New variants of alpha-1-antitrypsin : structural simulations and clinical expression

Alpha-1 antitrypsin deficiency (AATD) is characterized by reduced serum levels of the AAT protein and predisposes to liver and lung disease. The characterization at structural level of novel pathogenic SERPINA1 mutants coding for circulating AAT could provide novel insights into the mechanisms of AAT misfolding. The present study aimed to provide a practical framework for the identification and analysis of new AAT mutations, combining structural simulations and clinical data. We analysed a total of five mutations (four not previously described) in a total of six subjects presenting moderate to severe AATD: Gly95Alafs*18, Val210Glu, Asn247Ser, Pi*S + Asp341His and Pi*S + Leu383Phe + Lys394Ile. Clinical data, genotyping and phenotyping assays, structural mapping, and conformational characterization through molecular dynamic (MD) simulations were developed and combined. Newly discovered AAT missense variants were localized both on the interaction surface and the hydrophobic core of the protein. Distribution of mutations across the structure revealed Val210Glu at the solvent exposed s4C strand and close to the "Gate" region. Asn247Ser was located on the accessible surface, which is important for glycan attachment. On the other hand, Asp341His, Leu383Phe were mapped close to the "breach" and "shutter" regions. MD analysis revealed the reshaping of local interactions around the investigated substitutions that have varying effects on AAT conformational flexibility, hydrophobic packing, and electronic surface properties. The most severe structural changes were observed in the double- and triple-mutant (Pi*S + Asp341His and Pi*S + Leu383Phe + Lys394Ile) molecular models. The two carriers presented impaired lung function. The results characterize five variants, four of them previously unknown, of the SERPINA1 gene, which define new alleles contributing to the deficiency of AAT. Rare variants might be more frequent than expected, and therefore, in discordant cases, standardized screening of the S and Z alleles needs complementation with gene sequencing and structural approaches. The utility of computational modelling for providing supporting evidence of the pathogenicity of rare single nucleotide variations is discussed. The online version contains supplementary material available at 10.1186/s12931-022-02271-8

Utility of Transient Elastography for the Screening of Liver Disease in Patients with Alpha1-Antitrypsin Deficiency

Deficiència d'alfa1-antitripsina; Malaltia del fetge; Elastografia transitòriaAlpha1-antitrypsin deficiency; Liver disease; Transient elastographyDeficiencia de alfa1-antitripsina; Enfermedad del hígado; Elastografía transitoriaScreening of liver disease in alpha-1 antitrypsin deficiency (AATD) is usually carried out with liver enzymes, with low sensitivity. We conducted a multicenter cross-sectional study aiming to describe the utility of transient elastography for the identification of liver disease in patients with AATD. A total of 148 AATD patients were included. Among these, 54.7% were Pi*ZZ and 45.3% were heterozygous for the Z allele. Between 4.9% and 16.5% of patients had abnormal liver enzymes, without differences among genotypes. Liver stiffness measurement (LSM) was significantly higher in Pi*ZZ individuals than in heterozygous Z (5.6 vs. 4.6 kPa; p = 0.001). In total, in 8 (5%) individuals LSM was >7.5 kPa, considered significant liver fibrosis, and ≥10 kPa in 3 (1.9%) all being Pi*ZZ. Elevated liver enzymes were more frequently observed in patients with LSM > 7.5 kPa, but in 5 out of 8 of these patients all liver enzymes were within normal range. In patients with AATD, the presence of abnormal liver enzymes is frequent; however, most of these patients do not present significant liver fibrosis. Transient elastography can help to identify patients with liver fibrosis even with normal liver enzymes and should be performed in all Z-allele carriers to screen for liver disease.This research was funded by Grifols through an unrestricted grant from the Catalan Center for Research in Alpha-1 antitrypsin deficiency of the Vall d’Hebron Research Institute (VHIR) in the Vall d’Hebron Barcelona Hospital Campus, Barcelona, Spain; from the Madrid Center for Research in Alpha-1 antitrypsin deficiency of the Hospital Clínico San Carlos, Madrid, Spain; from the Galicia Center for Research in Alpha-1 antitrypsin deficiency of the University Hospital Complex of Vigo, Spain; as well as a research grant from Fundació Catalana de Pneumologia (FUCAP)

