Journal of Genetic Disorders & Genetic Reports ISSN: 2327-5790

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Case Report, J Genet Disor Genet Rep Vol: 2 Issue: 1

Long-Term Follow-Up of a Patient with Sitosterolemia and Hemolytic Anemia with Excellent Response to Ezetimibe

Alfonso Quintás-Cardama1* and John J. McCarthy2
1Department of Leukemia, M.D. Anderson Cancer Center, Houston, TX, USA
2Methodist Hospital, Houston, TX, USA
Corresponding author : Alfonso Quintás-Cardama
Department of Leukemia, UT MD Anderson Cancer Center, Unit 428, 1515 Holcombe Blvd, Houston, TX 77030
Tel: 713-745-4009
E-mail: [email protected]
Received: December 04, 2012 Accepted: January 10, 2013 Published: January 10, 2013
Citation: Quintás-Cardama A, McCarthy JJ (2013) Long-Term Follow-Up of a Patient with Sitosterolemia and Hemolytic Anemia with Excellent Response to Ezetimibe. J Genet Disor Genet Rep 2:1. doi:10.4172/2327-5790.1000102

Abstract

Long-Term Follow-Up of a Patient with Sitosterolemia and Hemolytic Anemia with Excellent Response to Ezetimibe

Sitosterolemia (MIM #210250), also known as phytosterolemia, first described in 1974, is characterized by disruption of the normal homeostatic mechanisms that regulate dietary cholesterol absorption and prevent the accumulation of non-cholesterol sterols. Phytosterols are almost undetectable in plasma from normal individuals. Sitosterolemia is inherited in an autosomal recessive fashion and results from mutations in two genes at the STSL locus that maps to human chromosome 2p21: the ATP-binding cassette,subfamily G, members 5 and 8 (ABCG5 and ABCG8), that encode two proteins known as sterolin-1 and -2.

Keywords:

Sitosterolemia (MIM #210250), also known as phytosterolemia, first described in 1974, is characterized by disruption of the normal homeostatic mechanisms that regulate dietary cholesterol absorption and prevent the accumulation of non-cholesterol sterols [1]. Phytosterols are almost undetectable in plasma from normal individuals [2]. Sitosterolemia is inherited in an autosomal recessive fashion and results from mutations in two genes at the STSL locus that maps to human chromosome 2p21: the ATP-binding cassette, subfamily G, members 5 and 8 (ABCG5 and ABCG8), that encode two proteins known as sterolin-1 and -2 [3,4]. Since the expression of these genes is strictly restricted to the intestinal epithelium and the liver, it is believed that the proteins encoded by ABCG5 and ABCG8 function as sterol efflux pumps. However, the relative importance of the liver and the intestine in maintaining sterol balance with respect to non-cholesterol sterols is unknown. Patients with sitosterolemia accumulate high concentrations of plant sterols in plasma and tissues that leads inexorably to the development of subcutaneous and tendon tuberoeruptive xanthomas during the first years of life and occasionally to the development of xanthelasmas, arcus corneae, and premature coronary artery disease. The development of hematologic abnormalities in patients with sitosterolemia, most importantly hemolysis and macrothrombocytopenia, is occasionally seen and their management is unknown [1]. Herein, we describe the longterm follow-up of a case of sitosterolemia associated with hemolytic anemia, successfully managed with lipid lowering therapy.
A 9-month-old Caucasian baby developed yellow streaks on her wrists. By 14 months of age, she underwent a skin biopsy of a right wrist lesion, which revealed foamy histiocytes compatible with xanthomas. At that time, her serum total cholesterol was 802 mg/dL, triglycerides were 190 mg/dL, and HDL was 32 mg/dL. All developmental milestones were achieved at appropriate ages. The patient was placed on a very strict low-fat diet that resulted in normalization of her total cholesterol and triglyceride levels. Interestingly, her family history was notable for a maternal grandmother with history of elevated cholesterol and xanthomas that developed at age 36 and resolved with minor dietary modifications. In addition, her paternal grandmother had developed xanthelasmas and her maternal grandfather had atherosclerosis that led to the development of multiple myocardial infarctions by age 55. The patient’s brother had no medical problems. At age 5, the patient underwent an extensive lipid work-up that demonstrated the presence of a normal total cholesterol level but an elevated sitosterol level at 30.7 mg/dL (Table 1 and Figure 1). Since then, her diet was implemented to avoid all oils except soy, as well as chocolate, nuts, and legumes. The strict diet notwithstanding, at 12 years of age the patient developed arcus juvenilis and by 13 years of age she presented with enlarging tendon and tuberous xanthomas that began on her knuckles and progressed to affect both elbows and Achilles tendons. She was also started on therapy with the bile acid binding drug colesevelam hydrochloride.
Figure 1: Pedigree of the patient with sitosterolemia. Both parents were carriers of the mutations detected in the proband (black circle).
Table 1: Levels of serum lipids and plasma phytosterols over time. Fasting blood samples were collected into test-tubes without anticoagulants from the patient. Determination of β-sitosterol, sitostanol, campesterol, campestanol, and cholestanol were quantified by high-performance liquid chromatography (HPLC), as previously described.
By 16 years of age, the patient was referred to our hematology clinic for evaluation of pancytopenia. On physical exam, she had xanthomas in both elbows and hepatomegaly and splenomegaly palpable 2 cm and 5 cm below the costal margin, respectively. Her initial peripheral blood cell count revealed white blood cell (WBC) count 3.4x109/L (neutrophils 58%, bands 7%, lymphocytes 31%, monocytes 2%, eosinophils 1%, basophils 1%), platelet count 83x109/L, hemoglobin 10.1 g/dL, and median corpuscular volume (MCV) 90 fL. Despite a very low serum ferritin level (18 ng/mL), her retyculocyte count was 7%. The peripheral blood smear exam revealed neutrophilic vacuolation, normocytic normochromic anemia with anisopoikilocytosis, and mild thrombocytopenia with frequent large platelets. Hepatitis B and C, HIV serologies, anti-nuclear antibodies, rheumatoid factor, and thyroid function tests were either negative or within normal limits. Both, hemoglobin and protein serum electrophoreses were normal. After 3 months on ferrous gluconate her hemoglobin only increased to 10.8 g/dL. The coding regions and intron/exon boundaries of ABCG5 and ABCG8 of the patient and her first degree relatives were amplified and sequenced as previously described [4]. This analysis revealed the patient to carry wild-type ABCG5 but mutant ABCG8 alleles: Trp361X (1173G→A)/Tyr658X (2064C→G).
Subsequently, the patient was lost to follow-up but 2 years later she presented again to our clinic with a WBC 4.8x109/L, hemoglobin 7.6 g/dL, and platelet count 83x109/L. At that time, there was evidence of hemolysis with a retyculocyte count of 7.1%, bilirubin 1.5 mg/ dL (indirect 1.3 mg/dL), lactate dehydrogenase (LDH) 725 U/L, and haptoglobin <6 mg/dL. A peripheral blood film revealed the presence of abnormally shaped erythrocytes with a moderate number of spherocytes, polychromasia, and macrothrombocytopenia. The serum ferritin level was <6 ng/mL and a bone marrow aspiration and biopsy revealed normal cellularity, increased erythroid precursors, no blast hyperplasia, and markedly decreased iron stores. Iron supplementation was again resumed with no significant improvement in hemoglobin levels. Remarkably, red cell studies showed a decreased erythrocyte osmotic fragility. The results of other routine hematologic tests to identify the cause of hemolysis were unremarkable, including Coombs’ test, Ham’s test, and glucose-6-phosphate dehydrogenase.
At age 23, routine blood tests demonstrated elevation of transaminases with ALT 321 U/dL and AST 144 U/dL. Given the inability of increasing doses of colesevelam to control her cholesterol and sitosterol levels, therapy with ezetimibe 10 mg daily was started. After 2 years on ezetimibe, her cholesterol levels were still high but her transaminase levels returned to normal and all signs of hemolysis disappeared, including normalization of the hemoglobin level, red cell morphology, reticulocyte count, bilirubin, and LDH levels. However, phytosterol levels remained high, with only a mild reduction in campestanol being observed. Therapy with a combination of ezetimibe and simvastatin was then started, which partially corrected her cholesterol levels.
Sterols are non-cholesterol sterols that along with phospholipids constitute the main components of cell membrane, being crucial for ions and metabolites transport as well as cell permeability and rigidity [5]. While cholesterol is preferentially absorbed in the intestinal tract by the sterol transporter Niemann-Pick C1L1, phytosterols are preferentially extruded by ABCG5/ABCG8 transporters [6]. As a consequence, phytosterol concentration in human plasma is less than 0.5% that of cholesterol, despite similar ingestion [7]. As a result, plant sterols accumulate in all tissues but the brain, manifesting as xanthomas and premature atherosclerosis [8]. Given the critical role that membrane flexibility plays in erythrocyte homeostasis and the high content of phytosterols on their surface in sitosterolemia, some patients with this disorder develop hemolysis [9]. The patient herein presented, who was followed for more than 25 years from birth, exemplifies this potential complication. Interestingly, anemia was observed at age 16, and became severe by 18 years of age, with unequivocal signs of hemolysis. While the mechanism of action whereby ezetimibe might improve hemolysis is currently unknown, it is tempting to speculate that therapy with this agent may modulate the lipid content at the red cell, thus increasing its resistance to lysis. Interestinly, a recent case report disclosed similar peripheral blood manifestations (i.e. thrombocytopenia and hemolysis) in a 31 year old woman with mutations at ABCG5 [10]. Therapy with ezetimibe progressively corrected the manifestations of hemolysis over a period of 24 months. Therapies for sitosterolemia such as bile salt-binding resins or HMG-CoA reductase inhibitors are largely ineffective [7]. Recently, ezetimibe, a selective inhibitor of the NPC1L1 intestinal sterol transporter, has been shown to block the transport of dietary cholesterol and phytosterols and to progressively reduce the levels of sitosterol and campesterol, the predominant plant sterols [11]. Notably, in our case, no significant decline in the levels of these plant sterols was observed. Yet, all markers of hemolysis and liver dysfunction normalized during ezetimibe therapy, while platelet counts remain low and unchanged, suggesting that this agent may improve some but not all features of the phenotype present in patients with sitosterolemia. Long-term follow-up is warranted to fully assess the ability of ezetimibe to further reduce plasma and tissue phytosterol levels.

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