ALPHA-1 ANTITRYPSIN RESEARCH

CT lung densitometry in young adults with alpha-1-antitrypsin deficiency

2011-05-09T13:55:00.001-07:00

Background
Severe (PiZZ) and moderate (PiSZ) alpha-1-antitrypsin (AAT) deficiency predispose to lung emphysema, especially in smokers. We hypothesized that multi-slice computed tomography (CT) might be superior to pulmonary function tests (PFT) to detect lung emphysema in AAT-deficient individuals at the age of 32 years.

Methods
A subgroup of PiZZ and PiSZ individuals identified during the Swedish newborn screening programme in 1972–74 underwent multi-slice CT and PFT at the age of 32 years. From the CT scans the percentile density at 15% (PD15) and the relative area below –910 Hounsfield Units (RA−910 HU) were calculated. The results of PFT and CT were compared between the AAT-deficient individuals and an age-matched control group.

Results
Twenty-five PiZZ, 11 PiSZ and 17 PiMM individuals participated in the study. All Pi subgroups had normal lung function. The mean PD15 was 81 (SD 22) g/L in the PiZZ individuals, 96 (SD 35) g/L in the PiSZ individuals and 79 (SD 17) g/L in the PiMM individuals (ns), and the RA-910 were 30 (SD 18)%, 24 (SD 20)%, and 32 (SD 18)%, respectively (ns). For the never-smoker subgroups, in the PiZZ (n = 23), PiSZ (n = 8) and PiMM (n = 12), the mean PD15 were 95 (SD 35) g/L, 81 (SD 22) g/L, and 75 (SD 12) g/L, respectively (ns). PD15 was significantly correlated to CT derived lung size (r = −0.72; p < 0.001).

Conclusions
CT densitometry revealed no signs of emphysema and no differences between the AAT-deficient individuals identified by neonatal screening and age-matched control subjects.

Respiratory Medicine
Volume 105, Issue 1, January 2011, Pages 74-79

Make-A-Wish grants 5-year-old's dream

2010-11-15T12:02:00.000-08:00

By Deneesha Edwards
The Dispatch

Who ever thought wishes did not come true, doesn't know 5-year-old Walker Fritts.

Walker, whose family lives in Reeds, was granted a wish to go to Walt Disney World to see his biggest inspiration — Mickey Mouse.

The Make-A-Wish Foundation announced Wednesday at a private party at Pizza Hut that Walker and his family — his parents, Marshana and Alan Fritts, his older brother Carson, 14, and younger sister Malan, 3 — will get the chance to visit the “happiest place on earth” in Florida.

“It's very overwhelming,” said Walker's mother, Marshana Fritts. “We're very lucky to have Walker and we're very lucky Make-A-Wish Foundation is going to send us on the trip. There's other kids that deserve this too.”

Make-A-Wish starting granting wishes of children with life-threatening medical conditions in 1980. The organization grants the wishes of children to enrich the human experience with hope, strength and joy.

“This is a send-away party,” said Mary Finch, one of the foundation's grant wishers for the area. “Walker wants to see Mickey, so we're making this happen for him. We're just trying to create a happy moment. Everybody here has been instrumental in Walker's life.”

Walker is a special needs boy that was born with a genetic liver disease called Alpha 1-Antitrypsin Deficiency. Walker, who also has Down syndrome, was born five weeks premature,

Fritts said Walker has eaten with a feeding tube for most of his life, however he can eat small food items like pizza and macaroni and cheese.

Fritts said there is no cure for the disease and Walker has been on the waiting list for getting a liver transplant since he was born. She calls him a “Brenner (Children's Hospital, in Winston-Salem) baby” because he's been in and out of the hospital throughout his life.

“It's an emotional roller coaster,” she said. “We have literally stood over his bed thinking this is his last breath. There are great days. The good days are really good. The bad days are really bad. He's happy, we know his life is going to be short.”

The family arrived with his family to the restaurant in a white limousine. Close family friends, church members, teachers and administrators from Reeds Elementary School cheered the family as they arrived to the restaurant. Walker is in the special needs pre-kindergarten program at Reeds.

