G. Pisano

Progression of carotid vascular damage and cardiovascular events in non-alcoholic fatty liver disease patients compared to the general population during 10 years of follow-up

BACKGROUND AND AIM Non-alcoholic fatty liver disease (NAFLD) is associated not only with liver related morbidity and mortality but also with an increased risk of cardiovascular disease. AIM to evaluate in patients with NAFLD and in matched Controls after 10 years of follow-up 1 the incidence of major cardiovascular and cerebral events 2 the progression of vascular damage. METHODS Clinical and cardio-metabolic data were collected in 125 NAFLD patients and 250 age and gender matched Controls at baseline and 10 years later. Incidence of cardiovascular and cerebral events was recorded. By ultrasonography, carotid intima-media thickness (cIMT), presence of plaques and presence of fatty liver were evaluated. RESULTS 25% of the overall series was lost to follow-up. Sixty-eight (37%) Controls developed steatosis. Major cardiovascular events were observed in thirty-five subjects (17/91 (19%) NAFLD and 18/182 (10%) Controls), with an estimated cumulative risk significantly higher in NAFLD than in Controls, log-rank test for equality of failure functions p = 0.007. At multivariate analysis, presence of plaques (hazard ratio 5.08 (95% C.I. 2.56-10.96) and of steatosis (hazard ratio 1.99 (1.01-3.94)) were the strongest predictors for cardiovascular events. Grade of steatosis, ALT and GGT levels were higher in NAFLD patients who developed cardiovascular events. cIMT value after 10 years was significantly higher in NAFLD than in Controls, but the mean progression rate was higher in Controls (0.015 and 0.006 mm/year, p = 0.001). In conclusion our results suggest that NAFLD has to be included among risk factors for cardiovascular damage and underline the utility to evaluate, once NAFLD is diagnosed, the presence of atherosclerotic lesions.

Role of Serum Uric Acid and Ferritin in the Development and Progression of NAFLD

Nonalcoholic fatty liver disease (NAFLD), tightly linked to the metabolic syndrome (MS), has emerged as a leading cause of chronic liver disease worldwide. Since it is potentially progressive towards non-alcoholic steatohepatitis (NASH) and hepatic fibrosis, up to cirrhosis and its associated complications, the need for predictive factors of NAFLD and of its advanced forms is mandatory. Despite the current “gold standard” for the assessment of liver damage in NAFLD being liver biopsy, in recent years, several non-invasive tools have been designed as alternatives to histology, of which fibroscan seems the most promising. Among the different serum markers considered, serum uric acid (SUA) and ferritin have emerged as possible predictors of severity of liver damage in NAFLD. In fact, as widely described in this review, they share common pathogenetic pathways and are both associated with hepatic steatosis and MS, thus suggesting a likely synergistic action. Nevertheless, the power of these serum markers seems to be too low if considered alone, suggesting that they should be included in a wider perspective together with other metabolic and biochemical parameters in order to predict liver damage.

NT-pro-BNP for differential diagnosis in patients with syncope

NT-pro-BNP has been proposed as a good predictor of syncope adverse outcome in the Emergency Department (ED) [Pfister R, Diedrichs H, Larbig R, Erdmann E, Schneider CA. NT-pro-BNP for differential diagnosis in patients with syncope. Int J Cardiol 2008 Jan 29]. We hereby summarize four critical points that should be taken into account when seeking to identify a cardiac cause of syncope or dealing with a risk stratification approach of the patient in the ED. The first issue is that patients admitted to the hospital after syncope are usually sicker than those discharged because of a higher rate of co-morbidity. Secondly, the focus on discharged patients is of paramount importance to assess the goodness of a predictor. Aging, which affects NT-pro-BNP levels, is a limiting factor in interpreting results. Finally, in order to add valuable information to the clinical practice, we suggest to compare results obtained by NT-pro-BNP values and the most used prognostic risk scores, such as the OESIL and SFSR.

