Severe reduction of blood lysosomal acid lipase activity in cryptogenic cirrhosis: A nationwide multicentre cohort study

Violi, Francesco; Angelico, Francesco; Pastori, Daniele; Baratta, Francesco; Ben, Maria Del; Polimeni, Licia; Labbadia, Giancarlo; Basili, Stefania; Raparelli, Valeria; Napoleone, Laura; Corradini, Stefano Ginanni; Ferri, Flaminia; Monica, Pellone; Mischitelli, Monica; Parlati, Lucia; Tozzi, Giulia; D’Amico, Jessica; Colzi, M; Andrea, Paola; Perticone, Francesco; Caroleo, Benedetto; Corazza, Gino Roberto; Masotti, Michela; Gaetano, Bergamaschi; Sacerdoti, David; Brocco, Silvia; Angélico, M.; Santopaolo, Francesco; Francioso, S.; Pujatti, Pietro Luigi; Faedo, Alessandra; Andriulli, Angelo; Ippolito, A.; Bolondi, Luigi; Tovoli, Francesco; Fargion, Silvia; Fracanzani, Anna Ludovica; Davı̀, Giovanni; Michele, Dario Di; Croce, Giuseppe; Averna, Maurizio; Giammanco, Antonina; Persico, Marcello; Bucci, Tommaso; Iuliano, Luigi; Ciacciarelli, Marco

doi:10.1016/j.atherosclerosis.2017.03.038

Cited by 22 publications

(21 citation statements)

References 25 publications

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“…Previous studies showed a progressive decrease in LAL activity from healthy subjects (HS) to subjects with NAFL and those with biopsy‐proven NASH . More recently, in patients with cryptogenic cirrhosis (CC), a further reduction in the activity of LAL has been described . These results were similar to those obtained in children with biopsy‐proven NASH …”

Section: Introductionsupporting

confidence: 73%

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Lysosomal acid lipase activity and liver fibrosis in the clinical continuum of non‐alcoholic fatty liver disease

Baratta

Pastori

Tozzi

et al. 2019

Liver International

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Background and Aims Recent evidence showed a reduced activity of the lysosomal acid lipase (LAL) in patients with non‐alcoholic fatty liver disease (NAFLD) and cryptogenic cirrhosis (CC). However, the relationship between LAL activity and liver fibrosis has never been investigated. Methods Cross‐sectional study including 575 outpatients referred for the management of cardio‐metabolic and liver disease. The absence of liver fibrosis was defined by a FIB‐4 < 1.30 and NAFLD fibrosis score (NFS) <−1.455. LAL activity was measured with dried blood spot technique. Results Overall, 515 patients had a diagnosis of NAFLD (454 NAFL and 61 biopsy‐proven NASH) and 60 of CC. The value of LAL activity progressively decreased from healthy subjects to NAFL/NASH patients to CC (P < .001). LAL activity was reduced by 10% in patients with NAFL, by 20% in NASH and by 50% in CC. The prevalence of CC decreased across the tertiles of LAL activity: 22.2% in the lowest, 4.6% in the intermediate and 0.5% in the highest tertile. In NAFLD patients, 69.9% had a FIB4 < 1.30, and 43.1% a NFS <−1.455. Multivariate logistic regression analysis showed that Log (LAL activity) was associated with FIB‐4 < 1.30 (Odds ratio [OR] 2.19 95% confidence interval [CI] 1.33‐3.62, P = .002) and NFS < −1.455 (OR 2.43, 95% CI 1.51‐3.91, P < .001) after adjustment for confounding factors. Conclusions We found a progressive reduction of LAL activity according to liver disease severity. LAL activity was inversely associated with markers of liver fibrosis in patients with NAFLD.

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Section: Introductionsupporting

confidence: 73%

“…LAL activity was dosed with dried blood spot (DBS) technique using the inhibitor Lalistat 2 as previously reported, and expressed as nmol/spot/h. DBS tests were performed in Bambino Gesù Hospital in Rome.…”

Section: Methodsmentioning

confidence: 99%

Lysosomal acid lipase activity and liver fibrosis in the clinical continuum of non‐alcoholic fatty liver disease

Baratta

Pastori

Tozzi

et al. 2019

Liver International

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“…However strong observational data from a large European meta-analysis suggests that NAFLD is not causal in acceleration of CVD [ 13 ]. Our data highlights the particularly increased prevalence in patients with cirrhosis and is broadly consistent with a previously reported cohort from Italy [ 19 ]. Indeed, hypertension has been highlighted as an independent risk factor for advanced fibrosis in NAFLD [ 42 ].…”

Section: Discussionsupporting

confidence: 92%

“…There is currently comparatively limited data on the prevalence of CVD in patients with NAFLD cirrhosis [ 18 ]. One study of 133 patients with cryptogenic cirrhosis found nearly half to have diabetes and 18% had experienced a major cardiovascular or cerebrovascular event [ 19 ]. CVD events are common post-transplant sequelae and chronic kidney disease is linked to reduced graft survival [ 20 ].…”

