Liver dysfunction as predictor of prognosis in patients with amyloidosis: utility of the Model for End-stage Liver disease (MELD) scoring system.

Amyloidosis prognosis is often related to the onset of heart failure and a worsening that is concomitant with kidney-liver dysfunction; thus the Model for End-stage Liver disease (MELD) may be an ideal instrument to summarize renal-liver function. Our aim has been to test the MELD score as a prognostic tool in amyloidosis. We evaluated 128 patients, 46 with TTR-related amyloidosis and 82 with AL amyloidosis. All patients had a complete clinical and echocardiography evaluation; overall biohumoral assessment included troponin I, NT-proBNP, creatinine, total bilirubin and INR ratio. The study population was dichotomized at the 12 cut-off level of MELD scores; those with MELD score >12 had a lower survival compared to controls in the study cohort (40.7 vs 66.3 %; p = 0.006). Either as a continuous and dichotomized variable, MELD shows its independent prognostic value at multivariable analysis (HR = 1.199, 95 % CI 1.082-1.329; HR = 2.707, 95 % CI 1.075-6.817, respectively). MELD shows a lower prognostic sensitivity/specificity ratio than troponin I and NT-proBNP in the whole study population and AL subgroup, while in TTR patients MELD has a higher sensitivity/specificity ratio compared to troponin and NT-proBNP (ROC analysis-AUC: 0.853 vs 0.726 vs 0.659). MELD is able to predict prognosis in amyloidosis. A MELD score >12 selects a subgroup of patients with a higher risk of death. The predictive accuracy seems to be more evident in TTR patients in whom currently no effective scoring systems have been validated.

Different NT-proBNP circulating levels for different types of cardiac amyloidosis.

AIM: Several studies suggest that the N-terminal fragment of pro-brain natriuretic peptide levels are quite different in wild-type transthyretin (TTR)-related amyloidosis (ATTRwt) and mutated TTR-related amyloidosis (ATTRm) compared with immunoglobulin light-chain cardiac amyloidosis. Our aim was to test this hypothesis in a cohort of patients with different types of cardiac amyloidosis. PATIENTS AND METHODS: Seventy patients with ATTRwt, ATTRm, and light-chain cardiac amyloidosis matched for left ventricular (LV) mass index were studied by standard echocardiography, tissue Doppler imaging, and plasmatic cardiac biomarkers. RESULTS: Despite similar LV mass and renal function, patients with ATTR cardiac amyloidosis showed lower levels of N-terminal fragment of pro-brain natriuretic peptide than do light-chain amyloidosis ones, especially when expressed as a function of LV mass index. CONCLUSION: Amyloidogenic light-chain-derived fibrils induce more severe myocardial dysfunction in light-chain amyloidosis than in ATTR, despite similar myocardial infiltration. Thus, the degree of cardiac dysfunction may be related not only to the amount of amyloid deposited, but also to qualitative differences among fibrils.

Anxiety and depression among amyloid light-chain cardiac amyloidosis patients: The role of life satisfaction.

BACKGROUND: The present study aimed to provide a contribution to the study of a rare disease, amyloid light-chain (AL) cardiac amyloidosis, which is the most common type of systemic amyloidosis. In AL amyloidosis prognosis is determined by cardiac involvement. Although the association between psychological distress (e.g. anxiety and depression) and AL cardiac amyloidosis is documented, very little is known about the psychosocial variables that may mediate the association. AIMS: The aim of the study is therefore to examine the potential mediating role of life satisfaction in the relationship between cardiac symptom severity (independent variable) and anxious and depressive symptoms (dependent variables) in AL patients. METHOD: Forty-three AL amyloidosis patients (57.1% males) with cardiac amyloidosis were administered the Satisfaction with Life Scale, the State-Trait Anxiety Inventory and the Centre for Epidemiological Study-Depression Scale. Clinical variables such as months since cardiac symptom onset and cardiac symptom severity were collected. RESULTS: Findings showed significant relationships between symptom severity and psychological disorders (e.g. anxiety and depression) and these were mediated by life satisfaction. CONCLUSION: Overall, findings highlight the importance of subjective well-being (e.g. life satisfaction) to reduce anxious and depressive symptoms and to improve general health in AL patients.

