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A1AT deciency is an under-recognized condition for which there are no screen-
ing programs established; thus, the diagnosis depends on a clinician’s inquisitive
mind, after which measures to prevent early complications or disease progression,
e.g., cigarette smoking cessation, screening for viral hepatitis, and vaccination, as
appropriate, should be implemented.
In homeostasis, there is a balance between proteases, which participate in pro-
teolytic processes, and their inhibitors, which inhibit the activity of the proteolytic
enzymes. The predominant family of inhibitors is the serine proteinase inhibitors
(serpins) to which A1AT belongs [5]. The serpins’ mechanism of action concerns a
conformational change, i.e., a change in the structure inhibits the protease and leads
toits destruction. The protein enters the lung by diffusion, where it inhibits neutro-
phil elastase; the protease/inhibitor complex is internalized and degraded by lyso-
somes [6]; A1AT is also reported to exert anti-inammatory effects, independent
from elastase inhibition [7].
A1AT is molecularly characterized by three beta sheets, A, B, and C, and nine
alpha helixes. Beyond the scaffold of the A1AT molecule protrudes the reactive
center loop (RCL) in a highly stressed conguration with methionine 358-serine
359 at the active center, which ducks the target enzyme, i.e., neutrophil elastase, to
form a substrate enzyme complex, i.e., Michaelis complex. After ducking at the
receptive sequence of the RCL, the protease is inactivated and sprung to the bottom
of the molecule where it hangs, after which the RCL inserts itself into the beta A
sheet, as another strand. The process of inactivation has been described as a "mouse-
trap" with a spring-like shift from a metastable to a hyperstable state [8, 9]. The
formation of the substrate–enzyme complex can lead to: (1) inactivation of the pro-
tease and (2) the formation of a fourth beta sheet by the RCL within the A1AT
molecule, allowing the protease to escape, leaving it in the active state, with the
serpin cleaved and inactive. Thus, in homeostasis, A1AT exists in: (1) a native inhib-
itory conformation, with the exposed reactive center loop, and (2) in a latent state
with a partially inserted RCL and a non-inhibitory conformation. The non- inhibitory
conformation occurs: (1) in the substrate–enzyme complex, i.e., A1AT and neutro-
phil elastase, which is removed from the circulation by the hepatocyte, (2) when the
RCL is cleaved by non-target enzymes, (3) after oxidation by reactive oxygen spe-
cies, and (4) polymerized as it happens with the A1AT variants, including Pi*ZZ,
associated with lung and liver disease, which are also reported to exert a chemotac-
tic action on neutrophils, thus triggering an inammatory cascade, now considered
part of the pathogenesis of emphysema in association with A1AT deciency [10].
Mutations in a strand of the beta sheet allow the RCL to insert itself into the A
beta sheet as a new strand, forming polymers, which can involve several molecules
of A1AT (Fig.10.1) [11] that are trapped in the hepatocyte’s endoplasmic reticulum
(ER) from where they cannot exit, leading to a deciency of circulating levels of
A1AT.In the ER, A1AT molecules interact with chaperones including Grp78/BiP,
Grp94, Grp170, and calnexin [12], the role of which is to facilitate the folding of
proteins required for translocation from the ER and to control the quality of the
proteins being secreted, by ensuring that inappropriately folded proteins remain in
the ER or are degraded by proteasomes, via a mechanism known as ER-associated
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degradation (ERAD) [13]. In the ER, the interaction between the protein and the
chaperones takes the form of soluble and conglomerate compounds, the latter iden-
tied by their characteristic stain features, i.e., peroxidase acid Schiff (PAS)-positive
and diastase-resistant bodies that appear as magenta granules (Fig. 10.2). In the
context of degradation, autophagy is a process identied as important in the elimi-
nation of A1AT polymers by the formation of autophagosomes. It is a mechanism
being explored to develop treatments for A1AT deciency-related liver disease. In
this regard, drugs that increase autophagy, rapamycin, and carbamazepine, were
ab
cd
Fig. 10.1 (a)Through(d)depict the polymerization of A1AT molecules. The amino acid substitu-
tion in the Z allele interferes with the folding and structure of the protein, changing the relationship
between the reactive center loop (RCL (red ribbon)) and the beta sheet A (yellow ribbons), and
allows for the opening of the latter to accept the partial insertion of RCL(a andb). Subsequently,
the patent beta sheet A accepts the RCL of another A1AT molecule to form a dimer that extends by
the insertion of another A1AT molecules forming chains of loop-sheet polymers(c and d). A1AT
polymers accumulate in the cisterna of the rough endoplasmic reticulum, with a signicant reduc-
tion of secretion, leading to the accumulation of the polymers in the hepatocytes that appear as
periodic acid-Schiff-positive, diastase-resistant globules as shown in Fig.
