ZAATD to prevent widespread cellular death, but the
inhibition is insufficient in some cells, leading to
a constant rate of hepatocellular death.
Analogy to other serpinopathies
AATD is a conformational disease, 43 a term used
to describe conditions that are characterised by
mutations altering the folding pathway and final
protein conformation. Conformational diseases
lead to aggregation and retention of protein with
consequent late or episodic onset of symptoms.
Classic examples include Alzheimer’s disease and
other neurodegenerative diseases such as Parkinson’s
and Huntington’s, all involving the aberrant
accumulation of proteins. In Alzheimer’s disease,
the accumulation of insoluble aggregates of the
amyloid-b peptide in the brain is thought to be a key
pathological event underlying the loss of brain cells. 44
It is hoped that attempts to treat
AATD by preventing polymerisation and
improving secretion of potentially toxic
proteins might have an effect on other
serpinopathies such as this
Recent research has postulated a conformational
aspect to other conditions such as CF 45 and
hereditary haemochromatosis. 46 A subclass of
conformational disease includes the serpinopathies.
ZAAT deficiency is the classic example for these
diseases, which also include thrombosis, angio-
oedema and emphysema due to loss-of-function
of anti-thrombin, C1 inhibitor and alpha-1
antichymotrypsin, 47 respectively, and gain-of-
function dementia familial encephalopathy with
neuroserpin inclusion bodies (FENIB). 48 In the
latter, the neuron-specific neuroserpin undergoes
polymerisation and formation of inclusion bodies
in a manner very similar to ZAAT. This neuroserpin
accumulation leads to neurodegeneration and early-
onset dementia.
It is hoped that attempts to treat AATD by
preventing polymerisation and improving secretion
of potentially toxic proteins might have an effect on
other serpinopathies such as this.
30 McElvaney NG et al. Aerosol
alpha 1-antitrypsin treatment
for cystic fibrosis. Lancet
1991;337(8738):392–4.
31 Bergin DA et al. Airway
inflammatory markers in
individuals with cystic fibrosis
and non-cystic fibrosis
bronchiectasis. J Inflamm Res
2013;6:1–11.
32 Greene C et al. Local
impairment of anti-neutrophil
elastase capacity in community-
acquired pneumonia. J Infect Dis
2003;188(5):769–76.
33 Carp H et al. Potential
mechanism of emphysema: alpha
1-proteinase inhibitor recovered
from lungs of cigarette smokers
contains oxidized methionine and
has decreased elastase inhibitory
capacity. Proc Natl Acad Sci U S A
1982;79(6):2041–5.
34 Taggart C et al. Oxidation
of either methionine 351
or methionine 358 in alpha
1-antitrypsin causes loss of anti-
neutrophil elastase activity. J Biol
Chem 2000;275(35):27258–65.
35 Patel D, Teckman JH.
Alpha-1-antitrypsin deficiency
liver disease. Clin Liver Dis
2018;22(4):643–55.
36 Greene CM et al. Alpha-1
antitrypsin deficiency: a
conformational disease
associated with lung and liver
manifestations. J Inherit Metab
Dis 2008;31(1):21–34.
37 Lawless MW et al.
Activation of endoplasmic
reticulum-specific stress
responses associated with the
conformational disease Z alpha
1-antitrypsin deficiency.
J Immunol 2004;172(9):5722–6.
38 Harding HP et al.
Transcriptional and translational
control in the Mammalian
unfolded protein response. Annu
Rev Cell Dev Biol 2002;18:575–99.
39 Lawless MW et al.
Activation of endoplasmic
reticulum-specific stress
responses associated with the
conformational disease Z alpha
1-antitrypsin deficiency.
J Immunol 2004;172(9):5722–6.
40 Miller SD et al.
Tauroursodeoxycholic acid
inhibits apoptosis induced
by Z alpha-1 antitrypsin via
inhibition of Bad. Hepatology
2007;46(2):496–503.
41 Hidvegi T et al. Accumulation
of mutant alpha1-antitrypsin Z
in the endoplasmic reticulum
activates caspases-4 and -12,
NFkappaB, and BAP31 but not
the unfolded protein response.
J Biol Chem 2005;280(47):
39002–15.
42 Hurley K et al. Alpha-1
antitrypsin augmentation therapy
corrects accelerated neutrophil
apoptosis in deficient individuals.
J Immunol 2014;193(8):3978–91.
43 Carrell RW, Lomas DA.
Alpha1-antitrypsin deficiency
– a model for conformational
diseases. N Engl J Med
2002;346(1):45–53.
44 Bucciantini M et al. Inherent
toxicity of aggregates implies a
common mechanism for protein
misfolding diseases. Nature.
2002;416(6880):507–11.
45 Knorre A et al. DeltaF508-
CFTR causes constitutive
NF-kappaB activation through
an ER-overload response in
cystic fibrosis lungs. Biol Chem
2002;383(2):271–82.
46 Lawless MW, Mankan
AK, Norris S. Hereditary
hemochromatosis should be
considered a conformational
disorder. Med Hypotheses
2008;70(4):783–4.
47 Gooptu B, Lomas DA.
Polymers and inflammation:
disease mechanisms of the
serpinopathies. J Exp Med
2008;205(7):1529–34.
48 Miranda E et al. The
intracellular accumulation of
polymeric neuroserpin explains
the severity of the dementia
FENIB. Hum Mol Genet
2008;17(11):1527–39.
hospitalpharmacyeurope.com | 2019 | 9
immunity. Transplant Proc
2008;40(2):455–6.
25 Pileggi A et al. Alpha-1
antitrypsin treatment of
spontaneously diabetic nonobese
diabetic mice receiving islet
allografts. Transplant Proc
2008;40(2):457–8.
26 Kalis M et al. α 1-Antitrypsin
enhances insulin secretion and
prevents cytokine-mediated
apoptosis in pancreatic ß-cells.
Islets 2010;2(3):185–9.
27 Crystal RG et al. The alpha
1-antitrypsin gene and its
mutations. Clinical consequences
and strategies for therapy. Chest
1989;95(1):196–208.
28 Wewers MD et al.
Replacement therapy for
alpha 1-antitrypsin deficiency
associated with emphysema.
N Engl J Med 1987;316(17):
1055–62.
29 Cantin AM, Lafrenaye S,
Bégin RO. Antineutrophil
elastase activity in cystic fibrosis
serum. Pediatr Pulmonol
1991;11(3):249–53.