The Val142Ile transthyretin cardiac amyloidosis: not only an Afro-American pathogenic variant? A single-centre Italian experience.

Transthyterin amyloidosis is a life-threatening disorder caused by the deposition of hepatocyte-derived transthyretin (TTR) amyloid in various tissues and organs. The most common worldwide pathogenic variant with almost exclusive cardiac involvement is Val142Ile with an allele frequency of 3.5% in U.S. African-American population, but supposed extremely rare, with only sporadic cases in Caucasian patients. Unexpectedly, in our amyloidosis referral centre, we identified five patients (15.1% of all TTRm diagnosed patients, three families, two singleton) with Val142Ile variant belonging to unrelated families of Caucasian origin. Molecular study was performed in a total of 10 individuals of which three were Italian families (three affected individuals and five unaffected individuals) and two were singleton (one Italian patient and one patient from Argentine with Spanish ancestry). Sequence analysis of TTR gene revealed the presence of the heterozygous Val142Ile in the five affected patients and in five asymptomatic individuals. All probands underwent, at diagnosis, a complete clinical, echocardiographic and biohumoral evaluation. To the best of our knowledge, we describe the larger report of Caucasian patients with Val142Ile cardiomyopathy. All patients at diagnosis showed symptoms of heart failure with increased thickness of left ventricular walls and systo-diastolic left ventricular dysfunction. They also showed increased plasma values of NT-proBNP and troponin I. Our data confirm that Caucasian patients with the Val142Ile pathogenic variant have phenotypic manifestations similar to that of African-American one. Moreover, our data clearly show that Val142Ile pathogenic variant is not only an African-American mutation but could be also an underestimated Caucasian variant.

Echocardiographic and biohumoral characteristics in patients with AL and TTR amyloidosis at diagnosis.

BACKGROUND: Few studies have analyzed the clinical and echocardiographic differences between light-chain (AL) and transthyretin (TTR) amyloidosis. HYPOTHESIS: The aim of the present research was to compare, in a real-world setting, the clinical and echocardiographic profiles of these kinds of amyloidosis, at the time of diagnosis, using new-generation echocardiography. METHODS: Seventy-nine patients with AL and 48 patients with TTR amyloidosis were studied. RESULTS: According to the criterion of mean left ventricular (LV) thickness >12 mm, 45 AL (C-AL) and all TTR patients had cardiac amyloidotic involvement, whereas 34 AL patients did not. TTR patients had increased right ventricular (RV) and LV chambers with increased RV and LV wall thickness and reduced LV ejection fraction and fractional shortening. Furthermore, TTR patients showed lower N-terminal pro Brain Natriuretic Peptide concentrations and New York Heart Association functional class when compared with C-AL. CONCLUSIONS: Our data show that at time of first diagnosis, TTR patients have a more advanced amyloidotic involvement of the heart, despite less severe symptoms and biohumoral signs of heart failure. We can hypothesize that we observed different diseases at different stages. In fact, AL amyloidosis is a multiorgan disease with quick progression rate, that becomes rapidly symptomatic, whereas TTR amyloidosis might have a slow progression rate and might remain poorly symptomatic for a greater amount of time.

[Free light chains reduction on acute kidney injury in multiple myeloma: critical role of high cut-off membranes]. / Il trattamento del danno renale acuto in corso di mieloma multiplo: ruolo della rimozione delle catene leggere libere con membrane ad elevato cut-off.