10.2
Fig. 10.2 Histological study of a liver biopsy specimen from a patient with PI*ZZ alpha-1-
antitrypsin deciency. The eosinophilic inclusion bodies are periodic acid-Schiff-positive, diastase-
resistant globules that contain polymerized, unsecreted Z-type alpha-1-antitrypsin (A1AT)
(Courtesy of Dr. Maria Isabel Fiel, MD, FAASLD, Professor of Pathology, Icahn School of
Medicine at Mount Sinai, NewYork, NewYork)
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reported to decrease A1AT ZZ polymers and liver brosis in a mouse model of the
disease [14, 15].
Although A1AT deciency has been traditionally viewed as a condition arising
from a protease-antiprotease imbalance in the lungs, neutrophils’ role as facilita-
torsof inammation in the pathogenesis of lung disease and other specic comor-
bidities is being recognized, adding an inammatory component to the pathogenesis
of the disease [16].
The plasma concentration of A1AT ranges from 0.9 to 2.0g/L.A1AT is an acute
phase reactant; thus, during inammation, the concentrations increase by several
folds [17]. In addition to neutrophil elastase (NE), A1AT inhibits other proinam-
matory proteases, including proteinase 3 and cathepsin G [18].
Genetics
The A1AT protein is encoded by the SERPINA1 gene (also known as PI), located in
chromosome 14q32.1,3–7. The disease is inherited in an autosomal recessive man-
ner with codominant expression [19]. The two most common alleles found in A1AT
deciency-associated diseases are S and Z.
The Z variant contains a substitution of the amino acid glutamine for lysine in the
342 position. This mutation concerns an amino acid at the base of the center loop of
the molecule [20], which can move in and out of the A-sheet that comprises the
major feature of the molecule [21]. It was shown that by increasing the environ-
ment’s temperature or under mild denaturing conditions, the center loop could
move, and polymerization occur between A1AT molecules of the M, normal pheno-
type. The polymerization could be stopped by adding a synthetic-free peptide,
which inserts itself into the A-sheet, forming a binary complex. The synthetic-free
peptide was a 13-residue peptide derived from the reactive center loop of another
serpin, antithrombin, and homologous to the amino acid sequence 345 to 357 of the
center loop. The formation of the binary complex with A1AT was documented by
the loss of the inhibitory activity, by features exhibited in electrophoresis, and by
changes in physical properties [21]. It was further noted that the Z mutation at the
hinge of the center loop enhanced polymerization, which spontaneously happened
at 37 degrees, and that was accelerated at temperatures of 41 degrees; the synthetic-
free peptide blocked polymerization regardless of the temperature used in the exper-
iment. The polymerization rate also depended on the Z antitrypsin concentration,
with an increased proportion of polymerization in association with increased con-
centrations of antitrypsin. The M antitrypsin did not polymerize itselfunder these
conditions. The results of these experiments explained the accumulation of A1AT
conglomerates in the hepatocytes of patients who were homozygotes for the Z
mutation. Gel electrophoresis revealed ndings to conrm that the inclusion bodies
are bound together by non-covalent bonds and dissociate into monomers in the right
experimental conditions; furthermore, electron microscopy revealed that the poly-
mers were comprised of laments identical to those observed in incubated isolated
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Z antitrypsin. Loop-sheet polymerization is reported as equilibrium, and it occurs at
a critical concentration of Z antitrypsin before it goes into the ER; 85% of the Z
antitrypsin polymerizes itself, and the rest is secreted into the circulation as mono-
mers, the concentration of which, however, is not adequate to protect the lungs from
the proteolytic destruction by neutrophil elastase [22]. In addition to a low periph-
eral concentration, the Z allele is dysfunctional, as it has a decrease in the inhibitory
activity of A1AT because of a diminished binding afnity to neutrophil elastase [23].
