BACKGROUND & AIMS: Homozygous Pi∗Z mutation in alpha-1 antitrypsin (Pi∗ZZ genotype) predisposes to pulmonary loss-of-function and hepatic gain-of-function injury. To facilitate selection into clinical trials typically targeting only 1 organ, we systematically evaluated an international, multicenter, longitudinal, Pi∗ZZ cohort to uncover natural disease course and surrogates for future liver- and lung-related endpoints. METHODS: Cohort 1 recruited 737 Pi∗ZZ individuals from 25 different centers without known liver comorbidities who received a baseline clinical and laboratory assessment as well as liver stiffness measurement (LSM). A follow-up interview was performed after at least 6 months. Cohort 2 consisted of 135 Pi∗ZZ subjects without significant liver fibrosis, who received a standardized baseline and follow-up examination at least 2 years later, both including LSM. RESULTS: During 2634 patient-years of follow-up, 39 individuals died, with liver and lung being responsible for 46% and 36% of deaths, respectively. Forty-one Pi∗ZZ subjects who developed a hepatic endpoint presented with significantly higher baseline liver fibrosis surrogates, that is, LSM (24 vs 5 kPa, P < .001) and aspartate aminotransferase-to-platelet ratio index (1.1 vs 0.3 units, P < .001). Liver-related endpoints within 5 years were most accurately predicted by LSM (area under the curve 0.95) followed by aspartate aminotransferase-to-platelet ratio index (0.92). Baseline lung parameters displayed only a moderate predictive utility for lung-related endpoints within 5 years (forced expiratory volume in the first second area under the curve 0.76). Fibrosis progression in those with no/mild fibrosis at baseline was rare and primarily seen in those with preexisting risk factors. CONCLUSIONS: Noninvasive liver fibrosis surrogates accurately stratify liver-related risks in Pi∗ZZ individuals. Our findings have direct implications for routine care and future clinical trials of Pi∗ZZ patients.
- MeSH
- alfa-1-antitrypsin * genetika krev MeSH
- biologické markery krev MeSH
- časové faktory MeSH
- deficit alfa1-antitrypsinu * genetika diagnóza komplikace MeSH
- dospělí MeSH
- elastografie MeSH
- genotyp MeSH
- homozygot MeSH
- jaterní cirhóza * genetika diagnóza MeSH
- lidé středního věku MeSH
- lidé MeSH
- longitudinální studie MeSH
- mutace MeSH
- plíce patofyziologie patologie diagnostické zobrazování MeSH
- plicní nemoci genetika etiologie diagnóza MeSH
- progrese nemoci * MeSH
- rizikové faktory MeSH
- stupeň závažnosti nemoci MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- multicentrická studie MeSH
Primární biliární cholangitida (PBC) je chronické, imunologicky podmíněné jaterní onemocnění, které ve svém dlouhodobém průběhu vede k destrukci malých žlučovodů, cholestáze, fibróze a cirhóze jater s jaterním selháním. PBC postihuje ve více než 90 % ženy středního věku, většina pacientů je nyní diagnostikována v asymptomatickém stadiu. Diagnóza onemocnění je obvykle stanovena na základě kombinace laboratorních vyšetření, elevace sérové ALP nad 1,5násobek normy trvající déle než 6 měsíců a přítomnosti AMA protilátek v titru 1: 40 nebo vyšším. Typický histologický nález potvrzuje diagnózu, stadium jaterního onemocnění je však nyní možné určit i pomocí neinvazivních metod. Kyselina ursodeoxycholová je v současné době léčbou první volby, v případě intolerance nebo nedostatečné odpovědi na léčbu je možné zahájit léčbu elafibranorem, duálním agonistou PPAR a/d. Transplantace jater je indikována u pacientů s PBC, kteří dospěli do stadia jaterního selhání i přes podávanou medikamentózní léčbu.
