{"id":6513,"date":"2024-06-02T15:13:15","date_gmt":"2024-06-02T13:13:15","guid":{"rendered":"https:\/\/alpha1-deutschland.org\/?p=6513"},"modified":"2025-04-22T15:24:45","modified_gmt":"2025-04-22T13:24:45","slug":"dr-malin-fromme-alpha-1-antitrypsin-mangel-leberstress-und-lungenemphysem-verstehen","status":"publish","type":"post","link":"https:\/\/alpha1-deutschland.org\/en\/dr-malin-fromme-alpha-1-antitrypsin-mangel-leberstress-und-lungenemphysem-verstehen","title":{"rendered":"Dr. Malin Fromme: Alpha-1 Antitrypsin Deficiency: Understanding Liver Stress and Pulmonary Emphysema"},"content":{"rendered":"<div id=\"fws_6a8f287b3db0f\"  data-column-margin=\"default\" data-midnight=\"dark\"  class=\"wpb_row vc_row-fluid vc_row full-width-section\"  style=\"padding-top: 0px; padding-bottom: 50px; \"><div class=\"row-bg-wrap\" data-bg-animation=\"none\" data-bg-animation-delay=\"\" data-bg-overlay=\"false\"><div class=\"inner-wrap row-bg-layer\" ><div class=\"row-bg viewport-desktop\"  style=\"\"><\/div><\/div><\/div><div class=\"row_col_wrap_12 col span_12 dark left\">\n\t<div  class=\"vc_col-sm-12 wpb_column column_container vc_column_container col no-extra-padding inherit_tablet inherit_phone\"  data-padding-pos=\"all\" data-has-bg-color=\"false\" data-bg-color=\"\" data-bg-opacity=\"1\" data-animation=\"\" data-delay=\"0\" >\n\t\t<div class=\"vc_column-inner\" >\n\t\t\t<div class=\"wpb_wrapper\">\n\t\t\t\t<div class=\"vc_separator wpb_content_element vc_separator_align_center vc_sep_width_100 vc_sep_border_width_5 vc_sep_pos_align_center vc_sep_color_grey wpb_content_element vc_separator-has-text\" ><span class=\"vc_sep_holder vc_sep_holder_l\"><span class=\"vc_sep_line\"><\/span><\/span><h4>Author<\/h4><span class=\"vc_sep_holder vc_sep_holder_r\"><span class=\"vc_sep_line\"><\/span><\/span>\n<\/div>\n<div class=\"wpb_text_column wpb_content_element\" >\n\t<p style=\"font-weight: 400;\"><strong>Summary: Gabi Niethammer, as published in <a href=\"https:\/\/alpha1-deutschland.org\/en\/alpha1-journal\/\">Alpha1 Journal 1\/2024<\/a>.<\/strong><\/p>\n<\/div>\n\n\n\n<div class=\"divider-wrap\" data-alignment=\"default\"><div style=\"margin-top: 25px; height: 5px; margin-bottom: 25px;\" data-width=\"100%\" data-animate=\"\" data-animation-delay=\"\" data-color=\"default\" class=\"divider-border\"><\/div><\/div>\n<div class=\"wpb_text_column wpb_content_element\" >\n\t<p>It is known that the effects of alpha-1 antitrypsin deficiency (AATD) begin in the liver, where misfolded alpha-1 antitrypsin accumulates and cannot be completely eliminated. This causes stress, which can lead to liver remodeling and the deposition of connective tissue. Simultaneously, alpha-1 is lacking in the lungs, potentially leading to pulmonary emphysema.<\/p>\n<p>The more connective tissue accumulates in the liver, the more it scars and hardens. This leads to liver fibrosis. The end stage is liver cirrhosis. This remodeling impairs liver function and can lead to decompensation. Decompensation brings with it various complications such as impaired kidney function or altered mental status; advanced liver fibrosis also predisposes to tumor formation. This process usually takes several years; significant liver fibrosis does not typically develop quickly.<\/p>\n<p>The liver is an organ that doesn&#039;t give early warning signs. That&#039;s why regular checkups are so important. First, we have acute damage, which we can detect through blood tests. For chronic damage, there are several monitoring mechanisms:<\/p>\n<ul>\n<li>Liver biopsy as the gold standard, for use in cases of justified suspicion.<\/li>\n<li>MR elastography, a good tool for detection, but unfortunately not widely available.