We report our experience with five patients, with dialysis dependent AKI and multiple myeloma (MM). Two of them were already suffering from a mild degree of renal insufficiency, one was on follow-up for smouldering MM and two had a relapse of symptomatic MM. Median concentration of the involved FLC (iFLC) was 15104 mg/L (range 1196-24384). All patients underwent three times per week HCO-HD for 6 hour sessions using Theralite 2100 (median 10, range 6-13 sessions) with one having further twelve sessions of 4 hours using SUPRA device (Bellco). In addition, they followed a bortezomib and dexamethasone regimen according to a bi-weekly schedule (3-5 cycles) plus Thalidomide. iFLC concentrations were measured by immunonephelometry in blood at the beginning of each dialysis session. All patients but one, showed a very good partial hematological response. The only exception demonstrated a partial response. iFLCs decreased between 72,8% and 99,7% in a median period of three weeks. After 6 months three patients underwent autologous stem-cell transplantation (ASCT), one of whom repeated the procedure 6 months later. In conclusion, three patients became dialysis independent at the end of the HCO-HD period, one patient became dialysis independent three months later and one remained dialysis dependent. Recovery of renal function in 4 out of 5 patients with a very good hematological response is a consequence of an early and fast removal of the iFLC joined to an efficient therapeutic regimen.

Biohumoral markers as predictor of right ventricular dysfunction in AL Amyloidosis.

AIM: In AL amyloidosis, the importance of right ventricle (RV) involvement has recently been underlined and its role in predicting prognosis has been emphasized. Little is known about the relationship between RV involvement, N-terminal pro-brain natriuretic peptide (NT-proBNP) and troponin levels. Aim of our study was to clarify the relationship between NT-proBNP and troponin and RV involvement and analyze their independent value as predictors of RV dysfunction. METHODS AND RESULTS: We examined 76 consecutive patients with biopsy-proven AL amyloidosis. Each patient received complete clinical evaluation, troponin I, NT-proBNP assay and comprehensive echocardiographic evaluation. Considering a tricuspidal annulus plane systolic excursion (TAPSE) value <16 mm, 23 patients (30%) presented RV systolic dysfunction, whereas 53 (70%) did not. Patient with reduced TAPSE had thicker left ventricle (LV) walls and RV free walls, reduced LV fractional shortening, impaired LV diastolic function and worse LV and RV myocardial performance index. For RV dysfunction the best predictive value for NT-proBNP was identified as 2977 ng/l with sensitivity and specificity of 87% and 84%, respectively; best cut-off for troponin I was identified as 0.085 ng/l, with sensitivity and specificity of 85% and 90% respectively. At multivariable logistic regression analysis, both NT-proBNP and troponin I emerged as independent predictors of RV dysfunction presence but troponin appears to have a higher predictive power. CONCLUSION: Our study demonstrated that cut-off values of 2977 ng/ml for NT-proBNP and 0.085 ng/l for troponin were able to identify a subgroup of AL patients with RV dysfunction. Troponin I is more accurate and seems to be the best biohumoral marker of RV dysfunction.

Depression and cardiac symptoms among AL amyloidosis patients: the mediating role of coping strategies.

BACKGROUND: Amyloidosis is a rare disease group. AL amyloidosis represents the most common type of systemic amyloidosis and cardiac involvement determines prognosis. Although some studies have revealed that amyloidosis patients present high levels of depression, few data are available about depression-contributing factors. No investigations have been conducted about the coping strategies that AL amyloidosis patients use to face the disease and there is little research on patients with cardiac symptoms that are strongly related to the prognosis. OBJECTIVES: to examine coping strategies (avoidance, social support seeking and problem-solving) as potential mediator in the relationship between cardiac symptom severity (independent variable) and depressive symptoms (dependent variable) in AL cardiologic patients. METHOD: Thirty-four AL patients with cardiac-related symptoms were administered the Coping Strategy Indicator and the Centre for Epidemiological Study-Depression Scale. Clinical variables such as months since cardiac symptom onset and cardiac symptom severity were collected. RESULTS: According to questionnaire normative values, all patients presented clinical depression. Moreover, out of the coping strategies, avoidance and social support seeking mediated the link between cardiac symptom severity and depressive symptoms. No mediational effect was found for problem-solving. DISCUSSION: As cardiac symptoms have low severity, AL patients can avoid the disease. However, as cardiac symptoms proceed and interfere with daily activities, they can no longer ignore their signs thus perceiving the severity of their medical condition. This status makes individuals prone to seek less social support and thus to prefer social isolation. Results suggest the need for early psychological support on coping strategies for AL cardiologic patients.

