What is Lipoprotein X-Induced Hyperlipidemia?

Hyperlipidemia, or high levels of fat in the blood, is known to cause heart disease and metabolic syndrome. However, it can have multiple types and causes. There are several versions inherited through families, including variant forms of combined hyperlipidemia, defective apolipoprotein B, hypertriglyceridemia, and hypercholesterolemia. Whereas most hyperlipidemias increase the risk of heart disease and atherosclerosis, which is the build-up of fats in the arteries, some versions may not cause these conditions. Lipoprotein X (Lp-X) induced hyperlipidemia is one such type.

This unusual type of lipid, Lp-X, mostly occurs in patients with liver problems, in particular those with issues related to bile flow either inside or outside the liver. It can also accumulate in patients with primary biliary cirrhosis, obstructive liver disease, and a deficiency in a specific enzyme involved in cholesterol metabolism.

Despite it being rare for this condition to lead to cardiovascular diseases and fat accumulation in the arteries, Lp-X induced hyperlipidemia can manifest in various ways and has potentially deadly consequences. Too much Lp-X in the blood can lead to generalized skin lesions, primarily a buildup of fat-filled cells and a sharp rise in cholesterol levels. In severe instances, possibly fatal blood clots and a thickening of blood can occur.

As a result, dealing with and managing Lp-X induced hyperlipidemia is different from managing typical high levels of blood fats. Medical professionals must be able to identify this condition and manage it correctly in order to improve the health outcomes of the patients. This simplified explanation seeks to make it easier for clinicians to treat this condition correctly and enhance the results for patients who have this disease.

What Causes Lipoprotein X-Induced Hyperlipidemia?

There are four commonly reported causes of high levels of lipid-poor X (LpX) in the blood, as detailed in medical literature. These include liver dysfunction leading to interruption of bile flow, lack of an enzyme called lecithin-cholesterol-acyl-transferase, a condition where transplanted cells attack the patient’s liver, and infused lipids.

Increased LpX levels usually accompany cases of liver dysfunction, no matter the root cause. This is because specific enzymes, like cholesterol 17 alpha-hydroxylase enzyme, usually convert cholesterol into bile acids. An interruption in bile flow, known as cholestasis, prevents this normal process, leading to LpX formation.

LpX is mainly made of phospholipid and unesterified cholesterol, complemented by proteins (primarily albumin) and a protein on the surface called apolipoprotein C (apo-C). The body’s disposal system and the kidneys clear LpX from the system. Historically, high LpX levels have been associated with patients suffering from cholestasis. This issue allows cholesterol synthesis to carry on unchecked, leading to high levels of cholesterol in obstructive jaundice. In addition to primary biliary cholangitis, a condition leading to slow liver damage, LpX elevation can occur in pregnant women experiencing cholestasis.

This condition can also occur in patients with mutations in the LCAT enzyme, limiting their ability to convert free cholesterol. These patients will likely produce more LpX. Total parenteral nutrition, a method of feeding through the veins, can also cause an increase in unesterified cholesterol and phospholipids, which form most of LpX.

Generally, the most common cause of LpX-induced hyperlipidemia (high levels of fat in the blood) is cholestatic liver disease. More than 75% of patients diagnosed with primary biliary cholangitis show hypercholesterolemia, marked by high cholesterol levels. Although these patients exhibit significant changes in blood lipids and a high occurrence of dyslipidemias (abnormal levels of lipids), their risk of cardiovascular events appears to be similar to the general population.

Risk Factors and Frequency for Lipoprotein X-Induced Hyperlipidemia

High cholesterol due to increased Lipoprotein X (LpX) is pretty rare. This condition is not commonly seen, even in patients whose high cholesterol is difficult to manage or those who have clear secondary causes contributing to their high cholesterol levels. On the other hand, high cholesterol due to secondary causes, is more commonly caused by excessive drinking or uncontrolled diabetes.

Since Lipoprotein X-induced high cholesterol is a rare disease, there isn’t a lot of information available about how often it occurs and how many people it affects. Most of the information we have about this disorder comes from individual patient case studies, particularly those who are dealing with severe liver diseases that impede the normal flow of bile (cholestatic liver diseases). In people with liver disease, the occurrence of high cholesterol due to LpX is quite high. According to one study, of 97 liver disease patients, they found that 45% of patients with cholestasis had high Lipoprotein X levels. However, in liver disease patients without cholestasis, Lipoprotein X levels were not elevated. In this study, differences were observed in how common high Lipoprotein X levels were in different cholestatic diseases. For example, people with recent onset of extrahepatic obstruction (a blockage outside of the liver) showed high Lipoprotein X levels 75% of the time.

