A Descriptive Analysis of Patients with ABCG8 Mutation and Anemia. a Meta-Analysis and Systematic Review of an Uncommon Cause of Unexplained Anemia
Authors: Ashok Kumar Prashanth , Desai Devashish , Ghimire Krishna 
Published: December 2023

Background
Sitosterolemia is a rare inherited condition caused by elevated levels of plant sterols in the plasma. The genetic basis of the condition is characterized by homozygous and compound heterozygous mutations in ABCG5 and ABCG8 genes. The condition is very rare that information about this in literature is limited to case reports, case series and translational observational studies. A scarce occurrence in this already infrequent condition are hematological abnormalities such as hemolytic anemia, stomatocytosis, and macrothrombocytopenia. Basic details of the disease such are frequency of occurrence, demographic details of patients, and degree and type of anemia are not available. We conducted a meta-analysis and systematic review to answer these questions regarding patients who have hemolytic anemia and ABCG8 mutation. The study was also prompted by a clinical experience that our group encountered, of an adult male who had chronic severe hemolysis, at times requiring transfusion support, in whom, extensive investigation failed to reveal a cause for the hemolysis. The patient was ultimately found to have a mutation in the ABCG8 gene.
Methods
A controlled vocabulary encompassing ABCG8, sitosterolemia, phytosterolemia, anemia and hemolysis was used to perform a systematic search in PubMed, Embase, Scopus and Cochrane, from inception to July 2023. No restrictions on date, language, status, or outcomes were applied. 532 records were identified after duplicates were removed using Mendeley 1.19.8. The titles and abstracts were screened independently by 2 reviewers. We only included studies pertaining to patients with sitosterolemia, ABCG8 mutation and anemia of any cause or severity. Studies associated with ABCG5 mutation alone or lacked anemia were excluded. 13 reports were shortlisted for the final analysis (Observational studies-6, case series-4, case reports-3). Descriptive statistics were utilized to study the patient characteristics. The proportion of patients having both anemia and any ABCG8 mutation among all cases of sitosterolemia was determined using the DerSimonian-Laird random effects model with OpenMeta.
Results
From the 13 reports that we found in available literature, we identified 19 cases of ABCG8 mutation and anemia. From the random-effects proportions model, the chance of this event occurring among patients with sitosterolemia was 6.8% [0.068, 95% Confidence Interval (CI) 0.016-0.120, p=0.010] (I 2 24.68%) (14/145) (figure 1). Various characteristics of the cohort analyzed, including the different ABCG8 mutations, are summarized in figure 2. The mean age of the patients was 26 years (Age range: 0.1-61 years) and included neonates, pediatric, and adult patients. There were 7 females and 7 males among those whose sex were reported. 9/13 studies documented elevated sterols, while 8/13 clearly stated hemolysis as the cause of anemia. The hemoglobin ranged between 6.1 to 12.6 g/dl with a mean of 10.2 g/dl. Thrombocytopenia and stomatocytosis were frequently reported. Splenomegaly and xanthomas were other common associations. One example demonstrated an improvement in anemia after ezetimibe therapy, while splenectomy and supportive care was utilized in a couple of other reports to treat hemolysis.
Conclusions
To the best of our knowledge, we provide the first report of the prevalence of anemia, specifically in patients with sitosterolemia caused by a mutation in the ABCG8 gene. At 6.8%, this is an extremely rare occurrence in an already infrequent disease. A high index of suspicion is required to arrive at this diagnosis. The age distribution demonstrates a peculiar aspect of the disease, that it can occur very early in infancy, as well as in adults, likely triggered by environmental factors in an already predisposed patient. Unexplained hemolytic anemia, especially if associated with thrombocytopenia, splenomegaly and xanthomas should prompt testing for sterol levels and genomic sequencing to identify pathogenic variants of ABCG8 or ABCG5. The degree of anemia was mild in our analysis and hence unlikely to lead to significant mortality or morbidity. Heterogeneity between the various reports is a limitation of our analysis. While we specifically focused on ABCG8 and anemia, future research can also include ABCG5 related anemia and attempt to compare the two cohorts.