The S allele contains a substitution of glutamine for valine at the 264 position
(Glu264Val). In homozygotes, this mutation results in a decrease in the plasma
concentration by 40%, which does not result in major health problems; however, if
inherited with the Z mutation, i.e., the substitution of glutamine for lysine at the
342 position (Glu342Lys), which results in 85% reduction in the plasma concen-
tration of A1AT, it does. In summary, the low plasma concentration found with the
ZZ homozygotes and with the SZ compound heterozygotes is associated with
disease.
The M allele is encoded by the A1AT 2 gene and is associated with sufcient
serum concentrations of A1AT to prevent disease. Other variants that include the
M1, M2, G, X, C, and D alleles are not associated with health complications. Rare
alleles have been reported in association with disease in case reports [24]. The
alleles associated with intracellular accumulation of the protein related to liver and
lung injury, as a result, are M Malton, Siiyama, and Z, with the latter being associ-
ated with impaired inhibition of NE as well. The alleles associated with lung disease
related to intracellular degradation are M Heerlen, M procida, S, and M mineral
springs, which are also related to impaired NE inhibition. The null alleles, which
make very little amounts of A1AT, are QO
granite falls
, characterized by a stop codon
and absence of A1AT, and associated with emphysema, and QO
Ludwigshafen
, character-
ized by abnormal mRNA, leading to inadequate protein, and associated with liver
and lung disease, the QO
hongkong
, associated with a stop codon from a frameshift,
which results in a short protein and is associated with its intracellular accumulation,
and development of emphysema at an early age, QO
isola di procida,
characterized by
complete deletion without mRNA or protein, and associated with lung disease,
QO
Bolton,
characterized by a stop codon and no mRNA or protein, and associated
with lung disease [25]. The dysfunctional Pittsburgh allele is characterized by a
substitution (358 met-to-arg) that results in the acquisition of antithrombin proper-
ties and is associated with bleeding diathesis [26] and F, which has defective bind-
ing to NE and that results in normal A1AT concentrations but abnormal anti-elastase
functional activity [27, 28].
The mutant A1AT Z is synthesized appropriately and translocated to the ER of
the hepatocyte where it binds to chaperone proteins, the role of which is to help in
the folding of the molecule and to survey for abnormalities; as the mutant folds inef-
ciently, 85% of the molecules do not reach the conformation required for secretion
and thus, they are retained in the hepatocyte, as stated above, where they appear as
magenta granules(Fig.10.2) [22]. The accumulation of these structures from the
mutant Z molecule triggers liver injury in the individuals susceptible to disease, but
not in all individuals with the mutation.
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Epidemiology
A1AT deciency is under diagnosed, as screening guidelines are not strictly fol-
lowed and the disease, in its full manifestation of early emphysema, tends to be
diagnosed when preventive measures, e.g., smoking cessation, avoidance of envi-
ronmental and occupational exposure, cannot be instituted; thus the prevalence has
been calculated mostly by estimates. “AAT deciency is probably one of the most
common hereditary under-recognized disorders in the world, with only a small
minority of subjects currently detected,” as documented from a study that estimated
the prevalence of A1AT in the world [29].
In the United States, the prevalence of A1AT deciency in individuals of
European extraction is 1 case per 3000 to 5000 persons [35]. It was concluded from
a study that surveyed 4.4 billion people from 58 countries that there were at least
116 million carriers of A1AT Pi phenotypes PiMS and PiMZ and 3.4 million with
deciency allele combinations, phenotypes PiSS, PiSZ, and PiZZ, the latter two
being the most prevalent. These results reiterate that A1AT deciency may be one
of the most common single-locus genetic diseases that have serious clinical conse-
quences [30].
