Lipoprotein-X: A Case of Falsely Elevated LDL Hypercholesterolemia

Abstract

Lipoprotein-X is an extremely rare cause of severe hyperlipidemia. We present a case of a 26-year-old man with primary sclerosing cholangitis who developed lipoprotein X-induced pseudohyponatremia with severe hyponatremia. In this case report, we also discuss the diagnostic approach and the treatment for lipoprotein X. (Level of Difficulty: Advanced.)

Graphical abstract

History of Presentation

A 26-year-old man presented with generalized weakness, headache, and abdominal and neuropathic pain. He had normal vital signs, right upper quadrant abdominal tenderness, and multiple small, yellow, dome-shaped papules on his face and extremities on examination (Figures 1A to 1E). His basic metabolic panel revealed sodium of 112 mmEq. Isotonic saline failed to increase sodium or improve his symptoms. The absent therapeutic response persisted despite escalation to hypertonic saline. Subsequent workup showed serum osmolality 283.0 mOsm/kg and total cholesterol 2,554 mg/dL, confirming hyperlipidemia-induced pseudohyponatremia and raising hyperviscosity syndrome as the probable cause of his symptoms. Additional studies to delineate the etiology of lipoproteinemia were undertaken.

Learning Objectives

• •To differentiate LpX from LDL-C for appropriate treatment choices.
• •To recognize LpX as a cause of pseudohyponatremia.

Figure 1.

Eruptive Xanthomas on Different Aspects of Body on July 8, 2022

(A) Lower face. (B) Right elbow. (C) Left elbow. (D) Both palms. (E) Both knees.

Past Medical History

Patient’s past medical history includes primary sclerosing cholangitis (PSC) and ulcerative colitis.

Differential Diagnosis

Diagnostic considerations included familial hypercholesterolemia, obstructive liver disease, nephrotic syndrome, and hypothyroidism.

Investigations

Laboratory workup revealed elevated liver enzymes with cholestatic predominance on complete metabolic panel with alkaline phosphatase at 1,942 IU/L, total bilirubin at 8.1 mg/dL, and significantly elevated total and low-density lipoprotein (LDL) cholesterol on serum lipid panel (Tables 1 and 2). Further evaluation of hypercholesterolemia with lipoprotein electrophoresis showed significant elevation in total cholesterol, normal lipoprotein A, and low apolipoprotein B (ApoB) (Table 3). Lipoprotein electrophoresis detected lipoprotein X (LpX) and therefore inaccurate quantitation of LDL (Table 3). Magnetic resonance cholangiopancreatography showed hepatosplenomegaly with intrahepatic and extrahepatic biliary stenosis. Kidney function, cortisol (8 am), and thyroid-stimulating hormone were within normal limits. Direct potentiometry confirmed accurate sodium at 140 mmEq, vastly different from the sodium of 112 mmEq on his initial basic metabolic panel.

Table 1.

Complete Metabolic Panel on Admission and Follow-Up

	Admission	Follow-Up
Sodium (mmol/L)	112	136
Potassium (mmol/L)	3.7	4.1
Chloride (mmol/L)	82	98
Carbon dioxide (mmol/L)	17	23
Calcium (mg/dL)	8.8	9.6
Glucose (mg/dL)	88	101
Blood urea nitrogen (mg/dL)	9	8
Creatinine (mg/dL)	0.7	0.8
Estimated glomerular filtration rate (mL/min)	129	123
Total protein (g/dL)	6.2	6.5
Albumin (g/dL)	3.1	4.4
Total bilirubin (mg/dL)	8.2	4.9
Alkaline phosphatase (IU/L)	1942	625
Aspartate amino transferase (IU/L)	226	116
Alanine amino transferase (IU/L)	235	98

Table 2.

Lipid Panel on Admission and Follow-Up

	Admission	Follow-Up
Total cholesterol (mg/dL)	2,554	348
HDL cholesterol (mg/dL)	<3	44
Triglycerides (mg/dL)	278	154
Calculated VLDL (mg/dL)	2,637	30
Direct LDL (mg/dL)	>1,000	274

HDL = high-density lipoprotein; LDL = low-density lipoprotein; VLDL = very low-density lipoprotein.

Table 3.

Lipoprotein Electrophoresis on Admission

Total cholesterol (mg/dL)	2,586
HDL cholesterol (mg/dL)	<4
Triglycerides (mg/dL)	202
Calculated VLDL (mg/dL)	606
Direct LDL (mg/dL)	a
LDL triglycerides (mg/dL)	a
VLDL triglycerides (mg/dL)	64
Beta VLDL cholesterol (mg/dL)	(-)
Beta VLDL triglycerides (mg/dL)	(-)
Chylomicron cholesterol	(-)
Lp(a) cholesterol (mg/dL)	<5
LpX	(+)

(-) = not detected; + = detection or presence; HDL = high-density lipoprotein; LDL = low-density lipoprotein; Lp(a) = lipoprotein A; LpX = lipoprotein X; VLDL = very low-density lipoprotein.

^aCannot be accurately quantified due to presence of LpX.

Management

Initial therapy with cholestyramine, atorvastatin, and evolocumab failed to produce cholesterol reduction or clinical response. The patient was admitted for total plasma exchange and endoscopic retrograde cholangiopancreatography (ERCP). He underwent ERCP with biliary sphincterotomy, balloon sweeps of the biliary tree, and serial balloon dilation as well as 2 session of total plasma exchange. His symptoms improved significantly, and his total cholesterol decreased by 87%.