Signs and Symptoms of Lipoprotein X-Induced Hyperlipidemia

People usually find out they have high blood cholesterol (hyperlipidemia) when a routine blood test shows extremely abnormal results. However, a patient’s history and physical examination are crucial in guiding doctors towards what might be causing the high cholesterol. Doctors will often ask about current medications, whether there are any family members with very high cholesterol, or a history of early heart disease. If the high cholesterol runs in the family, this becomes a primary suspect. If not, other causes such as liver disease, deficiency of a fat regulating enzyme called LCAT, or fat infusions might be considered.

Physical signs of hyperlipidemia can include yellowing of the skin or eyes (jaundice or scleral icterus), pain in the upper right part of the abdomen, or an enlarged liver. Some patients might also have lumps under the skin, especially around tendons, elbows, and palms, called xanthomas. These are caused by fat depositing in certain immune cells of people with very high cholesterol.

In a condition called graft versus host disease, high cholesterol may produce yellowish plaques on the eyelids called xanthelasmas, or growths containing cholesterol. Patients with an LCAT deficiency may have low levels of good cholesterol (HDL), anemia, cloudy corneas, protein in the urine, and persistent kidney disease.

A strange feature of LCAT deficiency is pseudo-hyponatremia, or falsely lowered sodium levels in the blood. Doctors should consider LCAT deficiency in all patients with pseudo-hyponatremia associated with a blockage of bile flow. The buildup of certain fats in the blood could also thicken it, leading to hyperviscosity syndrome. Rare symptoms, like central retinal vein thrombosis causing loss of vision, may also occur.

Testing for Lipoprotein X-Induced Hyperlipidemia

Most people only discover they have a problem when a routine test shows they have a very high cholesterol level, often higher than 1000 mg/dL, and they have developed xanthomas, which are fatty deposits under the skin.

One of the culprits causing this high cholesterol is a lipid (or fat) called lipoprotein X (LPX). This particular lipid is often mistaken for another cholesterol particle known as LDL because they have similar densities. However, LPX is different from other lipoproteins, like VLDL, IDL, LDL, and HDL, that are produced in the liver. The distinguishing factor is that LPX doesn’t have the same structure and lacks a protein known as apolipoprotein B100 (apo-B).

If your doctor suspects that you might have an excessive amount of LPX, they might order a few tests, including a serum metabolic panel, liver function test, lipid measurement, and apo-B measurement. It’s important to note, the presence of LPX could lead to some unreliable measurements, affecting the overall accuracy not only of LDL levels calculation, but also of tests looking at other proteins and electrolytes.

Unfortunately, direct tests to measure LPX aren’t widely available. Some methods of detecting it, like using particular types of gels or magnets are only used in specialty labs. A more commonplace method, gel electrophoresis, is not foolproof and can give varying results.

There are certain ways you can indirectly measure LPX, like looking at how much total cholesterol to apo-B is in the structure. If the ratio is high, this might indicate a buildup of LPX-induced cholesterol in your body. However, for some patients these levels might not be extremely high, as they might also have elevated LDL cholesterol, which also contains apo-B protein.

Comparing calculated LDL levels with the directly measured LDL levels in a blood sample may offer an indirect way to point to the presence of LPX. A significant difference between these two values might suggest that the high cholesterol is due to LPX.

Treatment Options for Lipoprotein X-Induced Hyperlipidemia

To effectively treat elevated lipid levels caused by LpX, it’s important to address the root cause. Certain cholesterol-lowering drugs called statins won’t work for LpX-related high cholesterol because they rely on liver processes that LpX doesn’t follow. Additionally, statins could potentially build up to harmful levels in the body, as they’re largely excreted in bile, a process impaired in cholestasis. Another cholesterol drug, Ezetimibe, is also ineffective due to cholestasis interrupting its mode of action in reducing intestinal cholesterol absorption.

In patients with cholestasis, two types of acid, ursodeoxycholic and obeticholic, can be helpful. Ursodeoxycholic acid can lower total cholesterol and a bad form of cholesterol (LDL) in patients with a liver condition called primary biliary cholangitis (PBC). Obeticholic acid can decrease total cholesterol and a good form of cholesterol (HDL) in PBC patients who don’t respond well to ursodeoxycholic acid.

It’s crucial to remember that obeticholic acid is not suitable for patients with advanced liver cirrhosis, particularly if there is evidence of liver failure or high blood pressure in the veins that supply the liver.

For PBC patients who don’t respond well to ursodeoxycholic acid, fibrate therapy in combination with this acid could be an option. Medications like fenofibrate or bezafibrate, when added to ursodeoxycholic acid, can significantly reduce total cholesterol and triglycerides, amongst other things. However, fibrates should be used with caution and aren’t recommended for patients with serious liver disease.

In patients where a condition called graft-vs-host disease (GVHD) of the liver is causing LpX-induced high cholesterol, the primary treatment involves adjusting the patient’s immunosuppression therapy.