Reported per 1000 individuals in North and Central America, PI*S’s prevalence
ranged from 23in the United States to 33–45in Central America. The prevalence of
PI*Z from 6 to 8in Mexico and Central America to 10 and 13in the United States
and Canada; in the United States, the study documented an estimate of 14 million
MS, 6 million MZ, 160,000 SS, 150,000 SZ, and 34,000 ZZ, which one can inter-
pret as a result of its rich genetic pool [29].
Nineteen centers in the United States participated in a study that included 3152
subjects with xed airow obstruction who underwent pulmonary function tests; of
these, 0.63% were characterized as Pi*ZZ and Pi*SZ, and 10.88% were carriers of
mutations MS and MZ.However, pulmonary function test results did not allow the
prediction of the phenotypic expression of the A1AT mutations [31]. These data
support the measure of screening high-risk individuals prior to the establishment of
irreversible airway disease.
The factors that have been associated with liver disease in adults are age greater
than 50years, male gender, abnormal liver prole, viral hepatitis, and components
of the metabolic syndrome [25]. A consensus supports the idea that polymerization
of the altered phenotype that results in the accumulation of AA1T globules is not
sufcient to cause disease. Thus, environmental and other genetic and epigenetic
inuences are likely to be involved in the pathogenesis of A1AT deciency- related
liver disease [32–36]. In this regard, molecular epigenetic signatures have already
been documented in a group of patients with the A1AT deciency ZZ pheno-
type [37].
A study that included 262 patient cohorts from 71 countries, and 1,490,816 indi-
viduals with PiSZ phenotype of A1ATD, documented the prevalence of the disease
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as 708,792 in Europe, 582,984 in America and the Caribbean, 85,925 in Africa,
77,940in Asia, and 35,176in Australia and New Zealand [38].
Natural History
A1AT deciency can present in infancy with prolonged cholestatic hepatitis [39]. In
a prospective study that screened 200,000 infants, 120 PiZ, 48 Pi SZ, two PI Z, and
one Pi S were identied and followed under 6months. Prolonged cholestasis was
documented in 14 of the 120 (11.6%) infants, nine of whom had evidence of liver
disease, with ve exhibiting abnormal liver tests only. Twenty-two of the 120
(18.3%) infants with abnormal liver prole “seemed healthy” at 6months of age;
the other 98 did not have liver disease on clinical grounds, but liver tests were abnor-
mal in some at 3 and 6months of age. The number of small for gestational age
infants increased in patients with clinical liver disease. The infants with PiSZ did
not have liver disease; however, some had abnormal liver tests at 3 and 6months of
age. These data suggested that liver disease in children with the PiZ and PiSZ phe-
notypes presents itself by 3months of life [40].
By the use of DEFI-ALPHA as a source, a French study, retrospective up to 2010
and prospective from 2017 that included 153 children who were born since 1989
with A1AT concentrations below 0.8g/L and followed for 4.7±2.1years, docu-
mented a majority, 81.9%, with the PiZZ phenotype, with 8.1% being PiZZ, and
10% qualied as other, and a development of portal hypertension in 18.3%, at a
mean age of 2.5years (up to 11.6), with 15 children having a liver transplant, and
one death in a 3-year-old child, with neonatal cholestasis being signicantly associ-
ated with severe disease, dened as portal hypertension, liver failure, liver trans-
plantation, or death; the diagnosis of A1AT deciency was made before 2months in
65.4% of patients, with PiZZ being the most common, 89.3%, and the rest being
PiSZ, PiSZ, PiSZ, and PiM
like
Z, data interpreted to suggest that non PiZZ variants
can be associated with liver disease, possibly related to other factors, which remain
to be identied [41].