Non-Invasive Tests of Liver Fibrosis Help in Predicting the Development of Hepatocellular Carcinoma among Patients with NAFLD

Carcinoma hepatocelular; Elastografía transitoriaCarcinoma hepatocel·lular; Elastografia transitòriaHepatocellular carcinoma; Transient elastographyBackground: The potential role of non-invasive tests (NITs) for liver fibrosis for hepatocellular carcinoma (HCC) prediction remains poorly known. Methods: Retrospective analysis of a NAFLD cohort from a single university hospital in Barcelona, Spain. Incidence rates and cumulative incidence for the overall cohort, as well as cirrhotic and non-cirrhotic patients were calculated. Logistic regression analyses were carried out to investigate risk factors of HCC. Results: From the entire cohort of 1040 patients, 996 patients (95.8%) were analyzed, in whom 35 cases of HCC were detected, of which 26 (72.4%) HCC incident cases were newly diagnosed during a median follow-up of 2.5 (1.9–3.6) years. Two-hundred and thirty-one (23.2%) were cirrhotic at baseline. With the exception of 2 (7.7%) cases of HCC, the rest were diagnosed in cirrhotic patients. Overall HCC cumulative incidence was 9.49 (95% CI 6.4–13.9) per 1000 person-years. The incidence rate for cirrhotic patients was 41.2 (95% CI 27.6–61.6) per 1000 person-years and 0.93 (95% CI 0.23–3.7) per 1000 person-years for patients without cirrhosis. Overall mortality was significantly higher amongst patients with HCC (4.4% vs. 30.8%, p < 0.001). In patients with available liver biopsy (n = 249, 25%), advanced fibrosis (F3–F4) was significantly associated with higher HCC incidence, but not steatosis, lobular inflammation, nor ballooning. In the overall cohort, FIB-4 ≥1.3 (HR 8.46, 95% CI 1.06–67.4, p = 0.044) and older age (HR 1.06, 95% CI 1.01–1.11, p = 0.025) were associated with increasing risk of HCC over time, whereas in cirrhotic patients predictors of HCC included decreasing values of albumin (HR 0.34, 95% CI 0.13–0.87, p = 0.024), platelets (HR 0.98, 95% CI 0.98–0.99, p = 0.001), and increasing values of liver stiffness (HR 1.03, 95% CI 1.00–1.06, p = 0.016). Conclusions: In a Spanish cohort of NAFLD patients, HCC was rare in non-cirrhotic patients. NITs might play a relevant role at predicting HCC.The study was conducted in accordance with the Declaration of Helsinki and approved by the Vall d’Hebron University Hospital Campus Institutional Review Board (study protocol code PR(AG)626/2021)

Risk of infections in patients with NAFLD and Type 2 Diabetes under treatment with SGLT2 inhibitors and relationship with liver outcomes: A retrospective case-control study