Primary biliary cholangitis (PBC) is a chronic, autoimmune disorder of the liver. In its long-term course, it leads to small bile ducts destruction, cholestasis, liver fibrosis, cirrhosis and chronic liver failure. PBC is much common in women, especially of middle age. Most patients are diagnosed in an asymptomatic stage. The diagnosis is based on the combination of laboratory assessments, alkaline phosphatase elevation of more than 1,5 ULN for more than 6 months, and AMA antibodies in a titre 1: 40 or higher. The typical histological finding confirms the diagnosis, but the stage of liver disease may be determined based on the non-invasive liver stiffness measurement. Ursodeoxycholic acid represents nowadays standard-of-care in PBC patients, followed by elafibranor in intolerant patients or in non-responders. Liver transplantation is indicated in those with liver failure in whom conservative therapy failed.
- Klíčová slova
- Elafibranor,
- MeSH
- biliární cirhóza * diagnóza etiologie farmakoterapie MeSH
- chalkonoidy farmakologie terapeutické užití MeSH
- kyselina ursodeoxycholová farmakologie terapeutické užití MeSH
- lidé MeSH
- PPAR alfa farmakologie terapeutické užití MeSH
- PPAR delta farmakologie terapeutické užití MeSH
- propionáty farmakologie terapeutické užití MeSH
- transplantace jater MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- přehledy MeSH
Protein misfolding diseases, including α1-antitrypsin deficiency (AATD), pose substantial health challenges, with their cellular progression still poorly understood1-3. We use spatial proteomics by mass spectrometry and machine learning to map AATD in human liver tissue. Combining Deep Visual Proteomics (DVP) with single-cell analysis4,5, we probe intact patient biopsies to resolve molecular events during hepatocyte stress in pseudotime across fibrosis stages. We achieve proteome depth of up to 4,300 proteins from one-third of a single cell in formalin-fixed, paraffin-embedded tissue. This dataset reveals a potentially clinically actionable peroxisomal upregulation that precedes the canonical unfolded protein response. Our single-cell proteomics data show α1-antitrypsin accumulation is largely cell-intrinsic, with minimal stress propagation between hepatocytes. We integrated proteomic data with artificial intelligence-guided image-based phenotyping across several disease stages, revealing a late-stage hepatocyte phenotype characterized by globular protein aggregates and distinct proteomic signatures, notably including elevated TNFSF10 (also known as TRAIL) amounts. This phenotype may represent a critical disease progression stage. Our study offers new insights into AATD pathogenesis and introduces a powerful methodology for high-resolution, in situ proteomic analysis of complex tissues. This approach holds potential to unravel molecular mechanisms in various protein misfolding disorders, setting a new standard for understanding disease progression at the single-cell level in human tissue.
- MeSH
- alfa-1-antitrypsin metabolismus MeSH
- analýza jednotlivých buněk MeSH
- deficit alfa1-antitrypsinu * patologie metabolismus genetika MeSH
- fenotyp MeSH
- hepatocyty metabolismus patologie MeSH
- jaterní cirhóza patologie metabolismus MeSH
- játra patologie metabolismus MeSH
- lidé MeSH
- progrese nemoci MeSH
- proteom * analýza metabolismus MeSH
- proteomika * metody MeSH
- signální dráha UPR MeSH
- strojové učení MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