<\/li>\n<li>Fibroscan for the detection of early fibrosis and for assessing the extent of fibrosis<\/li>\n<li>Ultrasound for overall assessment of the liver and for the detection of cirrhosis<\/li>\n<li>Blood values from which specific scores can be calculated, such as the APRI value, which is composed of platelets and AST.<\/li>\n<\/ul>\n<p>The Alpha-1 Consortium, led by Prof. Pavel Strnad, was founded in 2015. At that time, the focus was primarily on the lungs as a damaged organ, while the liver received little attention. Together with Alpha1 Germany and the Alpha1 Centers, liver studies began; the first took place in hotel rooms during the Alpha1 Information Day in 2015.<\/p>\n<p>To date, ten medical doctoral theses and two habilitation theses have been submitted, and more than 2,000 subjects have been included in the long-term study.<\/p>\n<p>The most well-known genotypes are currently said to have the following frequencies in Europe: PiMM: 9:10 \/ PiMZ: 1:30 \/ PiSZ: 1:500 \/ PiZZ: 1:2,000, although in this presentation we will focus on the effects for the genotype PiZZ.<\/p>\n<\/div>\n\n\n\n\n\t\t\t<\/div> \n\t\t<\/div>\n\t<\/div> \n<\/div><\/div>\n\t\t<div id=\"fws_6a8f287b3f797\"  data-column-margin=\"default\" data-midnight=\"dark\"  class=\"wpb_row vc_row-fluid vc_row\"  style=\"padding-top: 50px; padding-bottom: 0px; \"><div class=\"row-bg-wrap\" data-bg-animation=\"none\" data-bg-animation-delay=\"\" data-bg-overlay=\"false\"><div class=\"inner-wrap row-bg-layer\" ><div class=\"row-bg viewport-desktop\"  style=\"\"><\/div><\/div><\/div><div class=\"row_col_wrap_12 col span_12 dark left\">\n\t<div  class=\"vc_col-sm-12 wpb_column column_container vc_column_container col no-extra-padding inherit_tablet inherit_phone\"  data-padding-pos=\"all\" data-has-bg-color=\"false\" data-bg-color=\"\" data-bg-opacity=\"1\" data-animation=\"\" data-delay=\"0\" >\n\t\t<div class=\"vc_column-inner\" >\n\t\t\t<div class=\"wpb_wrapper\">\n\t\t\t\t<div class=\"img-with-aniamtion-wrap\" data-max-width=\"100%\" data-max-width-mobile=\"default\" data-shadow=\"none\" data-animation=\"none\" >\n      <div class=\"inner\">\n        <div class=\"hover-wrap\"> \n          <div class=\"hover-wrap-inner\">\n            <img loading=\"lazy\" decoding=\"async\" class=\"img-with-animation skip-lazy\" data-delay=\"0\" height=\"689\" width=\"1570\" data-animation=\"none\" src=\"https:\/\/alpha1-deutschland.org\/wp-content\/uploads\/Informationsgrafik-Lebererkrankung.jpg\" alt=\"Informationsgrafik Lebererkrankung\" srcset=\"https:\/\/alpha1-deutschland.org\/wp-content\/uploads\/Informationsgrafik-Lebererkrankung.jpg 1570w, https:\/\/alpha1-deutschland.org\/wp-content\/uploads\/Informationsgrafik-Lebererkrankung-300x132.jpg 300w, https:\/\/alpha1-deutschland.org\/wp-content\/uploads\/Informationsgrafik-Lebererkrankung-1024x449.jpg 1024w, https:\/\/alpha1-deutschland.org\/wp-content\/uploads\/Informationsgrafik-Lebererkrankung-768x337.jpg 768w, https:\/\/alpha1-deutschland.org\/wp-content\/uploads\/Informationsgrafik-Lebererkrankung-1536x674.jpg 1536w\" sizes=\"auto, (max-width: 1570px) 100vw, 1570px\" \/>\n          <\/div>\n        <\/div>\n        \n      <\/div>\n    <\/div>\n\t\t\t<\/div> \n\t\t<\/div>\n\t<\/div> \n<\/div><\/div>\n\t\t<div id=\"fws_6a8f287b41899\"  data-column-margin=\"default\" data-midnight=\"dark\"  class=\"wpb_row vc_row-fluid vc_row\"  style=\"padding-top: 0px; padding-bottom: 0px; \"><div class=\"row-bg-wrap\" data-bg-animation=\"none\" data-bg-animation-delay=\"\" data-bg-overlay=\"false\"><div class=\"inner-wrap row-bg-layer\" ><div class=\"row-bg viewport-desktop\"  style=\"\"><\/div><\/div><\/div><div class=\"row_col_wrap_12 col span_12 dark left\">\n\t<div  class=\"vc_col-sm-12 wpb_column column_container vc_column_container col no-extra-padding inherit_tablet inherit_phone\"  data-padding-pos=\"all\" data-has-bg-color=\"false\" data-bg-color=\"\" data-bg-opacity=\"1\" data-animation=\"\" data-delay=\"0\" >\n\t\t<div class=\"vc_column-inner\" >\n\t\t\t<div class=\"wpb_wrapper\">\n\t\t\t\t\n<div class=\"wpb_text_column wpb_content_element\" >\n\t<p>Liver disease in individuals with ZZ syndrome follows a biphasic course. The first peak occurs in early childhood, when individuals with 2\u201310 ITP3T develop cholestatic liver disease, usually manifesting as elevated bilirubin levels, a palpable liver, and\/or prolonged jaundice. In almost all cases, liver function tests normalize during childhood and adolescence; only a very small percentage (0\u20132 ITP3T) experience serious complications.