• Pedijatrija danas 2005;1(2):73-80

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    • Abstract: Pedijatrija danas 2005;1(2):73-80ALPHA -1- ANTITRYPSIN DEFICIENCYDeficijencija alfa-1-antitripsinaNedim Had`i}Department of Child Health/Institute of Liver StudiesKing’s College Hospital, London, UKReview article

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Pedijatrija danas 2005;1(2):73-80
Deficijencija alfa-1-antitripsina
Nedim Had`i}
Department of Child Health/Institute of Liver Studies
King’s College Hospital, London, UK
Review article
Alpha-1-antitrypsin (A1AT) deficiency is the commonest genetic cause of liver disease in
children and chronic obstructive lung disease in young adult smokers. The pathogenetic mechanisms
are completely different. While low serum levels of A1AT cause reduced alveolar elasticity and
subsequent emphysema, the liver disease in children with PiZZ phenotype is due to retention of
abnormally folded A1AT in the hepatocytes. The symptomatic liver disease, however, develops in
only 10-15% of children carrying the PiZZ phenotype and not in PiSS, PiNull and PiSZ phenotypes
during childhood. The affected children have different degrees of severity of the liver involvement;
approximately 25% will develop early cirrhosis necessitating liver transplantation, which repre-
sents the only effective treatment at present. A1AT deficiency is being increasingly recognised
as a cause of liver disease in adults, where even a heterozygous state (PiMZ) may increase risks
of developing hepatopathy in presence of other risk factors, such as chronic hepatitis B and C,
alcohol abuse, autoimmunity or increased insulin resistance and steatohepatitis.
Key words: Alpha-1-antitrypsin deficiency, chronic liver disease, liver transplantation.
Revijalni ~lanak
Alfa-1-antitripsin (A1AT) deficijencija je naj~e{}i nasljedni uzrok oboljenja jetre
kod djece, te hroni~ne obstruktivne bolesti plu}a kod pu{a~a u srednjem `ivotnom dobu.
Njihovi patogenetski mehanizmi su kompletno razli~iti. Niski nivoi A1AT u serumu dovode
do smanjene elasti~nosti alveola i posljedi~nog emfizema, dok je oboljenje jetre kod djece sa
PiZZ fenotipom uzrokovano zadr`avanjem abnormalno preklopljenog A1AT u hepatocitima.
Oboljenje jetre sa klini~kim simptomima se razvija samo u 10-15% djece sa PiZZ fenotipom,
dok nije prisutno kod onih sa PiSS, PiNull i PiSZ fenotipovima tokom djetinjstva. Djeca sa
simptomima imaju razli~ite stepene oboljenja jetre; oko 25% pacijenata razvija progresivni
hroni~ni hepatitis i ranu cirozu, gdje je jedini efikasni tretman transplantacija jetre. A1AT
deficijencija se sve ~e{}e otkriva kao uzrok oboljenja jetre kod odraslih, gdje ~ak i hetero-
zigotno stanje (PiMZ) mo`e pove}ati rizik hepatopatije, posebno u prisustvu dodatnih faktora
Pedijatrija danas 2005;1(2):73-80
rizika kao {to su hroni~ni hepatitis B i C, alkoholizam, autoimunitet ili pove}ana rezistencija
inzulina sa steatohepatitisom.
Klju~ne rije~i: Alfa-1-antitripsin deficijencija, hroni~no oboljenje jetre, transplantacija jetre.
INTRODUCTION AND abnormal folding, augmented polymerisa-
DEFINITION tion and retention within the hepatocytes.
This has been well documented for the PiZZ
Alpha1-antitrypsin def iciency and PiSS A1AT variants (4).
(A1ATD) is the commonest metabolic
cause of chronic liver disease (CLD)
in Caucasians and the leading genetic EPIDEMIOLOGY
indication for liver transplantation in
children (1). Furthermore, smokers with A1ATD is a condition affecting
A1ATD are at risk of developing chronic mainly Caucasians, although individuals
obstructive lung disease in adulthood. with different variants have been anecdot-
Other complications such as vasculitis, ally reported from other ethnicities (5).
glomerulonephritis and panniculitis have Normal serum levels of the A1AT protein
also been described. are associated with the PiMM phenotypes,
Alpha1-antitrypsin (A1AT) is a while A1ATD is characterized by absent or
highly polymorphic 55-kD glycoprotein, significantly reduced serum A1AT levels
belonging to the serine protease inhibitor and phenotypic profiles PiNull, PiZ and
(serpin) superfamily (2). The Pi gene is lo- PiS on serum isoelectric focusing. Al-
cated on chromosome 14q31-32.1. A1AT most one hundred genetic A1AT variants
is produced at a rate of 34 mg/kg/day, have been described to date (6). PiZ and
primarily by hepatocytes, but also alveolar PiS deficiency are related to 342 Glu→
macrophages and intestinal endothelial Lys and 264 Glu→Val point mutations,
cells (2,3). The A1AT protease inhibitor respectively (6). A1ATD is inherited in
physiologically occurs in an unstable an autosomal codominant fashion; the
variant, which, upon activation, undergoes prevalence of PiZ and PiS alleles in non-
a structural change when its reactive centre consanguineous populations of European
is exposed to the attached target protease. descent is estimated to be between 0.5-2%
This conformational change has the role of and 1-9%, respectively (7).
