete response to UDCA resulted in significant reductions in total cholesterol, triglycerides, and non-high-density lipoprotein cholesterol.[23] A 2018 study evaluated the effect of bezafibrate compared to placebo in patients with incomplete response to UDCA therapy. The study results reported that bezafibrate plus UDCA therapy resulted in a more significant reduction in total cholesterol level after 24 months compared with placebo plus UDCA.[24] According to the AASLP practice guidelines, fibrates can be considered an "off-label" treatment for patients who have PBC and inadequate response to ursodeoxycholic acid.[22] They advise caution and discourage the use of fibrates in patients with decompensated liver disease (Child Pugh-Turcotte B or C).[22](B3)

In patients with graft-vs-host disease (GVHD) of the liver causing LpX-induced hyperlipidemia, treatment of the underlying GVHD by adjustment of immunosuppression is the mainstay of therapy.[25] Adjustment of immunosuppression was shown to significantly improve or resolve hypercholesterolemia in 3 out of the 5 patients.[25] (B3)

Initiate plasmapheresis in patients presenting with hyperviscosity syndrome, pulmonary embolism, or cholesteroloma of the lung.[12][25] Although the data regarding its efficacy is limited to case reports, most experts recommend plasmapheresis for the treatment of LpX-induced hypercholesterolemia that presents with hyperviscosity syndrome, thrombotic complications, graft-versus-host disease of the liver, and cholesteroloma of the lung.[12][25] Plasmapheresis, however, should be considered only as a temporary measure in most cases until a liver transplant, as this is the only definitive therapy for patients with primary liver disease.[12](B3)

Differential Diagnosis

The differential diagnosis should include primary familial causes of severe hyperlipidemia and other common causes of secondary hyperlipidemia, including the following:

• Familial hypercholesterolemia
• Familial defective apo-B
• Familial combined hyperlipidemia
• Type III hypolipoproteinemia
• Excessive alcohol intake
• Hypothyroidism
• Nephrotic syndrome
• Uncontrolled diabetes mellitus

Prognosis

In most cases, hyperlipidemia resolves with adequate treatment of cholestatic disease. A case report by Patel AM et al (2016), discussed the normalization of lipid profiles in a patient with primary sclerosing cholangitis who developed hypercholesterolemia due to LpX after undergoing treatment with corticosteroids and azathioprine.[26] 

Cutaneous xanthomas associated with cholestasis typically regress within months.[18] Xanthomas are non-life threatening and asymptomatic. In most patients, they resolve with the treatment of underlying hyperlipidemia and cholestasis. 

The risk of cardiovascular disease in patients with cholestatic diseases is generally not increased. Most studies evaluating this risk looked at patients with primary biliary cholangitis. Results from a 2008 study looking at 930 patients with primary biliary cholangitis concluded that there was no increased risk of myocardial infarction, stroke, or transient ischemic attack compared to age- and sex-matched controls.[7]

Complications

While LpX itself does not increase the risk of coronary artery disease, multiple case studies have linked it to hyperviscosity syndrome. Complications such as hyperviscosity syndrome and renal disease have been reported in patients with LCAT deficiency-associated hypercholesterolemia.[14]

Cutaneous xanthomas are common in patients with this disease. One case report, however, noted the development of cutaneous xanthelasmas and diffuse gastric xanthomas secondary to lipoprotein X-induced hypercholesterolemia.[27] This patient had PBC-associated cirrhosis, and the gastric xanthomas resolved completely following liver transplantation.