Hepatic outcomes; Infections; Sodium-glucose co-transporter-2 inhibitorsResultados hepáticos; Infecciones; Inhibidores del cotransportador de sodio-glucosa-2Resultats hepàtics; Infeccions; Inhibidors del cotransportador de sodi-glucosa-2Introduction: Non-alcoholic fatty liver disease (NAFLD) is the most prevalent chronic liver disease in developed countries, with its incidence growing parallel to the epidemics of obesity and type 2 diabetes mellitus (T2DM). Sodium-glucose co-transporter-2 inhibitors (SGLT2i) are becoming a cornerstone in the management of cardiovascular health and some studies suggest the potential role in NAFLD. However, patients under treatment with SGLT2i are at risk of developing genitourinary fungal infections (GFIs). Moreover, both NAFLD and SGLT2i have a strong influence on the immune system, and therefore the risk of infections other than GFIs could be increased in NAFLD patients treated with SGLT2i. We aimed to examine the possible association of SGLT2i with infections and hepatic outcomes in NAFLD patients. Methods: We conducted a case-control study including NAFLD patients with T2DM visited at the Liver Unit outpatient clinic from 2016 to 2021 with a minimum follow-up of 6 months by selecting 65 patients receiving SGLT2i and 130 matched patients with other types of antidiabetic treatment. Results: During follow-up, GFIs were significantly higher in the SGLT2i group (15.4% vs. 3.8%; p=0.008), whereas there were no differences in the occurrence of overall infections (41.5% vs. 30%; p=0.1) nor in other types of specific infections. In the multivariable analysis, treatment with SGLT2i was not independently associated with higher odds of overall infection. On the other hand, SGLT2i patients showed a significantly lower incidence of hepatic events (1.5% vs. 10.7%; p=0.02). There were no significant different in all-cause mortality between cases and controls. Conclusions: NAFLD patients with T2DM receiving SGLT2i more frequently presented GFIs, whereas the incidence of other types of infections was not found to be higher than in other patients with NAFLD and T2DM treated with other drugs. Moreover, SGLT2i-treated patients had a lower occurrence of hepatic events. Further studies are warranted to validate our data.Funds from European Commission/EFPIA IMI2 853966-2, IMI2 777377, H2020 847989, and ISCIII PI19/01898

Acuity, nurse staffing and workforce, missed care and patient outcomes. A cluster-unit-level descriptive comparison

Aim: To compare patient acuity, nurse staffing and workforce, missed nursing care and patient outcomes among hospital unit-clusters. Background: Relationships among acuity, nurse staffing and workforce, missed nursing care and patient outcomes, are not completely understood. Method: Descriptive design with data from four unit-clusters: medical, surgical, combined and stepdown units. Descriptive statistics were used to compare acuity, nurse staffing coverage, education and expertise, missed nursing care, and selected nurse-sensitive outcomes. Results: Patient acuity in general (medical, surgical and combined) floors is similar to step-down units, with an average of 5.6 required RN hours per patient day. In general wards, available RN hours per patient day reach only 50% of required RN hours to meet patient needs. Workforce measures are comparable among unit-clusters, and average missed nursing care is 21%. Patient outcomes vary among unit-clusters. Conclusion:Patient acuity is similar among unit-clusters, whilst nurse staffing coverage is halved in general wards. While RN education, expertise and missed care are comparable among unitclusters, mortality, skin injuries and risk of family compassion fatigue rates are higher in general wards. Implications for nursing management: Nurse managers play a pivotal role in hustling policy-makers to address structural understaffing in general wards, to maximize patient safety outcomes

Addictive and wonderful : the experience of reading the Harry Potter series

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Paper de l’elastografia hepàtica i esplènica en el diagnòstic, seguiment i tractament de la malaltia hepàtica crònica avançada compensada

