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Lipoprotein-X and Lipoprotein-Z Induced Hyperviscosity Syndrome in the Setting of Cholestatic Liver Failure

We describe a case referred for worsening hypercholesterolemia in the setting of atorvastatin and fenofibrate-induced liver injury. The patient reported neurological complaints attributed to hyperviscosity syndrome (induced by lipoprotein-X and lipoprotein-Z). Hepatic recovery was associated with reduction of whole blood viscosity and amelioration of neurological symptoms. (Level of Difficulty: Advanced.)


PAST MEDICAL HISTORY
The patient's past medical history was notable

LEARNING OBJECTIVES
To recognize the associations between severe liver injury and the presence of abnormal lipoproteins LP-X and LP-Z. To understand that LP-Z and LP-X elevations reflect erroneously elevated cholesterol measurements, which may not warrant lipid lowering pharmacotherapy. To recognize the association of LP-X and LP-Z with hyperviscosity syndrome, and the management of the condition.

DIFFERENTIAL DIAGNOSIS
The differential diagnosis included familial hypercholesterolemia vs mixed hyperlipidemia vs secondary hypercholesterolemia from cholestatic liver disease.

INVESTIGATION
Given the severe elevation of cholesterol in the setting of cholestatic liver injury, the presence of lipoprotein X (LP-X) and LP-Z was suspected. 1  Hepatic panel, WBV, serum viscosity, and NMR analyses were obtained on 2 separate visits. The NMR spectral deconvolution at the initial visit revealed discordance between measured and calculated serum lipid methyl signals ( Figure 1A) that resolved when LP-X and LP-Z were included in the model ( Figure 1B  The patient was additionally noted to be hyponatremic with sodium levels as low as 127 mEq/L.
Although calculations of serum osmolality were not obtained, we believe that this value was likely spuriously reduced secondary to the high presence of insoluble TG and LP-X in the plasma. Further contributions to hyponatremia stemming from the severe liver injury were additionally considered.
Because of presumed beta cell destruction by recurrent pancreatitis episodes, the patient developed diabetes mellitus. She was initiated on insulin therapy; however, the hemoglobin A 1C increased from 4.6% to 7.6%.
Finally, in light of persistent elevations in alkaline phosphatase, the gastroenterology service was consulted for management of liver hematoma and biliary stricture. Endoscopic retrograde cholangiopancreatography and biliary stenting were performed and serial imaging of the biliary hematoma was obtained. Subsequently, she developed an abscess at the site of the hematoma.

DISCUSSION
The initial case presentation suggested mixed (type 5) hyperlipoproteinemia, an uncommon disorder that results from impaired clearance of chylomicrons and very low-density lipoprotein particles. 3 The condition is associated with new-onset or worsening hypertriglyceridemia that is aggravated by a secondary disorder such as diabetes mellitus. Treatment is As LP-X and LP-Z are found within the same density range as LDL, their presence can cause measured "LDL-C" to be both highly elevated and inaccurate. 1,6 The patient's initial laboratory studies revealed a directly measured LDL-C of 662 mg/dL, a value incompatible with the 565 mg/dL total cholesterol level and 8 times higher than the 84 mg/dL value from 2 years prior. NMR-measured LDL particle number was extremely high (5,527 nmol/L) at the initial visit, 78% of which was accounted for by LP-Z ( Table 1).
A discordant, but elevated apolipoprotein-B level of 135 mg/dL was increased secondary to LP-Z.
High levels of LP-Z and LP-X can contribute to blood hyperviscosity. LP-Z particles are relatively small (18-20 nm) and homogenously sized, which we hypothesize raises WBV secondary to particle concentration. LP-X particles are larger and heterogeneously sized (30-100 nm), which increases WBV due both to molecular size and increased propensity for aggregation. 2 Table 2).
Physiologically, increases in WBV cause sluggish microcirculatory blood flow, increased erythrocyte aggregation, and impaired perfusion. 9 The symptoms of fatigue, blurred vision, paresthesia, and ataxia have recognized associations with hyperviscosity and are described in other hyperviscosity syndromes such as hyper-immunoglobulin M syndrome or Waldenstrom's macroglobunimia. 10 Treatment of LP-X and LP-Z dyslipidemia is based on alleviating the hepatic injury. 1 In patients with complications or debilitating neurological symptoms, plasmapheresis may be considered. 2,8 In this case, hepatic recovery warranted a conservative approach.

FOLLOW-UP
At the 3-month follow-up exam, hepatic recovery was found to be associated with substantial reductions of LP-X and LP-Z levels ( Table 1)