BACKGROUND & AIMS: Alpha-1 antitrypsin deficiency (AATD) causes/predisposes to advanced chronic liver disease. However, the role of the SERPINA1 Pi∗ZZ genotype in patients with decompensated cirrhosis is unclear. Thus, we evaluated the impact of the Pi∗ZZ genotype on the disease course after the first hepatic decompensation event. METHODS: We retrospectively included 59 adults with decompensated cirrhosis and severe AATD (Pi∗ZZ) from 12 European tertiary care centres. First decompensation was considered as baseline. To compare the course of AATD to other cirrhosis aetiologies, we applied propensity score matching for Child-Turcotte-Pugh (CTP) score as well as age/sex. Patients were followed until further decompensation, liver transplantation or liver-related death. RESULTS: Most patients were male (74.6%), with a mean age of 55 years. The most common type of first decompensation was ascites (n = 40; 67.8%), followed by variceal bleeding (n = 13; 22.0%) and overt hepatic encephalopathy (n = 6; 10.2%). Median CTP and MELD (model for end-stage liver disease) scores at first decompensation were 8 and 14, respectively. Median MELD scores were 16 and 20 points at listing and liver transplantation (median time on list: 2.9 [IQR 1.1-7.2] months), respectively. Patients with other aetiologies (subdistribution hazard ratio: steatotic liver disease: 0.62, 95% CI 0.44-0.88, p = 0.007; abstinent alcohol-associated liver disease: 0.50, 95% CI 0.35-0.71, p <0.001; hepatitis C virus-associated cirrhosis: 0.56, 95% CI 0.37-0.83, p = 0.004) had a significantly lower risk of further hepatic decompensation, liver transplantation, or liver-related death, compared to those with Pi∗ZZ. Exchanging further decompensation with acute-on-chronic liver failure yielded similar results. CONCLUSION: Our study defines the course of decompensated cirrhosis in patients with severe AATD (Pi∗ZZ), who are particularly prone to complications of cirrhosis and exhibit a more progressive disease course than those with cirrhosis of other aetiologies. IMPACT AND IMPLICATIONS: Alpha-1 antitrypsin deficiency is an inherited disease that affects the lung and the liver. Carrying two severely dysfunctional copies of the alpha-1 antitrypsin gene may cause advanced chronic liver disease/cirrhosis. Affected individuals with a first complication of cirrhosis are more prone to developing further liver-related events (including multiorgan dysfunction) and requiring liver transplantation (which cures the inherited liver disease) compared to patients who have similarly advanced liver disease. These findings should prompt the development of disease-modifying treatments and early listing for liver transplantation.
- Publikační typ
- časopisecké články MeSH
The increasing occurrence of multiple primary cancers (MPC) is a long-term trend, but the prevalence of MPC in patients with hepatocellular carcinoma (HCC) and its impact on overall survival (OS) remains unknown. We retrospectively analyzed 497 patients with HCC treated at two tertiary centers. The cohort was divided into two subgroups - liver transplant (LT, 324 patients) and non-liver transplant (non-LT, 173 patients). We analyzed MPC occurrence, its impact on survival, and identified variables predicting unfavorable outcomes. The MPC were detected in 88 patients (18%). The most common MPC were prostate (17%), skin (15.9%), kidney (12.5%), and lung (10.2%). The median OS of the whole cohort and the LT and non-LT subgroups were 70, 116, and 17 months, respectively (p<0.0001). The median OS in patients with HCC only and HCC with another cancer was 77 (95% CI, 67-96) and 50 months (95% CI, 37-62), respectively (p=0.25). The OS of LT patients was significantly better than that of those in whom LT had been contraindicated owing to concomitant MPC (116 vs. 35 months, p<0.0009). Autoimmune etiology, non-alcoholic steatohepatitis (NASH), HCC as the first diagnosed malignancy, and male sex were identified as factors significantly influencing the patients' outcomes (HR 0.43, 3.2326, 0.70, and 1.43, respectively). The MPC frequency was 18%. The impact of MPC on OS was not significant, except for individuals contraindicated for LT because of MPC. A better prognosis is associated with the autoimmune etiology of cirrhosis, and when HCC is diagnosed as the first malignancy. Male sex and NASH worsened the outcomes.
