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Postmortem Diagnosis of Sitosterolaemia PowerPoint Presentation

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Description : Postmortem diagnosis of sitosterolaemia

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Published on : Aug 16, 2022 | Views : 1115 | Downloads : 0

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Postmortem diagnosis of sitosterolaemia by next-generation sequencing in a patient with severe hypercholesterolaemia and cardiovascular failure
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1. Introduction Sitosterolaemia (STSL) is a relatively rare autosomal recessive disorder of lipid metabolism. These sterol, efflux half-transporters normally pump sterols out to intestinal lumen or into bile and if this action is defective, there is resultant accumulation of cholesterol and plant sterols (PS) in the blood and tissue due to the increased intestinal absorption and decreased biliary excretion of sterols . STSL patients often have extremely high plasma total sterol levels including total cholesterol (TC) and PS, which is manifested as pseudo-severe hypercholesterolaemia where plasma TC in the normal-to-high range and plasma low-density lipoprotein (LDL) sterol level is normal to moderately elevated . Patients with STSL present heterogeneous clinical phenotypes ranging from almost asymptomatic to major clinical features of xanthomas and severe hypercholesterolaemia leading to accelerated atherosclerosis and cardiac death.
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2. Patient and Patient's Family 2.1. Patient A 56-year-old male presented to the resuscitation room of our emergency department on December 16, 2016 with acute exacerbation of dyspnoea and chest tightness for 5 days, and cough with expectoration of white sputum for 18 days. He was diagnosed as acute-on chronic congestive heart failure,cardiopulmonary oedema, and pneumonia . The patient had a nearly 40-year history of thrombocytopaenia, and had undergone splenectomy in 1988 due to severe oral and nasal bleeding. Although there was no obvious thrombocytopaenia, the patient later developed nodular hyperplasia on both eyelids and subsequently, on the neck and limbs. He visited another hospital for surgical treatment and biopsy, and a pathological examination of the nodules indicated that they were fibroids, which relapsed in 1995 . He was admitted to another hospital in 2008 to treat the thrombocytopaenia asecond time, with no definite results found in the bone marrow examination and no improvement after treatment with glucocorticoids, rituximab, and intravenous gamma globulin.
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2. Patient and Patient's Family 2.1. Patient Further physical examination revealed multiple plaque nodules on the face, bilateral eyelids, neck, and extensor tendons of the dorsum of the hands; and acrotarsium, which had developed after splenectomy and was identifiedas xanthomas and xanthelasma 1 year later at our emergency department .There were no signs of haemolysis, arthralgia, or arthritis . Repeated biopsy of neck nodules was performed in December 2016 after his admission to emergency ward, and pathological examination revealed benign tissue fibroid hyperplasia . The electrocardiogram showed depressed ST segments in leads II, III, avF, and V1. Two-dimensional echocardiographic examination revealed structural abnormalities and low ejection fraction of the left ventricle (37%) . Abdominal ultrasound examination showed no liver steatosis. Routine biochemical and haematological tests revealed abnormal laboratory parameters including high levels of blood troponin (Tn)T/TnI (TnT 9.59 ng/ml, TnI 4.32 ng/ml), B-type natriuretic peptide (2465 pg/ml), and total plasma cholesterol (9.4 mmol/l, 363 mg/dl) as well as liver function injury (alanine aminotransferase, 199 U/l) and thrombocytopaenia (platelet count, 10 × 109/l).
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2. Patient and Patient's Family 2.1. Patient The marked elevation in peripheral leukocytes (20.6 × 109/L) and C-reactive protein (205 mg/l) indicated an acute infection. An emergency thoracic and abdominal high-resolution computed tomography (CT) scan followed by an enhanced CT scan indicated acute cardiogenic pulmonary oedema, severe arteriosclerosis of the aorta and anterior descending branch of left coronary artery, and local aneurysm formation in the abdominal aorta with mural thrombosis and formation of multiple aortic ulcers accompanied by hematoma. Although the heart failure improved after appropriate treatments over several admissions to the emergency ward, the patient passed away after 1 year due to cardiovascular failure. Before his death, he provided a blood sample for post-mortem analysis.
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2. Patient and Patient's Family 2.2. Patient's family His parents, who were closely related, had passed away many years prior as had two older sisters, both of whom had undergone splenectomy. The patient's eldest brother who was diagnosed with gastric cancer had passed away, His two elder sisters who had similar history and accepted surgical treatment of splenectomy also died at middle age, His second elder brother was healthy, His third elder sister who experienced subtotal gastrectomy was still alive but with poor health condition. His younger brother was still alive and was diagnosed with hepatitis B infection, cirrhosis, portal hypertension, splenomegaly, and thrombocytopaenia in 2015, and had very low platelet count (18 × 109/l) but normal plasma TC (5.32 mmol/l, 205.72 mg/dl) The younger brother refused splenectomy in view of his older brother and sister’s experiences, and followed up irregularly at the gastroenterology outpatient department, who without the clinical phenotype of xanthomas or xanthelasma .
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2. Patient and Patient's Family2.2 Patient's family
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3. Results Whole-exome sequencing of the patient revealed the homozygous mutation p. R263Q (c.788G > A) in the ABCG8 gene, which was a known pathogenic mutation. Sanger sequencing of DNA extracted from his younger brother revealed the same homozygous mutation . The patient's son and four nephews carried a heterozygous variant of p. R263Q (c.788G > A) in the ABCG8 gene. The ABCG8 gene mutation was also detected in the one of the proband's younger affected brother's grandchildren . The patient's cholesterol level was high (9.38 mmol/l), but the level in his younger brother's was normal (5.32 mmol/l). The patient’s plasma plant sterol level was extremely high (β-sitosterol: 107.5 μg/ml), and plasma β-sitosterol level was also abnormally high in his younger brother (51.5 μg/ml). The plasma β-sitoserol levels of other living family members including carriers of the heterozygous mutation of p. R263Q (c.788G > A) were all normal (i.e., undetectable). We made a definitive diagnosis of STSL based on the results of the genetic analysis and a very high plasma level of β-sitosterol.