“There's so many people that have helped with Walker,” Marshana Fritts said. “The Make-A-Wish Foundation does so much. There are so many kids that don't know if they'll be here for Christmas. Make-A-Wish is just a good organization.”

Mickey Mouse balloons and Make-A-Wish Foundation banners were decorated in a banquet room at Pizza Hut. There was pizza, face painting, a cake from Fancy Pastry Shop and, of course, a guest appearance from Mickey.

“We can't do this without people like Pizza Hut, they went above and beyond,” said Karen Dunlap, another wish granter for the area with the foundation. “Thank you to Pizza Hut, Fancy Pastry, At the Ritz Costume and Fantasy Limousine. We don't have a budget. We have to do it with people who are willing to help us.”

Dunlap said being a part of the foundation is a life-changing experience and the foundation is an awesome organization.

“Families go through a lot,” she said. “Just for one day or a week, we try to take all the pain away and make everyone smile and laugh.”

Lynn Conyers, the area general manager for NPC International Pizza Hut, presented the family with another surprise — free pizza for a year.

“We're honored to do this,” he said. “What a great cause and a great deal for the Make-A-Wish Foundation. It's just a honor for us to be able to do this. Walker is such a special kid. The local Pizza Hut manager, Marcia Chatin, and her staff did all the hard work today. It's been a labor of love.”

Walker's mother said her son thinks he gets to go to see Mickey Mouse because he's able to eat without the feeding tube. He has many of Mickey Mouse's toys, clothes and shoes. Marshana Fritts said Walker wasn't able to walk until he was 4, and placing Mickey Mouse stickers on his walker encouraged him.

The family will stay at the “Give Kids the World Village” for a week. They also will have tickets to Disney World, Universal Studios and Sea World. A late breakfast was arranged for Walker to have with Mickey Mouse.

“I'm speechless,” said Judy Wood, Walker's grandmother. “This is more than magical. I can't even describe what it's been like for the family up until this point. This has been a joy for them.”

Alpha-1 Antitrypsin Deficiency Genetic Testing

2010-09-15T12:43:00.000-07:00

What Is Alpha-1 Antitrypsin Deficiency?
Alpha-1 antitrypsin (AAT) is a protein normally found in the lungs and the bloodstream. It helps protect the lungs from diseases such as emphysema and chronic obstructive pulmonary disease (COPD). Some people do not make enough of this protein or they make an abnormal type of AAT, either of which can cause AAT deficiency. These people are more likely to have lung diseases and will get them at a younger-than-normal age (30 to 40 years old). Some types of abnormal AAT can also damage the liver. AAT deficiency is a rare disorder and is the only known genetic (inherited) factor that increases your chances for having lung diseases.

Alpha-1 antitrypsin deficiency is caused by a change, or mutation, in the gene that tells the body how to make alpha-1 antitrypsin. There are many kinds of possible changes in this gene, but only a few cause problems. To have this condition, you have to get the changed gene from both parents.

If you receive only one changed gene, you do not have the disease but are a carrier. The good copy of the gene you received from your other parent is enough to tell your body how to properly make alpha-1 antitrypsin. Some people who carry the changed gene may have very mild symptoms of the deficiency.

Treatment for alpha-1 antitrypsin deficiency mainly involves avoiding substances—especially cigarette smoke—that could harm your lungs. Also try to avoid dust and workplace chemicals. You also may want to avoid alcohol because of the risk of liver damage. Exercise can improve your stamina and overall health.

The only treatment available for the lack of the protein is plasma containing alpha-1 antitrypsin. This is usually given only to people who have very low levels of AAT in their blood. It is not clear that this treatment is any better than avoiding smoke and other lung-damaging chemicals. The plasma is made from the blood of many donors and is treated to reduce the chance of spreading an infectious disease. You receive the plasma through an IV, usually every 3 to 4 weeks for life.