- MeSH
- dospělí MeSH
- hepatocelulární karcinom * mortalita patologie MeSH
- lidé středního věku MeSH
- lidé MeSH
- mnohočetné primární nádory * mortalita patologie MeSH
- nádory jater * mortalita patologie MeSH
- prognóza MeSH
- retrospektivní studie MeSH
- senioři MeSH
- transplantace jater * mortalita MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
BACKGROUND & AIMS: α1-Antitrypsin (AAT) is a major protease inhibitor produced by hepatocytes. The most relevant AAT mutation giving rise to AAT deficiency (AATD), the 'Pi∗Z' variant, causes harmful AAT protein accumulation in the liver, shortage of AAT in the systemic circulation, and thereby predisposes to liver and lung injury. Although intravenous AAT augmentation constitutes an established treatment of AATD-associated lung disease, its impact on the liver is unknown. METHODS: Liver-related parameters were assessed in a multinational cohort of 760 adults with severe AATD (Pi∗ZZ genotype) and available liver phenotyping, of whom 344 received augmentation therapy and 416 did not. Liver fibrosis was evaluated noninvasively via the serum test AST-to-platelet ratio index and via transient elastography-based liver stiffness measurement. Histologic parameters were compared in 15 Pi∗ZZ adults with and 35 without augmentation. RESULTS: Compared with nonaugmented subjects, augmented Pi∗ZZ individuals displayed lower serum liver enzyme levels (AST 71% vs 75% upper limit of normal, P < .001; bilirubin 49% vs 58% upper limit of normal, P = .019) and lower surrogate markers of fibrosis (AST-to-platelet ratio index 0.34 vs 0.38, P < .001; liver stiffness measurement 6.5 vs 7.2 kPa, P = .005). Among biopsied participants, augmented individuals had less pronounced liver fibrosis and less inflammatory foci but no differences in AAT accumulation were noted. CONCLUSIONS: The first evaluation of AAT augmentation on the Pi∗ZZ-related liver disease indicates liver safety of a widely used treatment for AATD-associated lung disease. Prospective studies are needed to confirm the beneficial effects and to demonstrate the potential efficacy of exogenous AAT in patients with Pi∗ZZ-associated liver disease.
- MeSH
- deficit alfa1-antitrypsinu * komplikace farmakoterapie MeSH
- dospělí MeSH
- fenotyp MeSH
- genotyp MeSH
- jaterní cirhóza etiologie MeSH
- lidé MeSH
- Check Tag
- dospělí MeSH
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
BACKGROUND AND AIMS: Alpha-1 antitrypsin deficiency is an inherited disorder caused by alpha-1 antitrypsin (AAT) mutations. We analysed the association between alcohol intake and liver-related parameters in individuals with the heterozygous/homozygous Pi*Z AAT variant (Pi*MZ/Pi*ZZ genotype) found in the United Kingdom Biobank and the European Alpha1 liver consortium. METHODS: Reported alcohol consumption was evaluated in two cohorts: (i) the community-based United Kingdom Biobank (17 145 Pi*MZ, 141 Pi*ZZ subjects, and 425 002 non-carriers [Pi*MM]); and (ii) the European Alpha1 liver consortium (561 Pi*ZZ individuals). Cohort (ii) included measurements of carbohydrate-deficient transferrin (CDT). RESULTS: In both cohorts, no/low alcohol intake was reported by >80% of individuals, while harmful consumption was rare (~1%). Among Pi*MM and Pi*MZ individuals from cohort (i), moderate alcohol consumption resulted in a <30% increased rate of elevated transaminases and ~50% increase in elevated gamma-glutamyl transferase values, while harmful alcohol intake led to an at least twofold increase in the abnormal levels. In Pi*ZZ individuals from both cohorts, moderate alcohol consumption had no marked impact on serum transaminase levels. Among Pi*ZZ subjects from cohort (ii) who reported no/low alcohol consumption, those with increased CDT levels more often had signs of advanced liver disease. CONCLUSIONS: Pi*MZ/Pi*ZZ genotype does not seem to markedly aggravate the hepatic toxicity of moderate alcohol consumption. CDT values might be helpful to detect alcohol consumption in those with advanced fibrosis. More data are needed to evaluate the impact of harmful alcohol consumption.