Section: Introductionmentioning

confidence: 99%

Hospital admission with non-alcoholic fatty liver disease is associated with increased all-cause mortality independent of cardiovascular risk factors

et al. 2020

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Non-alcoholic fatty liver disease (NAFLD) is common and strongly associated with the metabolic syndrome. Though NAFLD may progress to end-stage liver disease, the top cause of mortality in NAFLD is cardiovascular disease (CVD). Most of the data on liver-related mortality in NAFLD derives from specialist liver centres. It is not clear if the higher reported mortality rates in individuals with non-cirrhotic NAFLD are entirely accounted for by complications of atherosclerosis and diabetes. Therefore, we aimed to describe the CVD burden and mortality in NAFLD when adjusting for metabolic risk factors using a ‘real world’ cohort. We performed a retrospective study of patients followed-up after an admission to non-specialist hospitals with a NAFLD-spectrum diagnosis. Non-cirrhotic NAFLD and NAFLD-cirrhosis patients were defined by ICD-10 codes. Cases were age-/sex-matched with non-NAFLD hospitalised patients. All-cause mortality over 14-years follow-up after discharge was compared between groups using Cox proportional hazard models adjusted for demographics, CVD, and metabolic syndrome components. We identified 1,802 patients with NAFLD-diagnoses: 1,091 with non-cirrhotic NAFLD and 711 with NAFLD-cirrhosis, matched to 24,737 controls. There was an increasing burden of CVD with progression of NAFLD: for congestive heart failure 3.5% control, 4.2% non-cirrhotic NAFLD, 6.6% NAFLD-cirrhosis; and for atrial fibrillation 4.7% control, 5.9% non-cirrhotic NAFLD, 12.1% NAFLD-cirrhosis. Over 14-years follow-up, crude mortality rates were 14.7% control, 13.7% non-cirrhotic NAFLD, and 40.5% NAFLD-cirrhosis. However, after adjusting for demographics, non-cirrhotic NAFLD (HR 1.3 (95% CI 1.1–1.5)) as well as NAFLD-cirrhosis (HR 3.7 (95% CI 3.0–4.5)) patients had higher mortality compared to controls. These differences remained after adjusting for CVD and metabolic syndrome components: non-cirrhotic NAFLD (HR 1.2 (95% CI 1.0–1.4)) and NAFLD-cirrhosis (HR 3.4 (95% CI 2.8–4.2)). In conclusion, from a large non-specialist registry of hospitalised patients, those with non-cirrhotic NAFLD had increased overall mortality compared to controls even after adjusting for CVD.

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“…To evaluate a possible role of LAL in cryptogenic cirrhosis, we carried out a cohort study including 274 patients with liver cirrhosis of different etiology from 19 centers in Italy[33]. Median LAL activity value was 0.58 nmol/spot per hour, 0.49 and 0.65 in the cryptogenic cirrhosis and alcoholic/viral cirrhosis groups, respectively ( P < 0.002).…”

Section: Lal-d and Liver Cirrhosismentioning

confidence: 99%

Reduced lysosomal acid lipase activity: A new marker of liver disease severity across the clinical continuum of non-alcoholic fatty liver disease?

Baratta

Pastori

Ferro

et al. 2019

WJG

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Lysosomal acid lipase (LAL) plays a key role in intracellular lipid metabolism. Reduced LAL activity promotes increased multi-organ lysosomal cholesterol ester storage, as observed in two recessive autosomal genetic diseases, Wolman disease and Cholesterol ester storage disease. Severe liver steatosis and accelerated liver fibrosis are common features in patients with genetic LAL deficiency. By contrast, few reliable data are available on the modulation of LAL activity in vivo and on the epigenetic and metabolic factors capable of regulating its activity in subjects without homozygous mutations of the Lipase A gene. In the last few years, a less severe and non-genetic reduction of LAL activity was reported in children and adults with non-alcoholic fatty liver disease (NAFLD), suggesting a possible role of LAL reduction in the pathogenesis and progression of the disease. Patients with NAFLD show a significant, progressive reduction of LAL activity from simple steatosis to non-alcoholic steatohepatitis and cryptogenic cirrhosis. Among cirrhosis of different etiologies, those with cryptogenic cirrhosis show the most significant reductions of LAL activity. These findings suggest that the modulation of LAL activity may become a possible new therapeutic target for patients with more advanced forms of NAFLD. Moreover, the measurement of LAL activity may represent a possible new marker of disease severity in this clinical setting.

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Severe reduction of blood lysosomal acid lipase activity in cryptogenic cirrhosis: A nationwide multicentre cohort study

Cited by 22 publications

References 25 publications

Lysosomal acid lipase activity and liver fibrosis in the clinical continuum of non‐alcoholic fatty liver disease

Lysosomal acid lipase activity and liver fibrosis in the clinical continuum of non‐alcoholic fatty liver disease

Hospital admission with non-alcoholic fatty liver disease is associated with increased all-cause mortality independent of cardiovascular risk factors

Reduced lysosomal acid lipase activity: A new marker of liver disease severity across the clinical continuum of non-alcoholic fatty liver disease?

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