What Is AAT Deficiency Testing?
A blood test can measure the amount of alpha-1 antitrypsin (AAT) in your blood. You may have AAT deficiency if your levels are low or if the blood test is not able to find any AAT in your blood. If your AAT level is lower than normal, the blood sample can be tested to look for abnormal types of alpha-1 antitrypsin. People who carry the changed gene may be more at risk for symptoms if they have certain types of alpha-1 antitrypsin.

The Role of Liver Sinusoidal Cells in Hepatocyte-Directed Gene Transfer

2010-01-28T10:42:00.000-08:00

Frank Jacobs*, Eddie Wisse and Bart De Geest*
From the Center for Molecular and Vascular Biology,* Department of Molecular and Cellular Medicine, University of Leuven, Leuven, Belgium; and EM Unit Pathology Department and Department of Internal Medicine, University of Maastricht, Maastricht, The Netherlands

Hepatocytes are a key target for gene therapy of inborn errors of metabolism as well as of acquired diseases such as liver cancer and hepatitis. Gene transfer efficiency into hepatocytes is significantly determined by histological and functional aspects of liver sinusoidal cells. On the one hand, uptake of vectors by Kupffer cells and liver sinusoidal endothelial cells may limit hepatocyte transduction. On the other hand, the presence of fenestrae in liver sinusoidal endothelial cells provides direct access to the space of Disse and allows vectors to bind to receptors on the microvillous surface of hepatocytes. Nevertheless, the diameter of fenestrae may restrict the passage of vectors according to their size. On the basis of lege artis measurements of the diameter of fenestrae in different species, we show that the diameter of fenestrae affects the distribution of transgene DNA between sinusoidal and parenchymal liver cells after adenoviral transfer.

The small diameter of fenestrae in humans may underlie low efficiency of adenoviral transfer into hepatocytes in men. The disappearance of the unique morphological features of liver sinusoidal endothelial cells in pathological conditions like liver cirrhosis and liver cancer may further affect gene transfer efficiency. Preclinical gene transfer studies should consider species differences in the structure and function of liver sinusoidal cells as important determinants of gene transfer efficiency into hepatocytes.

Outdoor air pollution is associated with disease severity in 1-antitrypsin deficiency

2009-11-24T09:49:00.000-08:00

European Respiratory Journal 2009; 34:346-353

The aim of this study was to determine whether long-term air pollution exposure is associated with clinical phenotype in alpha 1-antitrypsin deficiency.

In total, 304 PiZZ subjects underwent full lung function testing and quantitative high-resolution computed tomography to identify the presence and severity of the disease. Mean annual air pollutant data for 2006 was matched to the location of patients' houses and used in regression models to identify phenotypic associations with pollution, controlling for covariates. Relative trends in pollution levels were assessed to validate use of a single year's data to indicate long-term exposure.

Pollutant levels correlated significantly with one another, with higher levels of primary particles, SO2 and NO2 being associated with lower ozone levels. Regression models showed that estimated higher exposure to ozone was associated with worse gas transfer and more severe emphysema. Regression parameters suggested that significance from other pollutants was due to collinearity with ozone. The 2006 pollutant levels showed linear relationships with cumulative years, thus validating the model.

Higher exposures to ozone may be associated with worse respiratory status in 1-antitrypsin deficiency, identifying a group susceptible to ambient air pollution.

Division of Medical Sciences, School of Geography, Earth and Environmental Sciences, Dept of Occupational and Environmental Medicine, University of Birmingham, and 4Lung Investigation Unit, University Hospitals Birmingham, Birmingham, UK.

Lung volume reduction surgery for patients with alpha-1 antitrypsin deficiency emphysema

2009-08-20T08:42:00.000-07:00

Currently, A1AD is recognized in approximately 2% of patients who have emphysema, although this may be an underestimation of the prevalence of this disease. Given the relatively young age at which patients who have A1AD present with emphysema, therapies aimed at slowing the progression of this disease are imperative. In addition to abstaining from smoking, the use of augmentation therapy may benefit some patients who have moderate airflow obstruction. For patients who have severe airflow obstruction, the most effective therapy is surgical.

