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Michael Bode, MD
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Sarina Pasricha, MD
The North Carolina chapter of the American College of Physicians held the abstract competition during their 2012 Scientific Sessions.
Abstracts for both presentations are below. Drs. Bode and Pasricha are both residents in the Department of Medicine.
A case of late onset cardiomyopathy and carpal tunnel syndrome
Background: More than 100 mutations of the transthyretin gene which primarily lead to amyloid deposition in the heart or peripheral nerves. We present a case of late onset cardiomyopathy with a rare transthyretin mutation.
Case: A 58 year old German male with history of hypertension presented with recent onset of generalized fatigue, dyspnea on exertion (NYHA II), palpitations and a one year history of symptoms consistent with carpal tunnel syndrome (CTS). His father and paternal aunt had both died in their 70s after experiencing similar symptoms. Physical exam was consistent with volume overload. ECGs showed new intermittent atrial fibrillation. Chest x-ray was normal. Transthoracic echocardiography revealed hypertrophic cardiomyopathy with globally reduced left ventricular ejection fraction (LVEF) of 35% and severe diastolic dysfunction. Cardiac catheterization showed non-obstructive coronary artery disease. Pro-BNP was elevated at 2650 pg/ml. Laboratory results showed normal TSH, total protein and galactosidase. Serum and urine electrophoresis showed no paraproteins. Renal and liver function were normal. Cardiac MRI showed patchy septal and inferobasal late enhancement suggestive of amyloidosis. Bone marrow, fat pad and rectal mucosa biopsies were negative. Endomyocardial biopsy was positive for interstitial amyloid deposits. Transthyretin gene analysis revealed a heterozygous Val20Ile substitution in exon 2. The patient was medically managed with an ACE-inhibitor, beta-blocker, loop-diuretic, statin and Aspirin. His symptoms and cardiac function initially improved until he presented again nine months later with progressive dyspnea (NYHA III) despite adequate diuretic therapy. Pro-BNP was 6000 pg/ml, ECG showed sinus rhythm and frequent PVCs. LVEF had declined to 25% with a cardiac index of 1.37 L/min/m². Cardiac MRI showed increased late enhancement. The patient was listed for urgent orthotopic cardiac transplantation which he underwent three months later. His symptoms improved and he continues to do well on follow up two years later.
Conclusion: Human transthyretin is mainly secreted by the liver and is the primary carrier of T4 in the cerebrospinal fluid. It physiologically exists as a tetramer. Over 100 distinct mutations of transthyretin have been described, which generally show an autosomal dominant inheritance pattern. Two cases of Val20Ile substitution have been described in men of Irish and German descent. It has been shown to cause transthyretin tetramer destabilization and presents clinically as late onset cardiomyopathy with CTS. Both patients presented in their 60s with a similar presentation to our case. One of them received a cardiac transplant and survived; the other one was medically managed and died within a year. The very slow amyloid deposition with this specific mutation makes a potentially curative liver transplant unnecessary. Hereditary cardiac amyloidosis should be suspected in patients with late onset unexplained heart failure, CTS and positive family history and they should be evaluated for cardiac transplantation.
Identification of QTLs for the phenotypes of XBP-1s and SOCS3 in a murine model of non-alcoholic fatty liver disease
Sarina Pasricha, Jane Kenney-Hunt, Kristy A Anderson, Amanda Dewey, She-Yan Wong, James M Cheverud, Richard M Green
Background: Non-alcoholic fatty liver diseases (NAFLD) are now the most common cause of abnormal aminotransferase elevations in the United States and can lead to end-stage liver disease. Although there is a strong genetic component for NAFLD, little is known about the genetics of fatty liver. Quantitative Trait Loci (QTL) analysis is a commonly used genetic technique to identify genetic loci that are important in the pathogenesis of polygenic diseases. In addition, the high-fat, high caloric (HFHC) diet is a commonly employed murine nutritional model for NAFLD. The unfolded protein response regulator XBP-1s and inflammatory mediator SOCS3 have been previously identified in the pathogenesis of human non-alcoholic steatohepatitis. Thus, the purpose of this study was to utilize QTL analysis using the phenotypes of XBP-1s and SOCS3 hepatic gene expression to identify genetic loci that are important in the pathogenesis of NAFLD.
Methods: Male A/J and C57BL/6J mice (8-12 weeks) were fed a 60% HFHC diet for 8 weeks and hepatic gene expression of XBP-1s and SOCS3 was assayed using real-time PCR and microarray analysis. An F2 intercross was bred and these mice were employed for QTL analysis using the phenotypes of hepatic XBP-1s and SOCS3 gene expression. Genotyping was performed using an Illumina Mouse MD Linkage Panel.
Results: After 8 weeks on a HFHC diet, hepatic gene expression of XBP-1s was 1.13 +/- 0.27 and 0.49 +/- 0.15 (p<0.05) in A/J and C57BL/6J mice, respectively. Hepatic gene expression of SOCS3 was 1.04 +/- 0.13 and 0.57 +/- 0.09 (p<0.01) in A/J and C57BL/6J mice, respectively. Using F2 generation mice, overlapping QTLs for XBP-1s and SOCS3 were identified on chromosome 1 (181.5MB), with LOD scores of 6.18 and 4.79, respectively. Overlapping QTLs were also identified on chromosome 11 (56.2 and 58.4 MB) and a QTL for SOCS3 was identified on chromosome 12 (113.4 MB). Microarray analysis identified 8, 9 and 5 differentially-expressed candidate genes within the overlapping QTLs on chromosomes 1, 11 and in the QTL on chromosome 12, respectively.
Conclusions: We have fed mice a HFHC diet and identified 2 overlapping QTLs using the phenotypes of XBP1-s and SOCS3 on chromosomes 1 and 11. In addition, we have identified another QTL for SOCS3 on chromosome 12. We propose that these QTLs can be used to further define the genetic factors that are important in the pathogenesis of NAFLD.