- MeSH
- alfa-1-antitrypsin * genetika krev MeSH
- deficit alfa1-antitrypsinu * genetika krev diagnóza komplikace MeSH
- dospělí MeSH
- fenotyp * MeSH
- gama-glutamyltransferasa krev MeSH
- genotyp MeSH
- játra patologie MeSH
- kohortové studie MeSH
- lidé středního věku MeSH
- lidé MeSH
- pití alkoholu * škodlivé účinky MeSH
- senioři MeSH
- transferin * analýza metabolismus analogy a deriváty MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- Geografické názvy
- Evropa MeSH
- Spojené království MeSH
Deficit alfa-1-antitrypsinu (AATD) je jedním z nejčastějších genetických onemocnění. Většina osob nese dvě kopie divoké alely M genu SERPINA1, který kóduje alfa-1-antitrypsin (AAT), a má normální AAT v krvi. Devadesát pět procent případů těžkého deficitu AAT je důsledkem homozygotní záměny Glu342Lys (alela Z), která je přítomna u 1 z 25 osob evropského původu. Mírný nedostatek AAT je obvykle důsledkem mutace Glu264Val (alela S). AAT je syntetizován v játrech a vylučován do krve, kde je jeho hlavní úlohou chránit plicní tkáň před působením neutrofilní elastázy. Bodové mutace mohou vést k precipitaci AAT v játrech, což vede k jaterní fibróze a cirhóze vlivem proteotoxického stresu („gain of function“). Naopak nedostatek cirkulujícího AAT predisponuje homozygoty s těžkým deficitem k časnému vzniku plicního emfyzému („loss of function“). Článek podává přehled současných poznatků o patofyziologii deficitu AAT, možnostech jeho diagnostiky a diskutuje možnosti léčby plicního onemocnění i nové možnosti léčby jaterního onemocnění.
Alpha-1-antitrypsin (AAT) deficiency (AATD) is one of the most common genetic disorders. Most people carry two copies of the wild-type M allele of the SERPINA1 gene, which encodes AAT, and have normal blood concentrations of AAT. Ninety-five percent of cases of severe AAT deficiency result from the homozygous Glu342Lys substitution (Z allele), which is present in 1 in 25 persons of European descent. Mild AAT deficiency is usually due to the Glu264Val mutation (S allele). AAT is synthesized in the liver and secreted into the blood. Its primary role is to protect lung tissue from neutrophil elastase attack. Point mutations can lead to the retention of AAT in the liver, leading to liver fibrosis and cirrhosis due to proteotoxic stress ("gain of function"), whereas the lack of circulating AAT predisposes homozygotes with severe deficiency to early onset of pulmonary emphysema ("loss of function"). This article reviews current knowledge of the pathophysiology of AAT deficiency, and its diagnostic options and discusses treatment options for pulmonary and novel treatment strategies in liver disease.
Jaterní selhání při cirhóze i hepatocelulární karcinom (HCC) při HCV infekci představují v západních zemích stále jednu z hlavních indikací k transplantaci jater (LTx). U pacientů s kompenzovanou jaterní cirhózou C má být protivirová léčba zahájena neprodleně, neboť komplikace, tedy dekompenzace onemocnění i HCC, se mohou objevit v krátkém časovém horizontu. Úspěšná protivirová léčba HCV u pacientů s cirhózou snižuje riziko dekompenzace, HCC i riziko úmrtí na selhání jater, a snižuje tak potřebu LTx u těchto pacientů. Léčba u pacienta s dekompenzovanou jaterní cirhózou před LTx má za cíl nejen prevenci rekurence HCV v jaterním štěpu, ale též zlepšení jaterní funkce. U pacientů zařazených do čekací listiny může zlepšení jaterní funkce vést až k vyřazení z čekací listiny. LTx má být zvážena u všech pacientů s chronickým selháním jater při HCV, u nichž předpokládáme po LTx prodloužení života ve srovnání s přirozených průběhem jejich jaterního onemocnění, nebo u nich LTx významně zlepší kvalitu života. LTx má být zvažována v okamžiku, kdy je předpokládaná doba dožití z důvodu jaterního onemocnění jeden rok nebo méně. Před LTx má být pacient podrobně vyšetřen za účelem vyloučení komorbidit, které by LTx zásadně komplikovaly či znemožnily. Zavedení přímo působících antivirotik do léčebných režimů HCV představuje revoluční krok k zabránění rekurence HCV ve štěpu, ať již eradikací HCV ještě před LTx, nebo časnou léčbou po ní. V současné době již rekurence HCV ve štěpu jater nevede k horšímu přežití nemocných transplantovaných pro HCV, výsledky jsou zcela srovnatelné s výsledky LTx pro ostatní diagnózy.