Despite a possible increased risk for infectious complications, transplantation remains a viable option for these patients who have long-term results mirroring those of patients transplanted for smoking-related COPD. Given limited donor availability, however, LVRS must be considered in these patients possibly as definitive therapy but more likely as a bridge to transplantation. LVRS for patients who have A1AD remains relatively uncommon despite a general perception that it remains a surgical option.

In a survey of European thoracic surgical centers, Hamacher and colleagues42 found that two thirds of respondents included A1AD in their list of indications for LVRS. Although the durability of the benefits derived from LVRS in patients who have A1AD seems inferior to that of patients who have COPD, the available data show improved 6-minute walk distances and decreased dyspnea persisting for 1 to 2 years after LVRS in patients who had A1AD. Further experience is necessary to determine whether or not subgroups of patients who have A1AD, such as those who have clear heterogeneous distribution, may derive more long-lasting improvement from LVRS.

Donahue JM, Cassivi SD.
Division of General Thoracic Surgery, University of Maryland, 22 South Greene Street, N4E35, Baltimore, MD 21201, USA

Mortality in alpha-1-antitrypsin deficiency in the United Kingdom.

2009-05-20T13:14:00.000-07:00

University Hospital Birmingham/ University of Birmingham, UK.

BACKGROUND: Four hundred and eighty-eight PiZ alpha-1-antitrypsin deficient patients, who had joined the UK registry over a 9-year period, were followed in an observational study to determine mortality. None had received A1AT augmentation therapy.

METHODS: Cause of death was confirmed from death certification and medical records. Patients were censored according to length of time on the program or until they withdrew from the program. RESULTS: There were 56 deaths of which 30 were attributed to respiratory causes. Of the remaining 26 deaths, 4 were due to complications from lung transplant, 6 due to liver disease (including 2 post-liver transplant) and the other 16 due to a variety of causes. Kaplan-Meier plots indicated a cumulative hazard for mortality of 18.1% in 9 years, correcting for time of follow up. When categorised for FEV(1) percent-predicted, the group with severe impairment had increased mortality (p=<0.001) compared with the mild group and there was a direct relationship between severity and mortality. The severe group had increased mortality compared with the mild group when categorised for KCO percent-predicted (p<0.001), RV/TLC ratio (p<0.001) or emphysema score on CT scan (p<0.001 upper zone). Cox regression analyses indicated that these relationships remained when corrected for age. There were no differences in mortality after categorisation for educational level or occupational group.

CONCLUSION: Mortality in a cohort of A1AT deficient patients (PiZ phenotype) in the UK was 2% per year and was associated with lung function impairment and emphysema severity on CT scan, but not social status

Monoclonal anti-neutrophil elastase antibody characterisation: Ability to block function, detect free versus serpin-complexed enzyme and stain intrace

2008-07-07T11:00:00.000-07:00

Four commercially available monoclonal antibodies (clones NP57, 256-3K1, 39A and 203) were characterised for their ability to block human neutrophil elastase (HNE) activity; capture free purified HNE or neutralised HNE in complex with alpha-1-antitrypsin (AAT); detect HNE and HNE–AAT by Western blot analysis; and detect intracellular HNE by flow cytometry. The ability to block small substrate cleavage by HNE ranged from 0% (265-3K1) to 15–18% (39A and 203) to 100% (NP57). All antibodies had the ability to capture free HNE with varying degrees of sensitivity, but HNE neutralisation by AAT resulted in complete loss of detection (NP57) to 2–4-fold decreased detection (39A and 203) to a 8-fold increase in detection (265-3K1). None of the monoclonal antibodies could detect 200 ng of free HNE, or HNE in complex with AAT, by Western blot analysis, which was easily detected by polyclonal antibodies. NP57 and 265-3K1 gave 10-fold higher fluorescence when detecting intracellular HNE than 39A and 203, and intracellular fluorescence decreased by 10–28% following maximal stimulation of purified neutrophils with fMLP and cytochalasin B (compared to 40% release determined by functional assay). However, for sub-maximal stimulation of neutrophils intracellular anti-HNE antibody binding increased, likely due to increased accessibility following redistribution of enzyme, indicating that measuring residual intracellular HNE as an index of release is a less reliable method than directly measuring extracellular HNE.

