Hypercholesterolemia After COVID-19: Time to Include Lipoprotein X Among the Differential Diagnoses

Abstract

Background

Lipoprotein X (LpX) is an abnormal lipoprotein composed of phospholipids, free cholesterol, and albumin. Its overaccumulation is an infrequent cause of hyperlipidemia, which oftentimes presents in patients with cholestatic liver disease. The aim is to present the first 2 cases of patients with post-COVID cholangiopathy and LpX overaccumulation.

Case Report

We present 2 female patients (ie, a 34-year-old [patient 1] and a 56-year-old [patient 2]), who had complicated courses of COVID-19, requiring prolonged mechanical ventilation (>4 weeks). One month after discharge, patient 1 presented with abdominal pain. Patient 2 had gangrenous cholecystitis and later developed recurrent elevation of alkaline phosphatase and bilirubin. Both patients were diagnosed with cholestatic liver disease. During outpatient follow-up both patients were found to have elevated plasma low-density lipoprotein cholesterol (LDL-C) in routine lipid panels (723 mg/dL and 1389 mg/dL, respectively). Both patients underwent various treatments for elevated LDL-C before referral to endocrinology. Patients were diagnosed with LpX overaccumulation from post-COVID-19 cholangiopathy. In both patients, LDL-C fluctuations seen in routine lipid panels (affected by LpX levels) were tightly correlated with changes in alkaline phosphate and bilirubin.

Discussion

Our patients represent the first report of LpX overaccumulation in patients with post-COVID-19 cholangiopathy. Whether LpX accumulation is only the result of liver dysfunction, or COVID-19 infection plays a direct role in elevated LpX levels is still unknown.

Conclusion

In patients with complicated courses of COVID-19, LpX overaccumulation should be considered when a routine lipid panel shows significant LDL-C elevations. Awareness among health care providers regarding LpX is important to avoid unnecessary workup and treatment.

Highlights

• •Lipoprotein X is composed of phospholipids, free cholesterol, and albumin.
• •It is a rare cause of hyperlipidemia, sometimes seen in patients with cholestatic liver disease.
• •Its accumulation usually leads to incorrect diagnoses of LDL-C elevation.
• •Lipid lowering medications (e.g. statins, ezetimibe) are ineffective to reduce LpX.
• •LpX is not an atherogenic particle, and treatment is rarely necessary.

Clinical Relevance

We described 2 patients with complicated courses of COVID-19, who developed post-COVID-19 cholangiopathy. They presented to endocrinology due to elevated low-density lipoprotein cholestrol (LDL-C) (>500 mg/dL). Both patients were diagnosed with lipoprotein X, which can interfere with LDL-C assay in routine lipid panels. It is crucial to increase awareness about this diagnosis among health care providers.

Introduction

Lipoprotein X (LpX) is an abnormal lipoprotein predominantly composed of phospholipids (∼66%), free cholesterol (∼22%), and albumin (∼6%) and lacks the characteristic apolipoprotein B-100 (ApoB100) of low-density lipoprotein (LDL) particles.¹ Overaccumulation of LpX can be observed in intra- and extrahepatic cholestasis, lecithin-cholesterol-acyl-transferase deficiency, lipid-rich infusions (ie, total parenteral nutrition), and graft vs host disease in liver transplant patients.¹ It is an infrequent cause of hyperlipidemia, and it often leads to unnecessary workup and treatments.^2,3

Because LpX has a similar density as LDLs, it is difficult to differentiate the 2 with routine lipid tests.³ Calculating low-density lipoprotein cholesterol (LDL-C) using the Friedewald equation is invalid in the presence of LpX, as cholesterol present in LpX is incorrectly assumed to be part of LDL particles. LpX also causes interference with direct LDL-cholesterol assays. Therefore, LpX accumulation can lead to a misdiagnosis of familial hypercholesterolemia or severe LDL elevation. There are different options to directly or indirectly identify the presence of LpX in serum samples,^2,3 including measurement of phospholipids (ie, elevated in the presence of LpX), agarose gel lipoprotein electrophoresis (ie, can identify an LpX band), or measuring ApoB (ie, decreased in comparison to LDL-C levels). It is important to distinguish LpX from LDL-C for cardiovascular risk assessment and for appropriate therapeutic interventions.