For patients who present with conditions related to thick blood, lung clots, or cholesterol lumps in the lung, a procedure known as plasmapheresis might be necessary. Effectively a blood cleansing process, plasmapheresis is recommended in these cases, but it’s usually a temporary solution until a liver transplant can be done, which is the definitive treatment for patients with primary liver disease.

When a doctor is trying to diagnose the cause of someone’s very high cholesterol levels, they will need to consider several possible explanations. Among these are inherited (or “familial”) conditions that cause high cholesterol, like:

Familial hypercholesterolemia,
Familial defective apo-B,
Familial combined hyperlipidemia, and
Type III hypolipoproteinemia.

In addition, there are several other common causes of high cholesterol that can develop due to lifestyle factors or other health conditions. These include:

Drinking too much alcohol,
Having an underactive thyroid (hypothyroidism),
Experiencing kidney damage that leads to protein in the urine (nephrotic syndrome), and
Unmanaged diabetes.

By considering all these possibilities, the doctor can make an accurate diagnosis and recommend effective treatment.

What to expect with Lipoprotein X-Induced Hyperlipidemia

In the majority of cases, high cholesterol can be cured with the proper treatment of a certain liver condition known as cholestatic disease. This was evidenced in a case study done by Patel AM and others in 2016. They reported a patient with a liver disease called primary sclerosing cholangitis. This patient had high cholesterol due to a lipid-related compound, but after receiving treatment with corticosteroids and azathioprine, the cholesterol level returned to normal.

In relation to skin growths caused by cholesterol deposits (xanthomas) in connection with cholestatic disease, they usually shrink within a few months. These growths are usually harmless and cause no symptoms. In most patients, they disappear once the high cholesterol and cholestatic disease are treated.

As for the risk of heart disease in patients with cholestatic disease, it’s generally not heightened. Most research focusing on this risk has centered on patients with a specific liver condition known as primary biliary cholangitis. According to the findings from a 2008 study involving 930 patients with primary biliary cholangitis, there was no increased exposure to heart attack, stroke, or transient ischemic attack (a ‘mini stroke’) compared to a group of the same age and sex.

Possible Complications When Diagnosed with Lipoprotein X-Induced Hyperlipidemia

Lipoprotein X (LpX) itself does not raise the likelihood of coronary artery disease, however, it has been connected to a condition called hyperviscosity syndrome in multiple case studies. This syndrome, along with kidney disease, has been reported in patients with a lipid disorder linked to LpX that leads to very high cholesterol levels.

Patients with this disorder often have skin conditions known as cutaneous xanthomas. One report recorded a case where a patient developed both cutaneous xanthelasmas and spread-out skin conditions known as gastric xanthomas due to high cholesterol levels caused by LpX. The patient also had cirrhosis linked to primary biliary cholangitis (PBC), but improved completely after a liver transplant operation.

Some complications associated with this condition include:

Hyperviscosity syndrome
Renal or kidney disease
Cutaneous xanthelasmas
Diffuse gastric xanthomas
PBC-associated cirrhosis

Preventing Lipoprotein X-Induced Hyperlipidemia

Presently, there are no specific instructions or recommendations for checking elevated fat levels in the blood associated with Lipoprotein X in at-risk patients. The screening for abnormal levels of fat in these patients should follow the same guidelines advised for everyone. The European Association for the Study of the Liver (EASL), a respected authority in the field, states that there’s not enough evidence to suggest a higher risk of heart disease in patients with high fat levels in blood associated with a liver disease called PBC. Accordingly, they don’t recommend a different screening schedule for these patients.

Frequently asked questions

Lipoprotein X-Induced Hyperlipidemia is an unusual type of lipid that occurs in patients with liver problems, particularly those with issues related to bile flow. It can lead to generalized skin lesions, a buildup of fat-filled cells, a sharp rise in cholesterol levels, and potentially fatal blood clots and thickening of blood.

Lipoprotein X-Induced Hyperlipidemia is a rare disease.

Signs and symptoms of Hyperlipidemia include: - Yellowing of the skin or eyes (jaundice or scleral icterus) - Pain in the upper right part of the abdomen - Enlarged liver - Lumps under the skin, especially around tendons, elbows, and palms, called xanthomas - Yellowish plaques on the eyelids called xanthelasmas in graft versus host disease - Growth containing cholesterol in graft versus host disease - Low levels of good cholesterol (HDL) in LCAT deficiency - Anemia in LCAT deficiency - Cloudy corneas in LCAT deficiency - Protein in the urine in LCAT deficiency - Persistent kidney disease in LCAT deficiency - Pseudo-hyponatremia, or falsely lowered sodium levels in the blood, associated with a blockage of bile flow in LCAT deficiency - Thickening of the blood leading to hyperviscosity syndrome in LCAT deficiency - Rare symptoms like central retinal vein thrombosis causing loss of vision may also occur.