Cardiovascular risk after orthotopic liver transplantation, a review of the literature and preliminary results of a prospective study

Improved surgical techniques and greater efficacy of new anti-rejection drugs have significantly improved the survival of patients undergoing orthotopic liver transplantation (OLT). This has led to an increased incidence of metabolic disorders as well as cardiovascular and cerebrovascular diseases as causes of morbidity and mortality in OLT patients. In the last decade, several studies have examined which predisposing factors lead to increased cardiovascular risk (i.e., age, ethnicity, diabetes, NASH, atrial fibrillation, and some echocardiographic parameters) as well as which factors after OLT (i.e., weight gain, metabolic syndrome, immunosuppressive therapy, and renal failure) are linked to increased cardiovascular mortality. However, currently, there are no available data that evaluate the development of atherosclerotic damage after OLT. The awareness of high cardiovascular risk after OLT has not only lead to the definition of new but generally not accepted screening of high risk patients before transplantation, but also to the need for careful patient follow up and treatment to control metabolic and cardiovascular pathologies after transplant. Prospective studies are needed to better define the predisposing factors for recurrence and de novo occurrence of metabolic alterations responsible for cardiovascular damage after OLT. Moreover, such studies will help to identify the timing of disease progression and damage, which in turn may help to prevent morbidity and mortality for cardiovascular diseases. Our preliminary results show early occurrence of atherosclerotic damage, which is already present a few weeks following OLT, suggesting that specific, patient-tailored therapies should be started immediately post OLT.

PCSK9 deficiency results in increased ectopic fat accumulation in experimental models and in humans

Background Proprotein convertase subtilisin kexin type 9 (PCSK9) regulates low-density lipoprotein and very low-density lipoprotein receptor expression in several tissues. Here we evaluated whether PCSK9 may modulate the handling of triglycerides in the liver and peripheral tissues. Methods Subjects from the PLIC cohort were genotyped for the loss-of-function PCSK9 R46L variant and characterized for clinical and biochemical parameters, total and android fat mass, hepatic steatosis and epicardial fat thickness. Visceral adipose tissue and subcutaneous adipose tissue in PCSK9 KO and wild type mice were quantified by nuclear magnetic resonance imaging. Results Carriers of the R46L variant (n = 13) had lower low-density lipoprotein cholesterol levels, higher body mass index and increased percentage of total and android fat masses compared with non-carriers (n = 521). R46L variant associated with a two-fold increase prevalence of hepatic steatosis and higher epicardial fat thickness. These observations were replicated in PCSK9 KO mice, which showed increased visceral adipose tissue (but not subcutaneous adipose tissue) when fed chow or high-fat diet for 20 weeks, compared with wild type mice. Conclusions These data suggest that genetically determined PCSK9 deficiency might be associated with ectopic fat accumulation.

Liver and Cardiovascular Damage in Patients With Lean Nonalcoholic Fatty Liver Disease, and Association With Visceral Obesity