Liver failure due to cirrhosis and hepatocellular carcinoma (HCC) in hepatitis C (HCV) infection is still one of the main indications for liver transplantation (LTx) in Western countries. In patients with compensated liver cirrhosis C, antiviral therapy should be initiated promptly, as complications, i.e. decompensation of the disease and HCC, can occur in a short time frame. Successful antiviral treatment of HCV in patients with cirrhosis reduces the risk of decompensation, HCC, and death from liver failure, thus reducing the need for LTx in these patients. Treatment in a patient with decompensated liver cirrhosis before LTx aims not only to prevent HCV recurrence in the liver graft but also to improve liver function. In patients on the waiting list, improvement of liver function may lead to removal from the waiting list. LTx should be considered in all patients with chronic liver failure due to HCV in whom we expect prolongation of life expectancy after LTx compared to the natural course of their liver disease or for whom LTx will significantly improve the quality of life. LTx should be considered when life expectancy due to liver disease is one year or less. Before LTx, the patient should be thoroughly examined to exclude comorbidities that substantially complicate or preclude LTx. The advent of direct-acting antivirals into HCV treatment regimens represents a revolutionary step to prevent HCV recurrence in the graft, is either by eradicating HCV before LTx or by early treatment after LTx. Currently, HCV recurrence in the liver graft either by eradicating HCV before LTx or by early treatment after LTx. Currently, HCV recurrence in the liver graft no longer leads to worse survival in patients transplanted for HCV, and outcomes are fully comparable to those of LTx for other diagnoses.
Cholestatická onemocnění jater se vyznačují progresivní povahou a omezenými možnostmi konzervativní léčby. Jedinou efektivní metodou léčby terminálního stadia je transplantace jater, která signifikantně prodlužuje dobu přežití pacientů. Transplantace jater je v současnosti indikována nejen u pacientů s chronickým jaterním selháním nebo hepatobiliární malignitou, ale také u pacientů se sníženou kvalitou života při symptomech z obstrukce žlučovodů. Péče po transplantaci jater je specifická zejména z důvodu přítomnosti imunitně asociovaných onemocnění, např. idiopatických střevních zánětů u pacientů s primární sklerozující cholangitidou. Rekurence základního onemocnění v jaterním štěpu je častou dlouhodobou komplikací, která může negativně ovlivnit přežití štěpu i celkovou délku života. Navzdory riziku rekurence jsou dlouhodobé výsledky transplantace jater pro cholestatické nemoci výborné, přičemž pacienti s těmito diagnózami dosahují delšího přežití ve srovnání s ostatními transplantovanými pacienty.
Cholestatic liver diseases are characterized by their progressive nature and limited conservative treatment options. Liver transplantation is the only effective method of treatment for the terminal stage. Before the era of liver transplantation, patients with cholestatic disease had a significantly reduced life expectancy. Liver transplantation is now indicated not only for patients with chronic liver failure or hepatobiliary malignancy, but also for those with reduced quality of life from cholestatic symptoms. Post-transplant care is particularly specific because of the presence of immune-associated diseases, such as inflammatory bowel disease in patients with primary sclerosing cholangitis. Recurrence of the underlying disease in the liver graft is a common long-term complication that can negatively affect graft survival and overall life expectancy. Despite the risk of recurrence, the long-term outcomes of liver transplantation for cholestatic disease are excellent, achieving longer survival compared to other transplant recipients.
- Klíčová slova
- indikace k transplantaci,
- MeSH
- cholangitida * komplikace patologie terapie MeSH
- idiopatické střevní záněty komplikace terapie MeSH
- lidé MeSH
- sklerozující cholangitida komplikace patologie terapie MeSH
- transplantace jater * MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- přehledy MeSH