<\/p>\n<p>The second peak occurs in adulthood. Here, 20\u201335 individuals with PiZZ (%) show significant liver fibrosis, while only about 10 develop end-stage liver disease. It is very important to know that only 10\u201315 individuals with PiZZ have elevated liver enzymes! This means that elevated liver enzymes should also be investigated in individuals with ZZ (%), as high liver enzyme levels are not normal in this group either! We found that individuals with ZZ have a 20-fold increased risk of advanced liver fibrosis compared to patients without AATD (Adiposity Spectrum Disorder), while the risk is three times higher in individuals with SZ (%) and two times higher in individuals with MZ (%). To find out how individuals with PiZZ have fared since their enrollment in our study, we conducted numerous telephone interviews throughout Europe. Of 704 ZZ patients or relatives interviewed, 37 (5.3 %) had died in the meantime, 38 (5.4 %) had developed a liver complication and 37 (5.2 %) a lung complication in the course of three to five years.<\/p>\n<p>A good marker for predicting the likelihood of a liver complication is a high FibroScan score combined with a high APRI score. According to data from Aachen, a FibroScan score below 7.1 indicates no risk of developing a liver complication within three years.<\/p>\n<p>For the MZ genotype, it can be said that it does not cause liver disease on its own. With the aforementioned twofold increase in risk, it is more accurately described as a weakness than a disease. Only when a second risk factor (second hit), such as obesity or alcohol consumption, is present does the risk of actually developing liver disease increase. For example, there is a large study that shows that in MZ patients with heavy alcohol consumption, the risk of liver disease increased five to sixfold compared to consumers without alcohol use disorder.<\/p>\n<p>A slightly increased incidence of gallstones has also been observed in individuals with myeloproliferative disorder (MPD). New data suggests that the livers of MPD patients with cirrhosis decompensate more rapidly than cirrhotic livers of individuals without MPD. Therefore, it is recommended that MPD patients with cirrhosis consult a transplant center to obtain a thorough assessment of their individual health status.<\/p>\n<p>Thanks to hormone replacement therapy, there is now an effective treatment to better protect the lungs. Until now, there has been no medication option for the liver; recommendations focused on key preventative measures such as a healthy diet, sufficient exercise, and minimal alcohol consumption to avoid further risk factors for the liver.<\/p>\n<p>In recent years, various pharmaceutical companies have attempted to combat AATD-associated liver damage on three different levels. Protein production, and thus also alpha-1-antitrypsin production, begins with DNA, which is first transcribed into RNA. The RNA then serves as a template for protein synthesis.<\/p>\n<p>At the DNA and protein levels, pharmaceutical companies are still searching for effective therapeutic approaches; the most progress so far has been made at the RNA level. Here, AAT production can be inhibited by so-called siRNA, such as the drug fazirsiran.