In the adult population, life expectancy is compromised in patients with A1AT
deciency. From a study conducted in Sweden that included 246 patients with
severe PiZ A1ATD, diagnosed from 1963 to 1977, lung disease was present in 40%
of the patients, with the majority of deaths being from this group [42]. Forty-seven
patients (19%) had a diagnosis of liver cirrhosis by age 50years; 13% of the deaths
being from liver disease.
In regards to hepatic comorbidities, from 1184 subjects withnonalcoholic fatty
liver disease (NAFLD) documented histologically, and from 2462 with alcohol
use disorder, with appropriate control groups with and without cirrhosis, the cal-
culated odds ratio (OR) to develop cirrhosis in association with the Pi*Z variant
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of A1AT in patients with NAFLD was reported as 7.3, with a 95% condence
interval (CI) between 2.2 and 24.8, with 13. 8% of the subjects with the abnormal
phenotype having cirrhosis, versus the 2.4% of subjects without that variant. The
PiZ* was present in 6.2% of subjects who had alcohol use disorder and cirrhosis,
which was signicantly higherthan the 2.2% of patients with the same condition
but without “signicant liver injury,” with a calculated adjusted OR of 5.8 (CI: 2.9
to 11.7) indicating that patients who drink excessively, and carry this A1AT phe-
notype were at risk to develop cirrhosis. The adjusted OR for the patients who had
the Pi*S variant was 1.47 (95% CI: 0.99 to 2.19), a risk that, although small when
compared to the Pi*Z variant, should be discussed in regards to preventive mea-
sures, e.g., stopping cigarette smoking, when evaluating carriers of Pi*S [43].
In this regard, a retrospective review also from Sweden identied 17 cases (one
child and 16 adults) that had undergone an autopsy from 20 who had been diag-
nosed with A1AT deciency between 1963 and 1982. From an analysis that matched
the A1ATD cases with the non A1AT deciency controls, a strong relationship
between A1AT deciency and cirrhosis and hepatocellular carcinoma was identi-
ed, with a Mantel-Haenszel odds ratio (ORmh) of 7.8, with a 95% condence
limits from 2.4 to 24.7, and 20, with a 95% condence limits from 3.5 to 114.3,
respectively, with signicant association with male patients only, after data stratied
for gender. These data suggested that in addition to A1AT deciency, environmen-
tal, and possibly hormonal factors contribute to the development of HCC in patients
with this genetic condition [44].
From a prospective study that included 94 adult patients with A1AT deciency,
Pi*ZZ, the prevalence of liver brosis, measured by transient elastography, was
35.1%, which was signicantly associated with the presence of metabolic syndrome
(OR 14.2; 95% CI 3.7–55; p < 0.001). Histologically, the typical hepatocellular
A1AT globules and periportal inammation were reported in association with sig-
nicant brosis [25]. In addition to brosis, steatosis was documented in 39% out of
554 patients with A1AT deciency PiZZ variant by the use of transient elastography,
with controlled attenuation parameter ≥280dB/m, suggestive of severe steatosis,
versus in 31% of the control subjects; in addition, patients with A1AT deciency had
lower concentrations of triglyceride and low- and very-low-density lipoprotein cho-
lesterol as compared to those in the control group, data interpreted to suggest that
impaired hepatic secretion of lipids is a feature of A1AT decient PiZZ variant [45].
These results tend to support the ndings of a prior study that documented some
association between the A1AT deciency PiMZ variant and NASH [46]; in this
report, patients with both conditions had an increased risk for decompensation [46].
Clinical Manifestations
In the absence of screening campaigns, patients tend to be diagnosed when they
present with symptoms of pulmonary involvement, including COPD and asthma.
