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Amyloidosis occurs when certain soluble proteins are transformed into amyloid fibrils in the extracellular space. Most common are the light-chain amyloidoses; less common is the AA-amyloidosis, which follows chronic inflammatory diseases, and the amyloidoses of transthyretin (TTR) origin. We report on a women of Italian-German origin with the mutation TTR (Ser23Asn). Whole body scintigraphy using TC99m-DPD showed end stage hereditary amyloidosis caused by ATTR with predominant tracer retention in the myocardium. Myocardial biopsies revealed the presence of amyloid by Congo red staining. Further immunohistochemical analysis showed ATTR amyloidosis. DNA sequencing revealed a point mutation of the transthyretin gene leading to a single amino acid substitution. The only effective treatment in patients with manifest cardiac ATTR amyloidosis is combined heart and liver transplantation. Our patient was placed on a list for this procedure, but unfortunately she died during the standby procedure due to urosepsis.
Amyloidosis occurs when certain soluble proteins are transformed into amyloid fibrils in the extracellular space. Amyloid formation is associated with a profound conformational change during which a native soluble protein becomes insoluble and assumes a β-sheet conformation. Most common are the light-chain amyloidoses (AL), which originate from a monoclonal immunoglobulin light (L) chain that can be detected in plasma and/or urine. Less common is the AA-amyloidosis, which follows chronic inflammatory diseases, and the amyloidoses of transthyretin (TTR) origin; these occur in two varieties, one being the senile systemic amyloidosis SSA, which originates from wild-type TTR, and the other familial amyloid polyneuropathy (FAP) or familial cardiomyopathy (FAC), representing a large group of hereditary syndromes, which are transmitted as autosomal dominant traits with manifestation in the third decade of life or later. More than 100 of these point mutations have been described so far.
TTR is a homotetrameric protein with a prominent β-sheet secondary structure.1 TTR is synthesised in the liver, choroid plexus, and retina and has binding sites for thyroxine and retinol in complex with retinol.2 Amyloid affects various organs, such as peripheral nerves, blood vessels, the gut, kidneys, and in particular the heart.3 Heart transplantation or combined heart and liver transplantation are so far the only effective treatments for such patients.
We report here on a family of Italian-German origin with the mutation TTR (Ser23Asn), which was first reported by Connors et al in 1999.4
A 46-year-old women presented to our hospital with progressive shortening of breath during exercise (New York Heart Association (NYHA) functional class III). She reported diffuse chest and epigastrial discomfort of about 1 year’s duration, and for the past 6 months she had also suffered from shortening of breath during exercise and progressive peripheral oedema. She had never been seriously ill before. Her mother, her son and the mother’s family were always healthy. Regarding the history of her Italian father, she could not provide any information.
The physical examination showed a patient in reduced overall condition with low arterial blood pressure (90/60 mm Hg), elevated jugular venous pulse, peripheral oedema, a diffuse pain in the abdomen during palpation, especially in the right epigastrium, and a systolic murmur with punctum maximum over the mitral valve area. Blood sample analysis displayed an elevated glutamic oxaloacetic transaminase (GOT) of 33 U/l, a γ-glutamyl transferase (GGT) of 194 U/l, and an alkaline phosphatase (ALP) of 227 U/l. Bilirubin was 1.12 mg/dl and lactate dehydrogenase (LDH) 299 U/l. Creatinine was also slightly elevated, at 1.3 mg/dl. In the serum electrophoresis beta2-globulins were increased to 15.3% (normal range 7.8–13.1%).
The electrocardiogram (ECG) showed sinus rhythm with a heart rate of 69 beats/min, and a low voltage of QRS complexes in all strains (fig 1a). Except for supraventricular extrasystoles, no episodes of arrhythmia were detected during telemetric observation. Echocardiography revealed left and right concentric ventricular hypertrophy with speckling of the myocardium (fig 1a), normal end-diastolic (40 mm) and end-systolic (32 mm) left ventricular diameters, impaired left and right ventricular systolic function with a left ventricular ejection fraction (LVEF) of 47%, dilation of the left and right atrium, and mild mitral and tricuspid regurgitation. E/A ratio was inversed, indicating restrictive filling of the left ventricle.