ARTICLE

Terminally misfolded or unassembled proteins in the early secretory pathway are degraded by a ubiquitin- and proteasome-dependent process known as ER-

2008-07-02T11:40:00.000-07:00

Terminally misfolded or unassembled proteins in the early secretory pathway are degraded by a ubiquitin- and proteasome-dependent process known as ER-associated degradation (ERAD). How substrates of this pathway are recognized within the ER and delivered to the cytoplasmic ubiquitin-conjugating machinery is unknown. We report here that OS-9 and XTP3-B/Erlectin are ER-resident glycoproteins that bind to ERAD substrates and, through the SEL1L adaptor, to the ER-membrane-embedded ubiquitin ligase Hrd1. Both proteins contain conserved mannose 6-phosphate receptor homology (MRH) domains, which are required for interaction with SEL1L, but not with substrate. OS-9 associates with the ER chaperone GRP94 which, together with Hrd1 and SEL1L, is required for the degradation of an ERAD substrate, mutant 1-antitrypsin. These data suggest that XTP3-B and OS-9 are components of distinct, partially redundant, quality control surveillance pathways that coordinate protein folding with membrane dislocation and ubiquitin conjugation in mammalian cells.

Alpha-1 antitrypsin Null mutations and severity of emphysema

2008-06-30T13:08:00.000-07:00

Background
Alpha-1 antitrypsin (AAT) deficiency is an autosomal-codominant disorder, caused by mutations in the SERPINA1 gene on chromosome 14. Individuals affected by the most common mutations, SZ and ZZ, have serum AAT concentrations of 25% and 15% of normal levels, and present a higher risk of emphysema. Mutations causing total absence of serum AAT (Null mutations) were suggested to be associated with very early onset emphysema but their clinical phenotype is poorly known.

Hypothesis
Absence of AAT in Null mutations results in more severe emphysema as compared to ZZ and SZ.

Methods
We genotyped all known Dutch subjects (n=12) with absent serum AAT, and compared their lung function values (FEV1 and KCO) with those of individuals with ZZ and SZ genotype, matched for age and smoking history.

Results
All subjects with absent serum AAT presented homozygous Null mutations. In three subjects, a new mutation in exon 2 of the SERPINA1 gene was found. Subjects with Null mutations showed significantly lower lung function values than SZ and ZZ individuals (p=0.000 and 0.001 for FEV1 and KCO, respectively). In all groups, there was a positive correlation between serum AAT and lung function values (p=0.025 and 0.014 for FEV1 and KCO, respectively).

Conclusions
Serum levels of AAT are correlated with the severity of pulmonary phenotype. Subjects with Null mutations should be considered a subgroup at particularly high risk of emphysema within AAT deficiency (AATD). Early detection of carriers of this genotype would be important for preventive and therapeutic interventions.

Laura Fregonesea, Jan Stolka, Rune R. Frantsb and Barbera Veldhuisen

ARTICLE

Alpha-1 antitrypsin (A1AT) is a serine anti-protease produced chiefly by the liver. A1AT deficiency is a genetic disorder characterized by serum level

2008-06-20T13:57:00.000-07:00

Summary
alpha-1 antitrypsin (A1AT) is a serine anti-protease produced chiefly by the liver. A1AT deficiency is a genetic disorder characterized by serum levels of less than 11 μmol/L and is associated with liver and lung manifestations. The liver disease, which occurs in up to 15% of A1AT-deficient individuals, is a result of toxic gain-of-function mutations in the A1AT gene, which cause the A1AT protein to fold aberrantly and accumulate in the endoplasmic reticulum of hepatocytes. The lung disease is associated with loss-of-function, specifically decreased anti-protease protection on the airway epithelial surface. The so-called ‘Z’ mutation in A1AT deficiency encodes a glutamic acid-to-lysine substitution at position 342 in A1AT and is the most common A1AT allele associated with disease. Here we review the current understanding of the molecular pathogenesis of A1AT deficiency and the best clinical management protocols.