BACKGROUND & AIMS: Lean nonalcoholic fatty liver disease (NAFLD) is defined as NAFLD that develops in patients with a body mass index (BMI) less than 25 kg/m2. We investigated the differences between lean NAFLD and NAFLD in overweight and obese persons, factors associated with the severity of liver and cardiovascular disease, and the effects of visceral obesity. METHODS: We performed a retrospective cohort study of 669 consecutive patients with biopsy‐proven NAFLD seen at 3 liver centers in Italy. We collected anthropometric, clinical, and biochemical data, as well as information on carotid atherosclerosis (artery intima‐media thickness and plaque), liver histology (nonalcoholic steatohepatitis [NASH] and fibrosis), insulin resistance, and diabetes. Overweight was defined as a BMI of 25 to 29.9 kg/m2, and obese was defined as a BMI of 30 kg/m2 or greater. Patients were assigned to groups based on waist circumference, a marker of visceral obesity (low: men, <94 cm, women <80 cm; medium: men, 94–102 cm, women 80–88 cm; or high: men >102 cm, women >88 cm). DNA samples were analyzed for the rs738409 C>G (I148M in PNPLA3), the rs58542926 C>T (E167K in TM6SF2), and single‐nucleotide polymorphisms. Variables in men and women were analyzed using chi‐squared analysis and the Mann–Whitney or Kruskal–Wallis tests. Multiple linear or logistic regression analyses were adjusted for all the variables of clinical relevance or statistically significant at univariate analyses. The primary outcome was the difference in liver and cardiovascular disease between lean NAFLD and NAFLD in overweight and obese persons. Secondary outcomes were effects of visceral obesity, based on waist circumference, on hepatic, vascular, and metabolic features. RESULTS: Significantly lower proportions of patients with lean NAFLD (143 patients; 43 women; mean age, 46 ± 13 y) had hypertension (P = .001), diabetes (P = .0001), and metabolic syndrome (P = .0001) than overweight or obese patients with NAFLD (526 patients; 149 women; mean age, 49 ± 12 y). Significantly lower proportions of patients with lean NAFLD had NASH (17% vs 40% of obese or overweight patients with NAFLD; P = .0001), fibrosis of F2 or higher (17% vs 42%; P = .0001), or carotid plaques (27% vs 39%; P = .03). Patients with lean NAFLD had significantly thinner carotid intima‐media (0.74 ± 0.1 mm) than obese or overweight patients with NAFLD (0.84 ± 0.3 mm; P = .0001). There was no significant difference in the proportions of patients with rs738409 C>G in PNPLA3, but a significantly greater proportion of patients with lean NAFLD carried rs58542926 C>T in TM6SF2 (4%) than obese or overweight individuals with NAFLD (0.3%; P = .001). Of the 143 patients with lean NAFLD, 27 had grade 3 steatosis, 24 had a lobular inflammation score greater than 2, 10 had a ballooning score of 2, and 25 had a fibrosis score of 2 or higher. In patients with lean NAFLD, the only variable associated independently with NASH and a fibrosis score of 2 or higher was rs738409 C>G in PNPLA3. Patients with lean NAFLD and a medium waist circumference had a significantly higher risk of diabetes (odds ratio, 11; 95% confidence interval [CI], 1.2–106; P = .03) than overweight or obese patients with a similar waist circumference (odds ratio, 1.3; 95% CI, 0.4–4.2; P = .6). Lean and overweight or obese patients with high waist circumferences had significant increases in risk compared with patients with low and medium circumference and diabetes, hypertension, and fibrosis scores of 2 or higher. CONCLUSIONS: In a retrospective study of patients with lean NAFLD vs obese or overweight persons with NAFLD, we found 20% of patients with lean NAFLD to have NASH, fibrosis scores of 2 or higher, and carotid atherosclerosis. Lean patients with rs738409 C>G in PNPLA3 should be monitored for liver disease progression; studies including large series of patients with lean NAFLD will clarify the possible role of TM6SF2 polymorphisms.

Epicardial Adipose Tissue (EAT) Thickness Is Associated with Cardiovascular and Liver Damage in Nonalcoholic Fatty Liver Disease

Background and Aims Epicardial adipose tissue (EAT) has been proposed as a cardiometabolic and hepatic fibrosis risk factor in patients with non alcoholic fatty liver disease (NAFLD). Aim of this study was to evaluate the role of EAT in NAFLD by analyzing 1) the association between EAT, the other metabolic parameters and the severity of steatosis 2) the relationship between cardiovascular (cIMT, cplaques, E/A), liver (presence of NASH and significant fibrosis) damage and metabolic risk factors including EAT 3) the relationship between EAT and genetic factors strongly influencing liver steatosis. Methods In a cross-sectional study, we considered 512 consecutive patients with NAFLD (confirmed by biopsy in 100). EAT, severity of steatosis, carotid intima-media thickness (cIMT) and plaques were evaluated by ultrasonography and results analysed by multiple linear and logistic regression models. Variables independently associated with EAT (mm) were female gender (p = 0.003), age (p = 0.001), BMI (p = 0.01), diastolic blood pressure (p = 0.009), steatosis grade 2 (p = 0.01) and 3 (p = 0.04), fatty liver index (p = 0.001) and statin use (p = 0.03). Variables independently associated with carotid IMT were age (p = 0.0001), hypertension (p = 0.009), diabetes (p = 0.04), smoking habits (p = 0.04) and fatty liver index (p = 0.02), with carotid plaques age (p = 0.0001), BMI (p = 0.03), EAT (p = 0.02),) and hypertension (p = 0.02), and with E/A age (p = 0.0001), diabetes (p = 0.005), hypertension (p = 0.04) and fatty liver index (p = 0.004). In the 100 patients with available liver histology non alcoholic steatohepatitis (NASH) was independently associated with EAT (p = 0.04) and diabetes (p = 0.054) while significant fibrosis with EAT (p = 0.02), diabetes (p = 0.01) and waist circumference (p = 0.05). No association between EAT and PNPLA3 and TM6SF2 polymorphisms was found. Conclusion In patients with NAFLD, EAT is associated with the severity of liver and vascular damage besides with the known metabolic risk factors.