Ultrasound examination of the abdomen showed an enlarged liver with dilated liver veins and ascites. Due to the abdominal pain an endoscopic inspection of the upper and lower gastrointestinal tract was performed, which revealed antrum gastritis and unspecific diffuse inflammation of the colon mucosa. Cardiac catheterisation was performed, including coronary angiography and assessment of haemodynamics, and several myocardial biopsies were taken: cardiac output was 2.9 l/min and cardiac index 1.7 l/min/m2. The left ventricular pressure curve demonstrated a restrictive filling pattern. Coronary artery disease could be excluded. The myocardial biopsies revealed the presence of amyloid by Congo red staining (fig 2a–c). Further immunohistochemical analysis showed ATTR-amyloidosis, using validated antibodies against the major amyloid classes such as AA, ALλ, ALκ, Aβ2M, ATTR, AFibAα and AApoAI (antibodies form www.amYmed.de) as shown in fig 2d–i. DNA sequencing revealed a point mutation in exon 2, codon 23, of the transthyretin gene leading to a single amino acid substitution of serine by asparagine (fig 1c). Whole body scintigraphy using TC99m-DPD5 showed the typical image of end stage hereditary amyloidosis caused by ATTR (fig 1b) with predominant tracer retention in the myocardium. A weak retention of TC99m-DPD was observed in bones, bowel, lungs and skin, while liver and stomach showed almost no tracer uptake. The absence of the tracer in the liver, which produces TTR, demonstrates that the tracer does not bind to native TTR but to the TTR derived amyloid.
The most common reasons for left ventricular hypertrophy are arterial hypertension and aortic stenosis. Another important differential diagnosis is hypertrophic cardiomyopathy with and without obstruction. The athletic heart includes left ventricular hypertrophy as well, but is less severe (thickness of the interventricular septum <13 mm). However, all of these conditions are usually combined with signs of hypertrophy on the ECG. In the present case we found a low voltage of QRS complexes in all strains of the ECG. The severe concentric hypertrophy of the left and right ventricle with a diameter of the interventricular septum of 20 mm, and typical speckling of myocardium in the echocardiography in combination with the findings on the ECG, made the diagnosis of amyloidosis in our patient likely. Myocardial biopsies proved the diagnosis by demonstrating orange-red amyloid when viewed in Congo red fluorescence by blue excitation (FITC filter set). The subtype of amyloidosis could then be shown immunohistochemically. In our case it was ATTR amyloidosis. Differential diagnoses would be AL-amyloidosis and AA-amyloidosis. A rare secondary cause of cardiac hypertrophy, Fabry’s disease, an X-linked recessive glycolipid storage disease, was first considered, but seemed to be unlikely, as the typical echocardiographic findings were not seen in our patient (thickened hyperechogenic layer in the endocardium and underlying myocardium, and hypoechogenic layer paralleling the hyperechogenic layer all along the ventricular contour). There were also no relevant conduction abnormalities or arrhythmias present in the ECG. After amyloid was detected in the histological sections of the myocardium, we performed no further investigation to exclude Fabry’s disease.
The only effective treatment in patients with manifested cardiac and peripheral ATTR amyloidosis is combined heart and liver transplantation. After sole heart transplantation the graft may accumulate the mutated ATTR protein again, as the host’s liver will continue to produce the amyloidogenic mutant of TTR. In our case end stage amyloidosis was reached at the age of 47 years. Therefore, heart transplantation without liver transplantation would probably provide many years of life, before ATTR amyloidosis would enter its final stage again. Few data are available to date concerning patient outcome after exclusive heart transplantation. Harmour and colleagues reported on the first single heart transplantation in a man with ATTR amyloidosis, who was still well 3 years after transplantation.8
If the patient receives both organs at the same time, or within an acceptable time interval, the transplanted heart should not accumulate amyloid at the usual rate anymore, since the normal liver will synthesise regular transthyretin. The continued synthesis of the amyloidogenic TTR by the chorioidea remains the sole problem, although this continues at a much lower rate. However, in certain very amyloidogenic variants this may be sufficient to reduce the efficiency of the transplants since they continue to accumulate amyloid. In the literature only a few cases have been reported with combined heart–liver transplantation, but survival rates were comparable to those in patients with heart transplantation for other purposes. Survival rates of those patients have been reported as 86% after 1 and 2 years and 64% after 5 years of follow-up.9 As there is no other causal therapeutic option, our patient decided to be placed on the list for the combined heart and liver transplantation. During the listing procedure the patient was treated with diuretics, low dose β-blockers and ACE inhibitors. Unfortunately, she died during the standby procedure due to urosepsis.
Competing interests: None.