En la malaltia hepàtica crònica es produeixen canvis en l’estructura del parènquima hepàtic que comporten l’aparició de fibrosi i, al llarg del temps, el desenvolupament d’una cirrosi hepàtica. Les principals complicacions de la cirrosi hepàtica són l’aparició d’hipertensió portal, la insuficiència hepàtica i l’augment de risc de presentar un carcinoma hepatocel·lular (CHC) o hepatocarcinoma. El tractament de la causa que ha generat la malaltia hepàtica pot canviar l’evolució natural millorant el pronòstic, sobretot si aquest es realitza en fases precoces. L’àmplia utilització de tècniques de diagnòstic no invasiu i, sobretot, de l’elastografia de transició (ET), ens ha permès diagnosticar a pacients amb malaltia hepàtica crònica avançada en fases més precoces. Aquests pacients, tot i no haver-se descompensat mai, tenen un risc augmentat de presentar hipertensió portal i CHC pel que serà important conèixer quins d’ells desenvoluparan complicacions al llarg del seguiment i, en el cas dels pacients que hagin rebut tractament de la causa subjacent, identificar quins tindran més probabilitats de millorar el pronòstic. La present tesi pretén estudiar diferents utilitats de l’ET durant el seguiment de pacients amb malaltia hepàtica crònica avançada compensada (MHCAc). Així doncs, els objectius de la tesi van ser avaluar la capacitat de l’ET per predir complicacions (varices d’alt risc, descompensacions o CHC) en pacients amb MHCAc i donar regles senzilles que permetin la identificació de grups de risc. Per a tal finalitat, es van dur a terme tres estudis independents on es va estudiar, respectivament, la utilitat d’uns nous criteris basats en l’elastografia hepàtica i la xifra de plaquetes que permetia identificar una població amb baix risc de presentar varices de risc, estudiar els canvis dinàmics que es produeixen en l’elastografia hepàtica i esplènica en els pacients tractats amb antivirals orals per l’hepatitis C i, finalment, es va estudiar la incidència de complicacions després d’un tractament eficaç amb antivirals orals per posteriorment dissenyar una eina simple per predir el risc de presentar CHC. Amb aquests estudis es va poder concloure que: 1) l’ET en combinació amb paràmetres analítics és útil per predir el risc de complicacions en la malaltia hepàtica crònica, 2) uns nous criteris (ET 110x109/L) permeten identificar una població amb baixa probabilitat de presentar varices de risc fet que permet estalviar un elevat número d’endoscòpies, 3) durant el tractament amb antivirals orals es produeix un ràpid descens de l’elastografia hepàtica i esplènica com a conseqüència de la milloria de la inflamació, 4) la incidència de complicacions posterior al tractament amb antivirals orals és baixa essent el CHC la més freqüent i, per últim, 5) un senzill nomograma basat en ET i nivells d’albúmina permet determinar el risc de CHC durant el seguiment de pacients amb MHCAc tractats amb antivirals orals.Regardless the underlying cause, in chronic liver disease there is a wound-healing process that produces fibrosis and, after a variable period of time, cirrhosis. The main complications of liver cirrhosis are portal hypertension, liver failure and hepatocellular carcinoma (HCC). Treating the underlying cause of liver disease can change the natural history improving prognosis especially in early stages. The extended use of non-invasive diagnostic methods, especially transient elastography (TE), have helped us to diagnose patients at early phase of advanced chronic liver disease. This patient population is of particular interest because, although they have never decompensated, they have an increased risk of portal hypertension and HCC, thus, it will be important to stratify the risk of presenting complications during follow up and, in patients who have treated the underlying cause of liver disease, to know which patients will have a better prognosis. The current thesis aims to study different uses of TE during follow up of patients with compensated advanced chronic liver disease (cACLD). The main objectives were to evaluate the capacity of TE for predicting liver-related events (varices needing treatment, decompensation or HCC) in cACLD patients and to provide simple rules to identify different risk groups of developing these complications. Three different studies were performed: in the first study, we evaluated the validity of new criteria based on TE and platelet count to identify a low risk group of having varices needing treatment; in the second study, we evaluated the dynamic changes of liver and spleen stiffness in patients treated with oral antivirals for chronic hepatitis C and, in the third study, we evaluated the incidence of liver-related events after a successful treatment with oral antivirals and we designed a simple tool to predict the risk of HCC. The conclusions of this thesis were: 1) TE combined with other laboratory parameters is useful to predict the risk of liver-related events in cACLD patients, 2) the new criteria (TE 110x109/L) can identify a low risk group of having varices needing treatment and save a high number of unneeded endoscopies, 3) during oral antiviral therapy, there is a rapid decrease in liver and spleen stiffness due to improvement in inflammation, 4) the incidence of liver-related events after achieving sustained virological response with oral antivirals in cACLD patients is very low, being HCC the most frequent event and, finally, 5) a simple nomogram based on TE and albumin levels at follow-up can help to determine the risk of presenting HCC during follow-up in hepatitis C cACLD patients treated with oral antivirals

Paper de l'elastografia hepàtica i esplènica en el diagnòstic, seguiment i tractament de la malaltia hepàtica crònica avançada compensada /