Severe acute respiratory syndrome-associated coronavirus 2 (SARS-CoV-2) infection has been shown to cause liver injury through a variety of mechanisms: ischemia, direct injury from the virus, and cytokine storm.^4,5 Post-COVID-19 cholangiopathy is an increasingly recognized entity that develops during the recovery phase in patients with severe COVID-19 courses.^6,7 To our knowledge, no prior reports have described significant LpX accumulation in patients with post-COVID-19 cholangiopathy. Interestingly, a pilot study assessing lipoprotein subfractions by nuclear magnetic resonance in patients with severe COVID-19, but without cholangiopathy, found that 70% of these patients had detectable levels of LpX.⁸ So, it is possible that severe COVID-19 may contribute to LpX accumulation independently of liver function.

In the current work, we present 2 similar patients, who were referred to us for hypercholesterolemia treatment after routine lipid panel showed elevated LDL-C. Both patients had a complicated course of COVID-19 requiring long admissions and developed post-COVID-19 cholangiopathy. Both patients presented in a relatively short period of time, suggesting that this complication may be more common than currently recognized.

Case Report

Patient 1 is a 34-year-old female without significant past medical history, who had a 2-month hospitalization for COVID-19, requiring a cesarean section at 37 weeks of gestation due to acute hypoxic respiratory failure. She was intubated for over 5 weeks and required venovenous extracorporeal membrane oxygenation (VV-ECMO) support for 3 weeks. She was decannulated and discharged to inpatient rehab. One month later, she developed severe right upper quadrant pain prompting hospital admission. Imaging demonstrated mild intrahepatic and extrahepatic biliary ductal dilation. Magnetic resonance cholangiopancreatography was without ductal abnormality. Liver biopsy revealed severe steatosis without steatohepatitis, edematous portal tracks, and bile duct injury with ductular proliferation. Labs were notable for an LDL cholesterol level of 723 mg/dL with hepatitis and autoimmune serologies negative. The patient reported normal LDL levels 2 months prior to her initial hospitalization and had no family history of hypercholesterolemia. She underwent 4 plasmapheresis sessions, with improvement in LDL to 200 mg/dL, and improvement in symptoms. She was discharged on atorvastatin and ursodiol, but at follow-up appointments, LDL-C started to increase, so patient was also started on ezetimibe and evolocumab. However, her right upper quadrant pain returned along with worsening nausea and pruritis. At a follow-up visit after ∼1 month, labs were remarkable for LDL-C greater than 1200 mg/dL, total cholesterol 1561 mg/dL, alkaline phosphatase 1693 mg/dL, AST 237 U/L, ALT 234 U/L, and bilirubin 7.3 mg/dL. She was admitted to the hospital for plasmapheresis and further workup. Lipoprotein electrophoresis detected the presence of LpX. ApoB was 90 mg/dL and the familial hypercholesterolemia panel was negative. Overall, her presentation favored a diagnosis of COVID-19 induced ischemic cholangiopathy with increased levels of LpX. Figure 1A summarizes LDL-C levels over time and treatments received.

Fig. 1.

A and B, Low-density lipoprotein cholesterol levels measured by routine lipid panel over time. C and D, Total bilirubin over time. E and F, Alkaline Phosphastase levels over time. A/U = Atorvastatin and Ursodiol; E/E = Ezetimibe and evolocumab; OSH = outside hospital; QOD = every other day; R/C = Rosuvastatin and cholestyramine.

Patient 2 is a 56-year-old female with a past medical history significant for hypertension, type 2 diabetes, and obstructive sleep apnea, who had a 3-month hospitalization for COVID-19 requiring prolonged mechanical ventilation, proning, paralytic medications, and eventual tracheostomy. Her course was complicated by acute kidney injury requiring continuous renal replacement therapy and gangrenous cholecystitis treated with percutaneous drainage and antibiotics. After treatment of the cholecystitis, liver enzymes normalized; however, 2 weeks later, she developed new elevations in liver tests. Hepatology was consulted with further lab workup revealing only weakly positive antimitochondrial antibody (1:80), so she was started on ursodiol. Alkaline phosphatase and bilirubin continued to increase, prompting workup with magnetic resonance cholangiopancreatography demonstrating a beading appearance of the intrahepatic ducts suggestive of sclerosing cholangitis. Endoscopic ultrasound with guided liver biopsy was completed revealing extensive ductular reaction and patchy cholestasis consistent with an obstructive ductal process. She was diagnosed with post-COVID-19 cholangiopathy. During hepatology workup, she was referred to endocrinology for hypercholesterolemia with LDL 1389 mg/dL. At that appointment she referred skin lesions in both hands, which the patient described as ‘uncomfortable’ and were consistent with xanthomas. Plasma LDL cholesterol before COVID-19 was 78 mg/dL. Advanced lipid testing and lipoprotein electrophoresis were ordered to confirm the diagnosis of LpX. Obtaining desired labs was complicated due to lipemic serum and high bilirubin levels. Finally, labs revealed ApoB of only 88 mg/dL. The xanthomas regressed over months with improvement in hypercholesterolemia. Patient was later evaluated for a liver transplant at another hospital, and she was started on rosuvastatin 40 mg daily by hepatologist. Figure 1B summarizes LDL cholesterol levels over time and treatments received.