Regarding subjects with liver disease, adult patients tend to be asymptomatic
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unless they have progressed to decompensation with all its complications or are
referred for evaluation of an abnormal liver panel. In patients with compensated
liver disease, the rst clue to the diagnosis is increased serum activity of trans-
aminases, which leads to a liver disease investigation that includes A1AT serum
concentrations. If these are low, which can happen in the presence of rare alleles
in addition to A1AT deciency, it is recommended to check the genotype. In case
of a discrepancy between A1AT concentration and genotype, phenotype analysis
is advised [47]. Of note, in patients with PI*Null alleles, this method does not
yield a result as the patients do not make circulating proteins. Also, rare genetic
variants that result in low levels of A1AT, including PI*M
heerlen
, or in normal
levels of a dysfunctional protein (e.g., PI*F) may not be detected; thus, genotype
testing can be added to the investigation [48]. Testing is recommended in sib-
lings [27].
Environmental modiers increase lung disease risk in patients with the Z protein
phenotype, including cigarette smoking, male gender, and asthma [49, 50]. In a
cross-sectional study, the heterozygous PiZ was not signicantly more prevalent in
patients with liver disease, 754, versus patients without, 651. From patients listed
for liver transplantation, 10 of the 173 (5.7%) had PiMZ versus 10 of the 478 (2.1%)
with liver disease considered to have “less severe” liver disease, which was reported
as signicantly different. In addition, there was an increased number of patients
with the PiZ variant among patients with decompensated liver disease from chronic
hepatitis C and nonalcoholic liver disease, 5.6%, and 5%, respectively, compared to
those with “less severe” liver disease from chronic hepatitis C, 1.2%, and from
NAFLD, 1.9%, reported as signicantly different between the compensated and the
“less severe” liver disease group. Cryptogenic cirrhosis was not associated with an
increase in the percentage of PiMZ, as compared to liver disease in which the cause
was known; thus, the presence of PiZ may accelerate the progression of liver disease
in patients with chronichepatitis C and NAFLD [46]. Although A1AT mutations
have been reported in association with NAFLD, high serum ferritin concentrations,
and an increase in the presence of sinusoidal siderosis, non-MM phenotypes were
not associated with increased liver injury in NAFLD [51].
In regards to liver disease, in a retrospective study that explored liver disease in
association with A1AT deciency in children, and that included 6 girls and 14 boys,
it was noted that the PiZZ phenotype was present in 8 (40%) of the children, and
PiMZ in 12 (60%). The most common nding was an abnormal liver prole, with
three patients having neonatal cholestasis and one compensated cirrhosis. Seven of
the eight patients who underwent liver biopsy had typical histology of A1AT de-
ciency with PAS positive, diastase resistant conglomerates in the hepatocytes. PiZZ
was associated with chronic hepatitis in all patients except one who had cirrhosis,
over 12–101months of follow-up versus only two of the patients who were PiMZ
who had chronic hepatitis [52].
Transient elastograpy is a noninvasive technique that measures liver stiffness,
which increases and correlates with brosis, expressed in kilopascals (kPa). In a
study that included 29 patients with A1AT deciency, ZZ phenotype, the median
liver stiffness was 4.5kPa (2.8–32.8), with an increase in patients with abnormal
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liver prole and ultrasound, but also, in patients with normal liver prole and ultra-
sound, albeit only 10% [53].
Patients with lung diseasefrom A1AT deciency should be referred to pulmo-
nary medicine for evaluation and treatment that include bronchodilators, oxygen
supplementation, and augmentation therapy.
Patients diagnosed with A1AT as part of the evaluation of abnormal liver tests
should also be referred to pulmonary medicine to evaluate for lung disease.
Laboratory Tests
The PI locus has approximately 123 single nucleotide polymorphisms; the differ-
ence in the migration rate that characterizes different protein variants is used to
identify the phenotype. The M migrates at a medium rate, and the Z allele at the
slowest rate. Null alleles can be inherited and are associated with no measurable
concentration of A1AT in plasma. The phenotype PI Z denes subjects who have
the Z pattern and include PIZZ and PIZ null variants. Although the phenotype refers
to the pattern of movement in protein electrophoresis, in general, it concerns the
clinical manifestations of the disease. PI Z phenotype is associated with plasma
levels of A1AT less than 15% of PI MM and the development of COPD at a rela-
tively early age. It was reported that the PI type is responsible for 72–92% of the
variation in serum A1AT levels within families of known PI Z individuals, thus
making the PI locus determinant of serum levels of AAT.
