Hemophagocytic lymphohistiocytosis (HLH) is associated with a number of rare diseases, including lysosomal acid lipase deficiency (LAL-D), according to findings from a review conducted in Japan and published in the journal Pediatrics International.

HLH, a potentially lethal hyperinflammatory condition, is associated with hypercytokinemia due to the excessive activation of T cells and macrophages. In other words, HLH is a severe immune system reaction in which the body releases too many cytokines too quickly into the bloodstream.

HLH is classified as either primary HLH or secondary HLH. Examples of primary HLH include familial HLH (FHL), X-linked lymphoproliferative syndrome (XLP), and FHL syndrome with hypopigmentation. In contrast, secondary HLH is associated with malignant tumors, infections, autoimmune diseases, and other disorders.

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With the causes of HLH being so variable, detection of the underlying disease is key to appropriate diagnosis. In Japan, around half of all patients with HLH develop symptoms prior to the age of 15 years, although some individuals exhibit symptoms after 60 years of age.

Recent research has focused on HLH that is associated with rare diseases, including inborn errors of immunity (IEIs) and inborn errors of metabolism (IEMs). The pathogenesis of HLH, which is known to vary according to the underlying disease, can occur in a variety of IEIs that have distinct genetic defects.

LAL-D, an autosomal recessive disorder, is linked to pathogenic variations in the LIPA gene. Overall, 120 disease-associated variants of LAL-D have been recognized.

Learn more about lysosomal acid lipase deficiency

Lysosomal acid lipase (LAL), which plays a key role in intracellular lipid metabolism, is an enzyme known to hydrolyze cholesterol esters (CEs) and triglycerides (TGs), resulting in the production of free cholesterol (FC) and free fatty acids (FFAs). In individuals with LAL-D, CEs and TGs are unable to be hydrolyzed in the absence of LAL, thus accumulating in lysosomes. Because FC and FFAs are not generated, cholesterol production and cellular uptake rise, which are linked to cellular damage.

Two distinct subtypes of LAL-D have been identified. Wolman disease (WD), the most severe form of LAL-D, has been reported in fewer than 1% of patients with the disorder. The mild form of LAL-D, known as cholesteryl ester storage disease (CESD), affects between 1% and 12% of individuals with LAL-D.

The diagnosis of LAL-D is often associated with HLH, which is typically observed within the first 6 months of life. Individuals with LAL-D–linked HLH usually exhibit such symptoms as fever and are later diagnosed with WD. Although the pathophysiology of secondary HLH in patients with WD has not been fully elucidated, the proposed mechanism of action is that the accumulation of intracellular cholesterol crystals activates macrophages.

“Patients with [lysinuric protein intolerance (LPI)] and LAL-D are more likely to develop HLH in childhood,” they authors emphasized, “which can be difficult to diagnose. More research is needed to investigate the pathogenesis of HLH in rare diseases.”


Kanegane H, Noguchi A, Yamada Y, Yasumi T. Rare diseases presenting with hemophagocytic lymphohistiocytosis. Pediatr Int. Published online February 26, 2023. doi:10.1111/ped.15516