Vascular Damage in Patients with Nonalcoholic Fatty Liver Disease: Possible Role of Iron and Ferritin

Non Alcoholic Fatty Liver Disease (NAFLD) is the most common chronic liver disease in Western countries. Recent data indicated that NAFLD is a risk factor by itself contributing to the development of cardiovascular disease independently of classical known risk factors. Hyperferritinemia and mild increased iron stores are frequently observed in patients with NAFLD and several mechanisms have been proposed to explain the role of iron, through oxidative stress and interaction with insulin metabolism, in the development of vascular damage. Moreover, iron depletion has been shown to decrease atherogenesis in experimental models and in humans. This review presents the recent evidence on epidemiology, pathogenesis, and the possible explanation of the role of iron and ferritin in the development of cardiovascular damage in patients with NAFLD, and discusses the possible interplay between metabolic disorders associated with NAFLD and iron in the development of cardiovascular disease.

An atypical case of typical chest pain

A 68-year-old woman presented to emergency department (ED) for a 2-week history of fatigue and recurrent episodes of chest pain on exertion described as constrictive and associated with dyspnea. The duration of each episode of pain was about 30 min. To relieve her symptoms, she used transdermic and sublingual nitrates with no benefit. The past medical history revealed primary biliary cirrhosis diagnosed in 1994, a celiac syndrome and a nonsteroidal antiinflammatory-induced gastropathy. She had also a long-standing history of Raynaud’s phenomenon, arthritis, sclerodactily and positive anticentromere antibodies. There was no history of coronary artery disease and no risk factor for cardiovascular diseases. Home medication were omeprazole, NSAID, and ursodeoxycholic acid. On general examination the patient was afebrile and mildly bradycardic (56 beats/min). The blood pressure was 110/60 torr. Pulmonary, cardiac, and abdominal examinations revealed no abnormalities. No oedema was observed in the lower limbs. An enlarged thyroid was palpable. The differential diagnosis of chest pain in a patient with known connective tissue disorder is extensive, ranging from benign to life-threatening etiologies. Musculoskeletal chest wall pain is a common etiology, particularly in rheumatic diseases due to frequent involvement of thoracic joints. This kind of pain is often localized and positional; it may be exacerbated by deep breathing, turning, and arm movement. Ischemic pain due to coronary artery disease has to be carefully considered as a cause of chest discomfort in patients with connective tissue disorders. This issue was emphasized in previous studies [1, 2] that show increased risk of cardiovascular events in connective tissue disorders, particularly in rheumatoid arthritis and erythematosus systemic lupus. The ischemic disease does not appear to be mediated through traditional risk factors, but may be the result of chronic inflammation associated with endothelial dysfunction and a hypercoagulable state [3]. The presence of a pleuritis or a pericarditis has to be excluded in our patient, since serositis is common in connective tissue disorders. Pericardial pain is typically sudden in onset, and occurs over the anterior chest. It may be exacerbated by inspiration, and may decrease in intensity when the patients sits up and leans forward. Also the presence of pulmonary hypertension has to be ruled out in initial evaluation of chest pain. This chronic condition is due to abnormalities in pulmonary vessels that are frequent in patients with rheumatoid arthritis, systemic erythematosus lupus, and systemic sclerosis. In this setting, chest pain is typically associated with exertional dyspnea and seems to be related both to pulmonary artery stretching and to right ventricular ischemia. The chest pain may also be related to an esophageal disease, particularly in our patient who had clinical features of limited cutaneous systemic sclerosis. Esophageal hypomotility and reduction in the lower-esophageal sphincter tone are common in patients with systemic sclerosis [4]. These motility abnormalities may result in gastroesophageal reflux and reflux esophagitis. Gastroesophageal reflux disease may cause symptoms similar to angina pectoris, including a sensation of chest pressure radiating to the neck and arms, which can be triggered by physical exercise and emotions, and relieved by nitrate F. Casella (&) I. Bossi G. Pisano N. Montano Department of Clinical Science, Division of Internal Medicine II, Luigi Sacco Hospital, University of Milan, Via GB Grassi 74, 20157 Milan, Italy e-mail: case.5@libero.it