Cardiac amyloidosis: the heart of the matter.

Amyloidosis comprises a unique group of diseases that share in common the extracellular deposition of insoluble fibrillar proteins in organs and tissue including the heart. Cardiac amyloidosis could be primary a part of systemic acquired amyloidosis, or a result of heredofamilial amyloidosis. Although the infiltration of the heart from different types of amyloid results in restrictive cardiomyopathy that manifests with refractory congestive heart failure and conduction abnormalities, unequivocal identification of the deposited amyloidogenic protein is mandatory in order to avoid misdiagnosis and inappropriate treatment. Recent developments in imaging techniques and extracardiac tissue biopsy have minimized the need for invasive endomyocardial biopsy for amyloidosis. Despite advances in treatment, the prognosis of a patient with amyloidosis is still poor and depends upon the underlying disease, and the type and degree of dysfunction of the involved organs. Thus, early diagnosis is mandatory because patients with advanced disease are usually too ill for intensive therapy. This review outlines current approaches to diagnosis, assessment of disease severity, and treatment of cardiac amyloidosis.

Prognostic value of fragmented QRS in cardiac AL amyloidosis.

BACKGROUND: In light-chain (AL) cardiac amyloidosis, the 12-lead electrocardiogram (ECG) reflects myocardial amyloid infiltration with low limb voltages, pseudoinfarction patterns, and conduction abnormalities. Moreover, it is not unusual to see "aspecific" QRS complex abnormalities, such as notches and RsR' pattern in the absence of QRS prolongation, i.e. a fragmentation of QRS complexes (fQRS), that has been associated with myocardial scars and prognosis. Since cardiomyocyte damage and interstitial fibrosis are associated with cardiac amyloid deposition, aim of the present study was to analyze the prevalence and the potential prognostic value of fQRS in patients with cardiac amyloidosis. METHODS: We enrolled 375 consecutive untreated patients in whom a first AL amyloidosis diagnosis was concluded between 2008 and 2010, 264 with and 111 without heart involvement. Patients with a positive history of coronary disease were excluded from the analysis. RESULTS: The prevalence of fQRS was significantly higher in patients with cardiac AL amyloidosis (28.5% vs. 11.7%; p=0.0008). After a median follow-up of 561 days, Kaplan-Meier survival analysis revealed a significantly higher mortality in the fQRS group when compared with the "normal" QRS group (p=0.0008). No association was found between the presence of fQRS and the duration of PQ, QRS, and QTc intervals, the presence of peripheral low voltages or pseudonecrosis, NT-proBNP serum levels or cardiac wall thickness. CONCLUSIONS: In patients with cardiac AL amyloidosis, the presence of fQRS at diagnosis has an independent prognostic value. Such a simple and cheap analysis in patients' diagnostic work-up may improve diagnosis and prognostic stratification.

Anxiety and depression among AL amyloidosis patients: the role of cardiac symptoms.

UNLABELLED: Light-chain (AL) amyloidosis has the worst prognosis out of the different forms of cardiac amyloidosis, However, data are not available about the incidence of the disease-related psychological impact of AL amyloidosis in this population. In particular, no data are available about the impact of diagnosis communication or about the impact of cardiac symptom onset and severity on anxiety and depression levels among AL patients. AIM: To evaluate the role of time that has passed since the diagnosis was communicated, time that has passed since the onset of cardiac symptoms, and actual cardiac symptom severity have on level of anxiety, depression and psychological stress among cardiology patients with AL. Thirty-two AL patients with cardiac-related symptoms were administered General Health Questionnaire, State-Trait Anxiety Inventory and Centre for Epidemiological Study-Depression Scale. Clinical variables such as months gone by since diagnosis, months gone by since the onset of cardiac symptoms, and cardiac symptom severity (New York Heart Association (NYHA) class) were measured. Troponin, NT-pro BNP levels, Mayo Stage and echocardiographic characteristics were also collected. RESULTS: According to questionnaire normative values, AL patients presented severe psychological distress, severe anxiety and clinical depression. Moreover, anxiety levels were determined by psychological distress (p < 0.001) and months gone by since the onset of cardiac symptoms (p < 0.01) while depression levels were influenced by NYHA class (p < 0.001). CONCLUSIONS: Our results suggest that there is a need to plan psychological support for these patients with consideration for the onset of cardiac symptoms and symptom severity.