Departament responsable de la tesi: Departament de Medicina.En la malaltia hepàtica crònica es produeixen canvis en l'estructura del parènquima hepàtic que comporten l'aparició de fibrosi i, al llarg del temps, el desenvolupament d'una cirrosi hepàtica. Les principals complicacions de la cirrosi hepàtica són l'aparició d'hipertensió portal, la insuficiència hepàtica i l'augment de risc de presentar un carcinoma hepatocel·lular (CHC) o hepatocarcinoma. El tractament de la causa que ha generat la malaltia hepàtica pot canviar l'evolució natural millorant el pronòstic, sobretot si aquest es realitza en fases precoces. L'àmplia utilització de tècniques de diagnòstic no invasiu i, sobretot, de l'elastografia de transició (ET), ens ha permès diagnosticar a pacients amb malaltia hepàtica crònica avançada en fases més precoces. Aquests pacients, tot i no haver-se descompensat mai, tenen un risc augmentat de presentar hipertensió portal i CHC pel que serà important conèixer quins d'ells desenvoluparan complicacions al llarg del seguiment i, en el cas dels pacients que hagin rebut tractament de la causa subjacent, identificar quins tindran més probabilitats de millorar el pronòstic. La present tesi pretén estudiar diferents utilitats de l'ET durant el seguiment de pacients amb malaltia hepàtica crònica avançada compensada (MHCAc). Així doncs, els objectius de la tesi van ser avaluar la capacitat de l'ET per predir complicacions (varices d'alt risc, descompensacions o CHC) en pacients amb MHCAc i donar regles senzilles que permetin la identificació de grups de risc. Per a tal finalitat, es van dur a terme tres estudis independents on es va estudiar, respectivament, la utilitat d'uns nous criteris basats en l'elastografia hepàtica i la xifra de plaquetes que permetia identificar una població amb baix risc de presentar varices de risc, estudiar els canvis dinàmics que es produeixen en l'elastografia hepàtica i esplènica en els pacients tractats amb antivirals orals per l'hepatitis C i, finalment, es va estudiar la incidència de complicacions després d'un tractament eficaç amb antivirals orals per posteriorment dissenyar una eina simple per predir el risc de presentar CHC. Amb aquests estudis es va poder concloure que: 1) l'ET en combinació amb paràmetres analítics és útil per predir el risc de complicacions en la malaltia hepàtica crònica, 2) uns nous criteris (ET 110x109/L) permeten identificar una població amb baixa probabilitat de presentar varices de risc fet que permet estalviar un elevat número d'endoscòpies, 3) durant el tractament amb antivirals orals es produeix un ràpid descens de l'elastografia hepàtica i esplènica com a conseqüència de la milloria de la inflamació, 4) la incidència de complicacions posterior al tractament amb antivirals orals és baixa essent el CHC la més freqüent i, per últim, 5) un senzill nomograma basat en ET i nivells d'albúmina permet determinar el risc de CHC durant el seguiment de pacients amb MHCAc tractats amb antivirals orals.Regardless the underlying cause, in chronic liver disease there is a wound-healing process that produces fibrosis and, after a variable period of time, cirrhosis. The main complications of liver cirrhosis are portal hypertension, liver failure and hepatocellular carcinoma (HCC). Treating the underlying cause of liver disease can change the natural history improving prognosis especially in early stages. The extended use of non-invasive diagnostic methods, especially transient elastography (TE), have helped us to diagnose patients at early phase of advanced chronic liver disease. This patient population is of particular interest because, although they have never decompensated, they have an increased risk of portal hypertension and HCC, thus, it will be important to stratify the risk of presenting complications during follow up and, in patients who have treated the underlying cause of liver disease, to know which patients will have a better prognosis. The current thesis aims to study different uses of TE during follow up of patients with compensated advanced chronic liver disease (cACLD). The main objectives were to evaluate the capacity of TE for predicting liver-related events (varices needing treatment, decompensation or HCC) in cACLD patients and to provide simple rules to identify different risk groups of developing these complications. Three different studies were performed: in the first study, we evaluated the validity of new criteria based on TE and platelet count to identify a low risk group of having varices needing treatment; in the second study, we evaluated the dynamic changes of liver and spleen stiffness in patients treated with oral antivirals for chronic hepatitis C and, in the third study, we evaluated the incidence of liver-related events after a successful treatment with oral antivirals and we designed a simple tool to predict the risk of HCC. The conclusions of this thesis were: 1) TE combined with other laboratory parameters is useful to predict the risk of liver-related events in cACLD patients, 2) the new criteria (TE 110x109/L) can identify a low risk group of having varices needing treatment and save a high number of unneeded endoscopies, 3) during oral antiviral therapy, there is a rapid decrease in liver and spleen stiffness due to improvement in inflammation, 4) the incidence of liver-related events after achieving sustained virological response with oral antivirals in cACLD patients is very low, being HCC the most frequent event and, finally, 5) a simple nomogram based on TE and albumin levels at follow-up can help to determine the risk of presenting HCC during follow-up in hepatitis C cACLD patients treated with oral antivirals