Discussion

Post-COVID-19 cholangiopathy is a rare hepatic complication of COVID-19 with few cases reported in the literature.^6,7 Both patients presented in this manuscript had a similar presentation as those previously described. Histologic findings from liver biopsies demonstrated ductal injury and retraction, consistent with post-COVID-19 cholangiopathy. While prior cases have not reported on patient’s cholesterol profile,^6,7 at least one case reported a total cholesterol of 1920 mg/dL, although this was not further addressed in the manuscript.⁹ Therefore, the cases reported here are unique in that they are the first to report the detection of LpX in patients with complicated courses of COVID-19.

While it is possible that LpX accumulation in our patients was just the result of post-COVID-19 cholangiopathy, similarly to what occurs in patients with other cholangiopathies, such as primary biliary cholangitis, there is also evidence that LpX is detected in patients with complicated courses of COVID-19, independently of the presence of cholangiopathy.⁸ More research is needed to determine if patients with post-COVID-19 cholangiopathy are at particularly high risk of developing LpX accumulation due to a direct action of SARS-CoV-2.

LpX is believed to be a nonatherogenic lipoprotein as it lacks ApoB100.^1,10 Therefore, treatment is recommended only in patients experiencing significant symptoms (ie, xanthomas), neuropathy, or if they develop hyperviscosity syndrome. LpX can also cause artifactual electrolyte abnormalities (eg, pseudohyponatremia). Due to the absence of ApoB100, statin therapy is likely to be ineffective, as these particles do not undergo LDL-receptor mediated clearance.¹¹ Moreover, statins should be used cautiously in cholestatic liver disease as there is impaired clearance, which can cause toxic effects. Ezetimibe is not recommended as intestinal cholesterol absorption does not contribute to high serum lipid levels due to poor micellar formation in these patients.¹¹ If therapy is needed, plasmapheresis is likely the most effective therapy based on prior reports.² However, the cornerstone of therapy should be directed at treating the underlying cause.

As evidenced by these cases, the presence of LpX led to unnecessary workup and treatment. In both cases, patients were started on treatments that were likely unnecessary and, in some cases, even ineffective. Therefore, it is important for clinicians to recognize the lipid manifestations of patients with cholestatic liver disease, especially among the growing number of patients with post-COVID-19 cholangiopathy. Several ways to differentiate LpX from LDL hypercholesterolemia have been described.^2,3 In our cases, we were able to identify LpX by electrophoresis (patient 1) and, indirectly, through normal levels of ApoB (patient 2). Regarding treatment, patient 1 received multiple medications and several sessions of plasmapheresis, with LpX levels increasing when plasmapheresis was stopped (ie, measured as LDL cholesterol in routine labs and represented in Fig. 1A). Patient 2 has shown progressive improvements in lipoprotein levels with resolution of symptoms (ie, disappearance of xanthomas).

In the study by Ballout et al,⁸ 70% of the patients with severe COVID-19 showed presence of LpX despite the absence of chronic cholangiopathy. This implies that severe SARS-CoV-2 infection may in itself contribute to the elevation of LpX. However, future studies are needed to discern the true role of SARS-CoV-2 in cases of LpX overaccumulation. In the meantime, hepatologists, cardiologists, endocrinologists and primary care providers are encouraged to remain vigilant in order to diagnose these patients early on and avoid unnecessary diagnostic and therapeutic procedures.

Disclosure

The authors have no multiplicity of interest to disclose.