There are four commonly reported causes of Lipoprotein X-induced hyperlipidemia: liver dysfunction leading to interruption of bile flow, lack of an enzyme called lecithin-cholesterol-acyl-transferase, a condition where transplanted cells attack the patient's liver, and infused lipids.

The doctor needs to rule out the following conditions when diagnosing Lipoprotein X-Induced Hyperlipidemia: - Familial hypercholesterolemia - Familial defective apo-B - Familial combined hyperlipidemia - Type III hypolipoproteinemia - Drinking too much alcohol - Having an underactive thyroid (hypothyroidism) - Experiencing kidney damage that leads to protein in the urine (nephrotic syndrome) - Unmanaged diabetes

To properly diagnose Lipoprotein X-Induced Hyperlipidemia, a doctor may order the following tests: 1. Serum metabolic panel: This test measures various substances in the blood, including cholesterol levels, to assess overall metabolic health. 2. Liver function test: This test evaluates the liver's ability to function properly and can help identify any liver-related issues that may be contributing to the high cholesterol levels. 3. Lipid measurement: This test specifically measures the levels of different types of lipids, including lipoproteins, in the blood. 4. Apo-B measurement: This test measures the levels of apolipoprotein B, a protein found in lipoproteins, which can help differentiate Lipoprotein X from other lipoproteins. It's important to note that direct tests to measure Lipoprotein X are not widely available, and indirect methods, such as comparing calculated LDL levels with directly measured LDL levels, may be used to indicate the presence of Lipoprotein X. Additionally, other tests may be ordered to assess overall liver function and to rule out other potential causes of high cholesterol.

Lipoprotein X-Induced Hyperlipidemia can be treated by addressing the root cause. Cholesterol-lowering drugs called statins and Ezetimibe are ineffective due to the liver processes that Lipoprotein X (LpX) doesn't follow and cholestasis interrupting their mode of action. In patients with cholestasis, ursodeoxycholic acid and obeticholic acid can be helpful. Ursodeoxycholic acid can lower total cholesterol and LDL cholesterol in patients with primary biliary cholangitis (PBC), while obeticholic acid can decrease total cholesterol and HDL cholesterol in PBC patients who don't respond well to ursodeoxycholic acid. Fibrate therapy in combination with ursodeoxycholic acid can be an option for PBC patients who don't respond well to ursodeoxycholic acid alone. Adjusting immunosuppression therapy is the primary treatment for Lipoprotein X-induced high cholesterol caused by graft-vs-host disease (GVHD) of the liver. Plasmapheresis, a blood cleansing process, may be necessary for patients with conditions related to thick blood, lung clots, or cholesterol lumps in the lung, but it is usually a temporary solution until a liver transplant can be done, which is the definitive treatment for patients with primary liver disease.

The side effects when treating Lipoprotein X-Induced Hyperlipidemia include: - Statins and Ezetimibe are ineffective due to the liver processes that Lipoprotein X (LpX) doesn't follow and cholestasis interrupting their mode of action. - Ursodeoxycholic acid can lower total cholesterol and LDL in patients with primary biliary cholangitis (PBC). - Obeticholic acid can decrease total cholesterol and HDL in PBC patients who don't respond well to ursodeoxycholic acid, but it is not suitable for patients with advanced liver cirrhosis or liver failure. - Fibrate therapy in combination with ursodeoxycholic acid can significantly reduce total cholesterol and triglycerides in PBC patients who don't respond well to ursodeoxycholic acid, but fibrates should be used with caution and aren't recommended for patients with serious liver disease. - Adjusting immunosuppression therapy is the primary treatment for Lipoprotein X-induced high cholesterol caused by graft-vs-host disease (GVHD) of the liver. - Plasmapheresis, a blood cleansing process, may be necessary for patients with conditions related to thick blood, lung clots, or cholesterol lumps in the lung, but it's usually a temporary solution until a liver transplant can be done. - Complications associated with Lipoprotein X-induced hyperlipidemia include hyperviscosity syndrome, renal or kidney disease, cutaneous xanthelasmas, diffuse gastric xanthomas, and PBC-associated cirrhosis.

The prognosis for Lipoprotein X-Induced Hyperlipidemia can vary depending on the individual case. In some instances, the condition may not lead to cardiovascular diseases or fat accumulation in the arteries. However, in severe cases, Lipoprotein X-Induced Hyperlipidemia can have potentially deadly consequences, including the formation of blood clots and thickening of the blood. Proper identification and management of the condition by medical professionals are crucial for improving health outcomes for patients.

A medical professional or doctor specializing in lipid disorders or hepatology.

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