[Severe recurrent intrahepatic cholestasis in systemic AL amyloidosis without obvious liver involvement: unexplained hepatic toxicity or a case of misdiagnosed liver amyloidosis?]. / Colestasi intraepatica in corso di amiloidosi sistemica AL senza evidenza istologica di un coinvolgimento epatico: un caso di epatopatia tossica o una mancata diagnosi di amiloidosi epatica?

We report the case of a 50-year-old woman who was admitted to the hospital for acute abdominal pain with nephrotic proteinuria, rapidly progressive renal failure, and moderate anemia. Laboratory tests showed mild Bence Jones (λ) proteinuria with negative serum immunofixation and a mild increase in λ free light chains. A bone marrow biopsy and a fat tissue aspirate showed multiple myeloma and amyloidosis. Because of the end-stage renal disease, the patient began regular dialysis treatment and was started on bortezomib 1.3 mg/m2 plus dexamethasone 40 mg on days 1, 4, 8 and 11 of 21-day cycles. Ten days later she complained of a new episode of abdominal pain with jaundice. A CT scan and an MRI scan ruled out all secondary causes of cholangitis including cancer. Acute intrahepatic cholestasis due to amyloid deposition was then hypothesized. After 4 well tolerated cycles of bortezomib and dexamethasone, blood tests showed a complete hematological response with full reversal of cholestasis. After three months, a new episode of abdominal pain occurred and this time the patient was operated on and found to have an intestinal volvulus. Because of the jaundice, a transjugular liver biopsy was performed showing no evidence of amyloid deposits. Two months later the patient died of septic shock. Although no autopsy was performed and the ultimate cause of the cholestasis could not be ascertained, amyloidosis remains the major culprit in this unfortunate case.

Right ventricular function in AL amyloidosis: characteristics and prognostic implication.

AIM: The importance of right ventricle (RV) dysfunction in AL amyloidosis has been underestimated. This study was designed to comprehensively evaluate RV function and its prognostic role in patients with AL amyloidosis with and without echocardiographic evidence of cardiac involvement. METHOD AND RESULTS: Fifty-two biopsy-proven AL amyloidosis patients underwent a thorough echocardiographic evaluation. Twenty-seven patients (CA) met the international echocardiographic criteria for cardiac involvement [left ventricular (LV) wall thickness ≥ 12 mm] and 25 patients had no cardiac amyloidosis features (NCA). Patients were compared with a sex- age-matched control group. Patients and controls underwent traditional, tissue Doppler (TDI), speckle-tracking left and RV echocardiographic evaluation. No difference was observed between groups in RV diastolic diameter, whereas CA patients showed increased RV free wall thickness (P< 0.0001). Compared with controls and NCA patients, traditional echocardiography, TDI, and speckle-tracking evaluation detected significantly (P< 0.0001) depressed RV longitudinal systolic function in CA patients. No difference was observed between groups at Doppler diastolic evaluation, whereas at tricuspidal annulus TDI analysis, CA subject showed significantly lower E' and A' values with increased E/E' ratio (P< 0.0001). Over a 19 months median follow-up period, 18 patients died. Cox multivariate analysis showed that N-terminal pro-Brain natriuretic peptide and RV longitudinal strain were the strongest death predictor. CONCLUSION: Our data show that in patients with AL amyloidosis, RV involvement develops later than LV amyloid deposition but when it occurs, prognosis dramatically worsens. Moreover RV longitudinal strain was the only echocardiographic predictor of prognosis. We suggest that RV function analysis should be performed routinely as a part of echocardiographic evaluation in these patients.