AN ATYPICAL CASE OF TYPICAL CHEST PAIN

A 68-year-old woman presented to emergency department(ED) for a 2-week history of fatigue and recurrent episodesof chest pain on exertion described as constrictive andassociated with dyspnea. The duration of each episode ofpain was about 30 min. To relieve her symptoms, she usedtransdermic and sublingual nitrates with no benefit.The past medical history revealed primary biliarycirrhosis diagnosed in 1994, a celiac syndrome and anonsteroidal antiinflammatory-induced gastropathy. Shehad also a long-standing history of Raynaud’s phenome-non, arthritis, sclerodactily and positive anticentromereantibodies. There was no history of coronary artery diseaseand no risk factor for cardiovascular diseases. Homemedication were omeprazole, NSAID, and ursodeoxy-cholic acid.On general examination the patient was afebrile andmildly bradycardic (56 beats/min). The blood pressure was110/60 torr. Pulmonary, cardiac, and abdominal examina-tions revealed no abnormalities. No oedema was observedin the lower limbs. An enlarged thyroid was palpable.The differential diagnosis of chest pain in a patient withknown connective tissue disorder is extensive, rangingfrom benign to life-threatening etiologies.Musculoskeletal chest wall pain is a common etiology,particularly in rheumatic diseases due to frequentinvolvement of thoracic joints. This kind of pain is oftenlocalized and positional; it may be exacerbated by deepbreathing, turning, and arm movement.Ischemic pain due to coronary artery disease has to becarefully considered as a cause of chest discomfort inpatients with connective tissue disorders. This issue wasemphasized in previous studies [1, 2] that show increasedrisk of cardiovascular events in connective tissue disorders,particularly in rheumatoid arthritis and erythematosussystemic lupus. The ischemic disease does not appear to bemediated through traditional risk factors, but may be theresult of chronic inflammation associated with endothelialdysfunction and a hypercoagulable state [3].The presence of a pleuritis or a pericarditis has to beexcluded in our patient, since serositis is common in con-nective tissue disorders. Pericardial pain is typically suddenin onset, and occurs over the anterior chest. It may beexacerbated by inspiration, and may decrease in intensitywhen the patients sits up and leans forward.Also the presence of pulmonary hypertension has to beruled out in initial evaluation of chest pain. This chroniccondition is due to abnormalities in pulmonary vessels thatare frequent in patients with rheumatoid arthritis, systemicerythematosus lupus, and systemic sclerosis. In this setting,chest pain is typically associated with exertional dyspneaand seems to be related both to pulmonary artery stretchingand to right ventricular ischemia.The chest pain may also be related to an esophagealdisease, particularly in our patient who had clinical featuresof limited cutaneous systemic sclerosis. Esophagealhypomotility and reduction in the lower-esophagealsphincter tone are common in patients with systemicsclerosis [4]. These motility abnormalities may result ingastroesophageal reflux and reflux esophagitis. Gastro-esophageal reflux disease may cause symptoms similar toangina pectoris, including a sensation of chest pressureradiating to the neck and arms, which can be triggered byphysical exercise and emotions, and relieved by nitrate