Histology
The mechanism by which A1AT deciency causes liver disease seems to be
unknown; however, it is reported that liver injury correlates with the amount of
A1AT protein, i.e., polymers, in the hepatocytes [54, 55]. Accumulated A1AT, the
hallmark of A1AT deciency, Z type, is exhibited by the PAS-positive, diastase
resistant globules in the hepatocytes around the portal tracts. These globules are the
polymerized A1AT molecules trapped in the ER, unable to exit and secreted into the
circulation (Figs. 10.1 and 10.2). Other ndings include bile stasis, steatosis, in
zone 1, and hemosiderosis. Inammation is not a dominant nding in
A1ATD. Cirrhosis in this disease can be macro and micronodular; bile ductular
proliferation may be present in cirrhosis [56].
Hepatocellular Carcinoma
The mechanism through which A1AT deciency causes HCC is unknown. It was
hypothesized that hepatocytes laden with A1AT globules are growth suppressed,
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and elaborate “trans-acting regenerative signals” transduced by globules-devoid
hepatocytes, which proliferate. Chronic regeneration in association with tissue
injury, which results from the accumulation of A1AT, as interpreted from animal
models [54, 55], leads to adenomata, which can degenerate into carcinoma [34].
In a study that included 675 patients with cirrhosis and end stage liver disease
(ESLD) from a tertiary center where patients had been referred for liver transplanta-
tion from 2003 to 2014, A1AT deciency was diagnosed in 47 (7%) patients, 14 of
whom had the PI*ZZ phenotype, 8 PI*MZ, 10 had PI*MZ phenotype, and 14 did
not have phenotype documented but were diagnosed by histology, with an incidence
of HCC of 8.5% versus 31%, signicantly different, in patients with cirrhosis from
other causes (e.g., chronic hepatitis C, nonalcoholic steatohepatitis, and liver dis-
ease from alcohol), and a cumulative rate of 0.88% per year as compared to 2.7% in
those with cirrhosis from chronic hepatitis C, 1.5% in those with NASH, and 0.9%
in those with cirrhosis from alcohol abuse, from which it was concluded that HCC
was relatively uncommon in patients from cirrhosis from AAT deciency [57].
Associated Conditions
Panniculitis is a rare condition associated with A1AT deciency, usually with Pi*ZZ
genotype, with an estimated prevalence of 1in 1000 persons. It presents itself with
painful ulcerating subcutaneous nodules that recur and leave a scar. Histologically,
it is characterized by inltrates of neutrophils deep in the dermis and connective
tissue with secondary lobular panniculitis. This rare condition can be the only mani-
festation of A1AT deciency, and thus, it is an indication to exclude the disease
[58]. A1AT polymers were documented in the skin of a patient with panniculitis in
association with A1AT deciency PiZZ, which has suggested that these conglomer-
ates of proteins exert proinammatory effects [59]. The treatment of panniculitis is
dapsone, and, if ineffective, augmentation therapy with human A1AT is indicated
[60]. In cases of rapidly progressive disease, plasma exchange has been reported as
an option [61].
Granulomatosis with polyangiitis (GPA) was also reported in association with
A1AT deciency Pi*Z, Pi*S, in addition to its association with PiZZ [62].
A retrospective study from Germany that included 4 million people identied
673 patients with A1AT deciency yielding a prevalence of 23.73 per 100,000
subjects from all age groups and 29.36 per 100 000 in individuals older than
30years with an estimated 19,162 patients with A1AT deciency over the study
period. Hypertension, renal disease, and diabetes were more common in patients
with A1AT deciency than in the control group not affected by A1AT deciency
but who had asthma or emphysema. The patients with A1AT deciency had higher
utilization of health care services, ndings that can be interpreted to suggest that
comorbidities beyond lung disease complicate the natural history of A1AT de-
ciency [63].
A1AT deciency has been considered a factor associated with arterial aneu-
rysms. However, an increased number of A1AT deciency alleles was not found
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