Marked Hyperferritinemia Does Not Predict for Hemophagocytic Lymphohistiocytosis (HLH) in the Adult Population
Authors: Schram Alison M , Mullally Ann , Campigotto Federico , Fogerty Annemarie E , Massarotti Elena , Neuberg Donna S. , Berliner Nancy 
Published: October 2019

Abstract
Introduction
Markedly elevated serum ferritin levels are often thought to be exclusively seen in rheumatologic and inflammatory disorders including adult-onset Still’s disease (AOSD), macrophage activation syndrome (MAS), and hemophagocytic lymphohistocytosis (HLH). In the pediatric population, ferritin >10,000 µg/L is highly sensitive and specific for HLH (Allen CE, et al. Pediatr Blood Cancer. 2008). In order to determine what conditions are associated with profoundly elevated ferritin levels in the adult population, we performed a retrospective analysis of patients with serum ferritin >50,000 µg/L in a large academic healthcare system.
Methods
Using a centralized clinical data registry, we searched for all patients at Brigham and Women’s Hospital (BWH), Massachusetts General Hospital (MGH), and Faulkner Hospital (FH) who had serum ferritin levels >50,000 µg/L between 8/1/1988-1/29/2014 for BWH and MGH, and 8/9/1995-1/29/2014 for FH. For patients who had multiple ferritin levels >50,000 µg/L, we used the highest value. Patients <18 years old were excluded and the medical charts of the remaining patients were manually reviewed. We collected demographic data including age, race, and gender. Each patient was categorized as having HLH, MAS, rheumatologic/inflammatory disorder, hematologic malignancy, solid tumor, renal failure, sepsis/infection, liver failure, iron overload, hemolytic anemia, or none of these conditions. Causes were not considered mutually exclusive. Univariate and multivariable linear regressions were used to evaluate the association of those factors with ferritin levels modeled using the logarithmic transformation of the actual ferritin levels. The Wilcoxon rank sum test was also performed along with the univariate analysis. Those covariates statistically significant at an alpha level of 0.2 were included in the multivariable stepwise linear regression model. In the multivariable analysis, a p-value <0.05 was considered statistically significant.
Results
We identified 113 total patients with ferritin levels above 50,000 µg/L at BWH, MGH, and FH during the study period. The patients ranged from 20 years old to 88 years old (mean 56 years old). The majority of patients were male (58%). The racial distribution included White (75%), Black (16%), Hispanic (4%), Asian (2%), and unknown (3%). Ferritin levels ranged from 50,129 to 439,500 µg/L with a median of 82,930 µg/L (notably, two patients had ferritin levels more than the assay of >100,000 µg/L). The characteristics of the patients with ferritin levels >50,000 µg/L included renal disease (65%), liver disease (54%), sepsis/infection (46%), hematologic malignancy (33%), rheumatologic/inflammatory conditions (18%), HLH (17%), iron overload (11%), hemolytic anemia (4%), solid malignancy (4%), and MAS (3%) (table 1). The majority of patients with HLH were thought to have secondary HLH triggered by a malignancy (9/19) or infection (6/19), with the minority having no clear precipitating cause (4/19). All 9 patients with malignancy-associated HLH had a hematologic malignancy (4/9 had T-cell lymphoma, 3/9 had DLBCL, 1/9 had transformed AML, and 1/9 had erythroleukemia). The stepwise linear regression showed that presence of hemolytic anemia was the only variable associated with a differential ferritin level (β=1.51, p=0.03).
Conclusions
Extremely elevated ferritin levels are associated with many conditions and most often seen in patients with hematologic malignancies, liver failure, and renal failure. Although less common in our cohort, those patients with hemolytic anemia had higher ferritin levels compared to patients without hemolytic anemia. In contrast to what has been described in the pediatric population, there does not appear to be any value above which ferritin is specific for HLH in the adult population.
Figure 1 Figure 1.

Disclosures
No relevant conflicts of interest to declare.