Trends in Diagnosis of Alpha-1 Antitrypsin Deficiency Between 2015 and 2019 in a Reference Laboratory

Alpha-1 antitrypsin deficiency (AATD) remains largely underdiagnosed despite recommendations of healthcare institutions and programmes designed to increase awareness. The objective was to analyse the trends in AATD diagnosis during the last 5 years in a Spanish AATD reference laboratory. This was a retrospective revision of all alpha-1 antitrypsin (AAT) determinations undertaken in our laboratory from 2015 to 2019. We analysed the number of AAT determinations performed and described the characteristics of the individuals tested, as well as the medical specialties and the reasons for requesting AAT determination. A total of 3507 determinations were performed, of which 5.5% corresponded to children. A significant increase in the number of AAT determinations was observed from 349 in 2015 to 872 in 2019. Among the samples, 57.6% carried an intermediate AATD (50-119 mg/dL) and 2.4% severe deficiency (<50 mg/dL). The most frequent phenotype in severe AATD individuals was PI*ZZ (78.5%), and aminotransferase levels were above normal in around 43% of children and 30% of adults. Respiratory specialists requested the highest number of AAT determinations (31.5%) followed by digestive diseases and internal medicine (27.5%) and primary care physicians (19.7%). The main reason for AAT determination in severe AATD adults was chronic obstructive pulmonary disease (41.7%), but reasons for requesting AAT determination were not reported in up to 41.7% of adults and 58.3% of children. There is an increase in the frequency of AATD testing despite the rate of AAT determination remaining low. Awareness about AAT is probably increasing, but the reason for testing is not always clea

Utility of Transient Elastography for the Screening of Liver Disease in Patients with Alpha1-Antitrypsin Deficiency

Screening of liver disease in alpha-1 antitrypsin deficiency (AATD) is usually carried out with liver enzymes, with low sensitivity. We conducted a multicenter cross-sectional study aiming to describe the utility of transient elastography for the identification of liver disease in patients with AATD. A total of 148 AATD patients were included. Among these, 54.7% were Pi*ZZ and 45.3% were heterozygous for the Z allele. Between 4.9% and 16.5% of patients had abnormal liver enzymes, without differences among genotypes. Liver stiffness measurement (LSM) was significantly higher in Pi*ZZ individuals than in heterozygous Z (5.6 vs. 4.6 kPa; p = 0.001). In total, in 8 (5%) individuals LSM was >7.5 kPa, considered significant liver fibrosis, and ≥10 kPa in 3 (1.9%) all being Pi*ZZ. Elevated liver enzymes were more frequently observed in patients with LSM > 7.5 kPa, but in 5 out of 8 of these patients all liver enzymes were within normal range. In patients with AATD, the presence of abnormal liver enzymes is frequent; however, most of these patients do not present significant liver fibrosis. Transient elastography can help to identify patients with liver fibrosis even with normal liver enzymes and should be performed in all Z-allele carriers to screen for liver diseas