Lysosomal acid lipase deficiency allograft recurrence and liver failure- clinical outcomes of 18 liver transplantation patients

Abstract

Lysosomal acid lipase deficiency (LAL-D) results in progressive microvesicular hepatosteatosis, fibrosis, cirrhosis, dyslipidemia, and vascular disease. Interventions available prior to enzyme replacement therapy development, including lipid lowering medications, splenectomy, hematopoietic stem cell and liver transplantation were unsuccessful at preventing multi-systemic disease progression, and were associated with significant morbidity and mortality. We report two sisters, diagnosed in infancy, who succumbed to LAL-D with accelerated disease progression following splenectomy and liver transplantation. The index patient died one year after hematopoietic stem cell transplant and liver transplantation. Her younger sister survived five years post liver-transplantation, complicated by intermittent, acute rejection. Typical LAL-D hepatopathology, including progressive, microvesicular steatosis, foamy macrophage aggregates, vacuolated Kupffer cells, advanced fibrosis and micronodular cirrhosis recurred in the liver allograft. She died before a second liver transplant could occur for decompensated liver failure. Neither patient received sebelipase alfa enzyme replacement therapy, human, recombinant, lysosomal acid lipase enzyme, FDA approved in 2015. Here are reviewed 18 LAL-D post-liver transplantation cases described in the literature. Multi-systemic LAL-D progression occurred in 11 patients (61%) and death in six (33%). These reports demonstrate that liver transplantation may be necessary for LAL-D-associated liver failure, but is not sufficient to prevent disease progression, or liver disease recurrence, since the pathophysiology is predominantly mediated by deficient enzyme activity in bone marrow-derived monocyte-macrophages. Enzyme replacement therapy addresses systemic disease and hepatopathology, potentially improving liver-transplantation outcomes. This is the first systematic review of liver transplantation for LAL-D, and the first account of liver allograft LAL-D-associated hepatopathology recurrence.

Introduction

Lysosomal acid lipase deficiency (LAL-D), a rare, lysosomal storage disease (LSD) resulting from deficient lysosomal acid lipase (LAL) activity due to biallelic LIPA gene mutations [1], is characterized by cholesteryl ester (CE) and lipid accumulation from deficient hydrolysis of esterified cholesteryl and triglycerides into free cholesterol and free fatty acids [2,3,4]. The LAL enzyme, integral to cholesterol homeostasis, is predominantly active in macrophages, including hepatic Kupffer cells and monocyte derived macrophages of the intestines and vascular endothelial system. Deficient LAL activity results in massive hepatic lipid accumulation, serum total and LDL cholesterol elevations and hypoalphalipoproteinemia, with HDL levels often less than half of normal controls [5]. Excessive vascular macrophage uptake of LDL complexes form atherogenic foam cells central to LAL-D pathophysiology. Monocyte-derived macrophages and Kupffer cells migrate to the sub-endothelium, initiating release of inflammatory factors, with smooth muscle cell matrix component transformation in vessel walls and myofibroblast proliferation in hepatic, perisinusoidal, lipid storing Ito cells, thereby forming vascular atherosclerotic plaques and hepatic fibrosis, respectively [6]. Lysosomal and cytoplasmic lipid accumulation result in hepatosplenomegaly and microvesicular hepatosteatosis, progressing to fibrosis, micronodular cirrhosis and liver failure, early-onset, accelerated atherosclerosis, cardiovascular and cerebrovascular disease and premature demise, often in infancy or childhood. Early onset cirrhosis and accelerated atherosclerosis are the most common causes of LAL-D patient deaths [7]. Prior to sebelipase alfa enzyme replacement therapy (ERT), interventions, including lipid lowering medications (LLMs), liver transplantation (LT), and hematopoietic stem cell transplantation (HSCT) did not ameliorate morbidities and mortality for the majority of LAL-D patients, including two sisters with LAL-D [8,9].