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This study describes a rare STSL case and findings in his family members, which were confirmed by clinical manifestations, pedigree and genetic analyses, and serum plant sterol detection. The STSL was caused by homozygous pathogenic mutation in the ABCG8 gene located on chromosome 2p21 encoding ABCG8 (sterolin-2). High cholesterol if present could come from excess absorption which can be improved on diet, though this case comes from coexisting familial hypercholesterolaemia which also manifests with tendon xanthomas and cardiovascular disease. Diet and ezetimibe both reduce sitosterol, but atovastain does not. However atovastation may help reduce cholesterol, if diet does not do so adequately . The patient was initially diagnosed with unexplained thrombocytopaenia and underwent splenectomy at young and middle age, and was then diagnosed with acute on chronic congestive heart failure in the emergency department, with xanthomas and xanthelasma that were not initially identified. 4. Discussion
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4. Discussion Although the diagnosis was postmortem, some of his family members had the opportunity to obtain information on their genetic and biochemical status, and also realised that the consanguineous marriage of their parents to some extent contributed to the disease. The patient's younger brother followed themedical advice of a low-cholesterol and plant sterol diet and refused treatment with the drug atorvastatin ezetimibe. The patient's younger brother, who was also homozygous for the c.788G > A mutation in the ABCG8 gene, was still alive and was previously diagnosed with splenomegaly, hepatitis B, and severe liver cirrhosis and thrombocytopaenia. A previous report described cryptogenic liver cirrhosis as the primary presenting feature of STSL, suggesting that phytosterol accumulation is responsible for the liver dysfunction phenotype. The classic features of STSL are the presence of xanthomas, tendinous or tuberous xanthomas on extensor sites, planar xanthomas, or intertriginous xanthomas, which were observed in the patient. Mild-to-moderate hypercholesterolaemia is common but severe hypercholesterolaemia (≥500 mg/dl or 12.93 mmol/l) has also been reported, constituting a phenotype that resembles heterozygous or homozygous familial hypercholesterolaemia .Moderate-to-severe hypercholesterolaemia may contribute to premature or accelerated atherosclerotic diseases such as coronary artery atherosclerosis and aortic lesions.
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4. Discussion In addition, STSL-associated haematologic abnormalities including haemolytic anaemia with stomatocytosis, thrombocytopaenia, or splenomegaly are still not recognised by most physicians, and many STSL patients are not diagnosed until adulthood . Previous findings suggest that blood cells are a main target for the toxic effect of plasma phytosterols . Thus ,the co-existence of a haematologic abnormality (i.e., thrombocytopaenia) in the patient and his younger brother represents a specific subtype of STSL. STSL cases may be misdiagnosed as immune thrombocytopaenia (ITP), Evans syndrome, or ITP secondary to arthritis, and consequently treated with ineffective or even harmful therapies such as steroid therapy and/or splenectomy . Nevertheless, clinical manifestations are heterogeneous and range from asymptomatic to severe ; the latter cases usually present at the emergency room with critical conditions such as premature coronary heart disease, accelerated atherosclerosis, sudden cardiac death, or else haematologic manifestations .
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4. Discussion Most of these clinical features accompanied by negative experiences were present in our patient (who was sixth among the family's seven children) or his younger brother due to previous technical limitations. Limited published data are available on the prevalence of STSL, but the condition is mainly due to ABCG8 mutations in Caucasians whereas in Chinese, Japanese, and Indian patients (20% of known cases), mutations in ABCG5 are more common . The patients in our study were Chinese Shanghai residents . Recent studies have revealed that heterozygous mutation carriers can also exhibit milder manifestations. A portion of hypercholesterolemia other than familial hypercholesterolemia can be explained by a deleterious mutation in the ABCG5/8 genes . A recent large population study showed that only about 0.050% of 207,926 subjects with LDL-C concentrations ≥190 mg/dl have plasma β-sitosterol concentrations above the 99th percentile and 0.334% has concentrations consistent with STSL (≥15.0 mg/l); therefore, this diagnosis should be considered in such patients .
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4. Discussion We evaluated plasma levels of β-sitosterol, which is the predominant form of plant sterol that are structurally similar to cholesterol and cannot be distinguished by physicians in patients at early states of hypercholesterolaemia. Both elevated plasma total sterol and PS levels can contribute to premature vascular disease in patients with STSL . The other family members (patient's son and nephews, n = 5) were heterozygote carriers who were asymptomatic with normal cholesterol and normal (very low) plasma sitosterol levels.
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4.1. Conclusions The present case report and review of clinical work provide information to emergency physicians of the rarity, insidious onset, deteriorating course, and lethality of STSL, which is potentially reversible with early diagnosis and intervention. failure and unexplainable liver dysfunction combined with the presence of xanthomas with elevated cholesterol should be recognised as the definitive features of STSL for accurate diagnosis . Although it is a relatively rare disease, it is nonetheless important because it can provide insight into the physiological pathways involved in sterol influx and efflux. In patients with tendon xanthomas and premature cardiovascular disease, familial hypercholesterolaemia and β-sitosterolaemia should be considered.
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Farhang Shapouran Matin Nakhaeizadeh References: Journal of Atherosclerosis: X Volume 2, September 2019, 100010 https://doi.org/10.1016/j.athx.2019.100010 Thank you for your attention