C. M. Greene1 , S. D. W. Miller1, T. Carroll1, C. McLean1, M. O’Mahony1, M. W. Lawless1, 2, S. J. O’Neill1, C. C. Taggart1, 3 and N. G. McElvaney1

Alpha1-Antitrypsin Deficiency Associated with Increased Risk of Lung Cancer

2008-06-03T15:07:00.000-07:00

The disorder, alpha1-antitrypsin deficiency (á1ATD), is one of the most common genetic conditions affecting the U.S. population and especially those of European descent, according to background information in the article. Individuals with two copies of the associated genetic mutation often develop emphysema at an early age. However, á1ATD carriers-those with only one copy of the mutated gene-do not normally have severe diseases related to á1ATD and may not be aware of their status. However, they may be more vulnerable to cancer-causing tobacco smoke than non-carriers.

Ping Yang, M.D., Ph.D., and colleagues at the Mayo Clinic, Rochester, Minn., tested for á1ATD carrier status in 1,443 patients with lung cancer. In addition, 797 community members without lung cancer and 902 siblings of lung cancer patients were tested as controls. Information was gathered about all participants' smoking history, demographic characteristics and family history of cancer.

A total of 13.4 percent of the lung cancer patients and 7.8 percent of unrelated controls were á1ATD carriers. When patients with lung cancer were compared to non-related controls, á1ATD carriers had a 70 percent higher risk of developing lung cancer than non-carriers. Comparing patients with lung cancer to their cancer-free siblings, á1ATD carriers had twice the risk of developing lung cancer. The researchers estimated that á1ATD carrier status may account for 11 percent to 12 percent of the patients with lung cancer enrolled in the study.

Among those who had never smoked, á1ATD carrier status was associated with a 2.2-fold higher risk of lung cancer, with a 2-fold increased risk among light smokers and a 2.3-fold increased risk among moderate to heavy smokers. "Patients with a family history of lung cancer or other cancers in their first-degree relatives had a similar á1ATD carrier rate to those without such a family history, all significantly higher than the controls," the authors write. "This finding suggests that increased lung cancer risk among á1ATD carriers is independent of a family history of cancer."

"In summary, our findings demonstrate a paradigm in lung cancer etiology research and risk assessment that incorporates clinical and genetic markers for lung damage into a gene-environment interaction," they conclude. "This knowledge may prove to be useful in further understanding the pathologic mechanisms of lung cancer development and in refining lung cancer risk assessment."

Alpha-1 Antitrypsin Null Mutations and Severity of Emphysema

2008-06-03T14:51:00.000-07:00

Background
Alpha-1 antitrypsin(AAT) deficiency is an autosomal-codominant disorder, caused by mutations in the SERPINA1 gene on chromosome 14. Individuals affected by the most common mutations, SZ and ZZ, have serum AAT concentrations of 25% and 15% of normal levels, and present a higher risk of emphysema. Mutations causing total absence of serum AAT (Null mutations) were suggested to be associated with very early onset emphysema but their clinical phenotype is poorly known.

Hypothesis
Absence of AAT in Null mutations results in more severe emphysema as compared to ZZ and SZ.

Methods
We genotyped all known Dutch subjects (n=12) with absent serum AAT, and compared their lung function values (FEV1 and KCO) with those of individuals with ZZ and SZ genotype, matched for age and smoking history.

Results
All subjects with absent serum AAT presented homozygous Null mutations. In three subjects, a new mutation in exon 2 of the SERPINA1 gene was found. Subjects with Null mutations showed significantly lower lung function values than SZ and ZZ individuals (p=0.000 and 0.001 for FEV1 and KCO, respectively). In all groups, there was a positive correlation between serum AAT and lung function values (p=0.025 and 0.014 for FEV1 and KCO, respectively).

Conclusions
Serum levels of AAT are correlated with the severity of pulmonary phenotype. Subjects with Null mutations should be considered a subgroup at particularly high risk of emphysema within AAT deficiency (AATD). Early detection of carriers of this genotype would be important for preventive and therapeutic interventions.

Laura Fregonesea, Jan Stolka, Rune R. Frantsb and Barbera Veldhuisen