Discussion

LpX is an extremely rare lipoprotein disorder. Only 9 cases of Lpx-induced pseudohyponatremia have been reported, and our case represents the lowest sodium ever documented.

As the sole effective pathway for cholesterol removal, bile acid production remains quintessential for the well-being of the human body.¹ Our patient had PSC with intraductal biliary stricture. Cholestasis halts bile excretion and consequently leads to bile-induced hepatotoxicity. To prevent this toxicity, hepatocytes bind bile to its farnesoid X receptors (FXR), stimulating bile secretion and inhibiting bile synthesis (Figure 2).² Limited bile production causes an inability to excrete cholesterol into bile, promoting free cholesterol migration into the blood. The merging of free cholesterol with phospholipid, albumin, and apolipoprotein-C and E forms LpX.² The lack of ApoB in LpX precludes clearance by the LDL/ApoB receptor, causing hypercholesterolemia (Figure 2). Conversely, the LDL cholesterol from the blood enters the liver through LDL/ApoB receptor, inhibiting the formation of free cholesterol. Because cholesterol binds to bile for secretion, intrahepatic cholesterol deficit causes no bile secretion. Deficient bile secretion leads to intrahepatic bilirubin accumulation, completing the cycle of LpX production (Figure 2).

Figure 2.

Mechanism of Lipoprotein-X

Cholestasis leads to bile accumulation in the liver. To prevent hepatotoxicity from bilirubin accumulation, (1) hepatocytes bind bile to FXR, which inhibits bile synthesis and stimulates bile secretion. The subsequent limitation in bile production due to binding of bilirubin to FXR leads to failure in cholesterol excretion, promoting (2) free cholesterol migration into blood. The merging of free cholesterol with phospholipid, albumin, and apolipoprotein-C and E forms LpX .² (3) The lack of ApoB in LpX precludes LpX clearance by the LDL/ApoB receptor, causing hypercholesterolemia. LDL-C entering through the LDL/ApoB receptor completes the LpX production cycle as this (4) inhibits cholesterol production, leading to decreased bilirubin excretion and formation of LpX. ApoB = apolipoprotein B; FXR = farnesoid X receptor; HMG-CoA = β-hydroxy β-methylglutaryl-conenzyme A; LDL-C = low-density lipoprotein cholesterol; LpX = lipoprotein X.

Understanding the characteristics and the proper testing techniques ensures correct detection of LpX. Accurate detection of LpX is vital for prognosis since management differs between cholestasis-induced hyperlipidemia and true hyperlipidemia. LpX can falsely elevate LDL on lipid assay owing to similar densities.³ The distinction can be supported by measuring ApoB, which is present in LDL and absent in LpX.² Lipoprotein electrophoresis remains the gold standard for direct LpX measurement.¹ Other methods for LpX diagnosis include nuclear magnetic resonance spectroscopy.⁴

Severe hypercholesterolemia owing to LpX can provoke hyperviscosity syndrome. Hyperviscosity syndrome can manifest as headache, neuropathic pain, lethargy, ataxia, seizure, and coma, symptoms that are also suggestive of hyponatremia.4, 5, 6 Laboratory findings can also obscure whether symptoms are caused by hyponatremia or hyperviscosity from LpX, because a decrease in plasma water from hypercholesterolemia can falsely represent low sodium levels via indirect potentiometry techniques such as a complete metabolic panel.⁷ Direct potentiometry delivers accurate sodium level by measuring the sodium concentration in plasma water without dilution, eliminating risk of inappropriately treating pseudohyponatremia.⁷ However, the most important aspect of precise diagnosis remains the history and physical examination. The history of PSC ignited our differential for cholestasis-induced hypercholesterolemia, and the presence of xanthomas on examination supported our diagnosis.

Confirmation of the diagnosis ascertained the appropriate therapeutic approach. Plasma exchange along with ERCP provided recovery from symptoms of hyperviscosity syndrome. The absent response to standard LDL-lowering therapies was consistent with multiple studies that revealed lack of evidence in LpX reduction other than in infants with cholestatic liver and biliary tract disease in the prestatin era, as well as no decrease in LpX side effects with statin therapy.^2,3

Follow-up

Two weeks after discharge, the resolution of symptoms suspected from hyperviscosity syndrome was evident; the patient reported no headache and improvement in his abdominal and neuropathic pain. Eruptive xanthomas are slowly improving. Continuous reduction in liver enzymes and normalizing serum sodium were noted (Table 1). Liver biopsy was consistent with PSC and negative for malignancy. The patient is now followed routinely in our lipid clinic with serial ERCPs and consideration for liver transplantation.

Conclusions

LpX can be a cause of hyperlipidemia-induced pseudohyponatremia and can falsely elevate LDL on routine lipid panel. Unlike LDL-induced hyperlipidemia, cholesterol-reducing agents will not decrease LpX or its manifesting symptoms. Additionally, the diagnosis of LpX cannot be readily made with routine laboratory work. Therefore, clinicians should heighten their suspicion by incorporating history and physical examination for an overall clinical picture to further gauge diagnostic approach. Further pursuit with lipoprotein electrophoresis can confirm the diagnosis of LpX. The primary focus of treatment is on resolving the cholestasis.