<\/p>\n<p>Fazirsiran leads to the degradation of RNA, resulting in less alpha-1 antitrypsin production and reducing liver stress caused by protein accumulation. In the phase 2 trial with 12 + 4 patients, participants received fazirsiran at varying doses and underwent liver biopsies after 24 and 48 weeks. The results were very encouraging, as the accumulation of alpha-1 antitrypsin in the liver decreased significantly, and liver function tests also improved. Simultaneously, FEV1 data remained stable despite the suppression of alpha-1 antitrypsin, which is crucial for lung function. The study has since been expanded to include a similar placebo-controlled trial, and the phase 2 data have already been published. Importantly, the intervention at the RNA level does not alter the genes themselves, and therefore the suppression is temporary.<\/p>\n<p>The Phase 3 trial began in Germany at the end of 2023; adult patients with PiZZ and F2 to F4 liver fibrosis are now being recruited for the study. Fazirsiran thus represents the first effective treatment option for AAT-associated liver disease.<\/p>\n<p>Despite these successes, 85\u201390% of PiZZ individuals still remain undiscovered. It is our collective responsibility to reduce this number, giving people with PiZZ the opportunity to make informed decisions and the best choices for their lives.<\/p>\n<\/div>\n\n\n\n\n\t\t\t<\/div> \n\t\t<\/div>\n\t<\/div> \n<\/div><\/div>\n\t\t<div id=\"fws_6a8f287b427dc\"  data-column-margin=\"default\" data-midnight=\"light\"  class=\"wpb_row vc_row-fluid vc_row has-row-bg-color  right_padding_30px left_padding_30px\"  style=\"padding-top: 30px; padding-bottom: 30px; --row-bg-color: #004267;\"><div class=\"row-bg-wrap\" data-bg-animation=\"none\" data-bg-animation-delay=\"\" data-bg-overlay=\"false\"><div class=\"inner-wrap row-bg-layer\" ><div class=\"row-bg viewport-desktop using-bg-color\"  style=\"background-color: #004267; \"><\/div><\/div><\/div><div class=\"row_col_wrap_12 col span_12 light left\">\n\t<div  class=\"vc_col-sm-12 wpb_column column_container vc_column_container col no-extra-padding inherit_tablet inherit_phone\"  data-padding-pos=\"all\" data-has-bg-color=\"false\" data-bg-color=\"\" data-bg-opacity=\"1\" data-animation=\"\" data-delay=\"0\" >\n\t\t<div class=\"vc_column-inner\" >\n\t\t\t<div class=\"wpb_wrapper\">\n\t\t\t\t\n<div class=\"wpb_text_column wpb_content_element\" >\n\t<h2>Assessment of your liver health using Fibroscan and APRI<\/h2>\n<p>In collaboration with Prof. Pavel Strnad and his team at the University Hospital Aachen, we can offer you an initial assessment including advice on liver health. <a href=\"\/en\/alpha-1-und-die-leber\/\">Learn more and take action now!<\/a><\/p>\n<\/div>\n\n\n\n\n\t\t\t<\/div> \n\t\t<\/div>\n\t<\/div> \n<\/div><\/div>","protected":false},"excerpt":{"rendered":"Author Summary: Gabi Niethammer, as published in Alpha1-Journal 1\/2024. It is known that the effects of alpha-1 antitrypsin deficiency (AATD) begin in the liver, because this is where misfolded alpha-1 antitrypsin accumulates...","protected":false},"author":1,"featured_media":6515,"comment_status":"closed","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[1,39,24],"tags":[],"class_list":["post-6513","post","type-post","status-publish","format-standard","has-post-thumbnail","category-allgemein","category-alpha-1-leber","category-alpha1-journal"],"yoast_head":"<!-- This site is optimized with the Yoast SEO plugin v28.3 - https:\/\/yoast.com\/product\/yoast-seo-wordpress\/ -->\n<title>Alpha-1-Mangel: Leber und Lunge im Fokus<\/title>\n<meta name=\"description\" content=\"Wie Alpha-1-Antitrypsin-Mangel Leber und Lunge belastet \u2013 aktuelle Forschung, Therapieans\u00e4tze und Handlungsempfehlungen f\u00fcr Betroffene.\" \/>\n<meta name=\"robots\" content=\"index, follow, max-snippet:-1, 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