inactivating the protease at the end of the
acute phase reaction (2). The A1AT variants CAUSES, RISK FACTORS,
other than the wild type (PiMM) appear to DISEASE ASSOCIATIONS
be less stable, leading to an increased inci-
dence of spontaneous opening of the main PiZZ A1ATD leads to CLD in 10-
sheet of the molecule, and, consequently, 20% of affected children (8). Liver disease
Pedijatrija danas 2005;1(2):73-80
has also been described with rare Pi Siiyama livers as early as 19 weeks post-conception
and Mmalton variants of A1AT. Possible ge- (10), when exposure to triggers of acute
netic modifiers leading to the development phase response is minimal. Some early
of CLD in only a minority of the affected studies have suggested an increased preva-
individuals with the PiZZ phenotype are lence of light-for-gestational age infants
yet to be identified. Of the symptomatic amongst PiZZ children who later require
PiZZ children, approximately one quarter liver transplantation (11). What is relation
progresses to end stage CLD and require between accumulation of Z A1AT polymers
liver replacement during childhood (1,9). and liver injury remains unclear at present.
Presence of fibrosis in the liver biopsies and However, these polymers are present also
jaundice after six months of age are associ- in the 80-85% of PiZZ A1AT-deficient indi-
ated with the highest risk of developing end viduals who do not develop clinically overt
stage CLD in childhood (1). liver disease and therefore are unlikely to be
Chronic obstructive lung disease can major effectors of damage per se.
develop in PiNull, PiZ and PiS A1ATD, albeit Liver histology in infancy dem-
only in a small proportion of patients and in onstrates non-specific portal and lobular
strong association with smoking. There is no hepatitis with variable cholestasis, mild
information as yet on whether symptomatic biliary features and fibrosis (Fig. 1).
children with liver disease are at risk of
developing lung disease later in life.
The mechanisms of liver and lung
disease in A1ATD are different. While
adults appear to develop chronic obstruc-
tive lung disease as a direct consequence
Fig.1.: Liver biopsy from an infant with
of low serum levels of the A1AT protein,
a1ATD denoting expansion of portal
with consequent decreased protease
tract, bile duct reduplication and portal
inhibitory activity during inflammatory
and periportal inflammation (H & E
processes in the lungs, the pathogenesis of
staining, x 150) (reproduced with per-
liver disease is less clear. It has been sug-
mission from: Hadzic N. and Mieli-Ver-
gested that conformational changes of the
gani G. Alpha-1-antitrypsin deficiency
unstable A1AT variants lead to retention
in Weinstein WM, Hawkey CJ and Bosch
of polymers of abnormally folded A1AT
J (eds) Clinical Gastroenterology and
in the hepatocytes endoplasmic reticulum
Hepatology, Elsevier Philadelphia,
(4). Their presence can be demonstrated
by immunoperoxidase staining in the foetal
Pedijatrija danas 2005;1(2):73-80
The appearances can sometimes hepatitis in adult patients with PiMM
mimic biliary atresia. Presence of peri- phenotype. Children with A1ATD related
portal microvesicular fat may represent an liver disease who present later during
important diagnostic clue (Fig. 2).
Fig. 3: Liver biopsy demonstrating re-
tained granules and globules of A1ATD
(arrow) (PASD staining, x 400) (repro-
Fig. 2: Liver biopsy in an infant with duced with permission from: Hadzic
PiZZ A1ATD showing severe periportal N. and Mieli-Vergani G. Alpha-1-an-
deposition of macrovesicular fat and titrypsin deficiency in Weinstein WM,
incipient portal fibrosis (H & E stain- Hawkey CJ and Bosch J (eds) Clinical
ing, x 150) (reproduced with permis- Gastroenterology and Hepatology,
sion from: Hadzic N. and Mieli-Vergani Elsevier Philadelphia, 2005)
G. Alpha-1-antitrypsin deficiency in
Weinstein WM, Hawkey CJ and Bosch J childhood usually have inactive fibrosis
(eds) Clinical Gastroenterology and or frank cirrhosis.
Hepatology, Elsevier Philadelphia,
The demonstration of magenta-co- The commonest presentation of
loured A1AT deposits on periacid Schiff A1ATD is with prolonged neonatal jaun-
(PAS) stain is usually not possible within dice, pale stools, dark urine, elevated
the first six months of life. Presence of liver enzymes and, less frequently, vi-
PAS-positive, diastase-resistant granules tamin K-responsive coagulopathy (9).
and globules in the periportal hepatocytes Approximately 15% of the symptomatic
of older children is highly suggestive of PiZZ children present later during child-
A1ATD (Fig. 3), but conventional pheno- hood with the signs of established CLD,
typing or genotyping is still required for including hepatosplenomegaly, impaired
the diagnosis, since these granules are liver synthetic function and/or complica-
seen in PiZ heterozygotes, and, at times, tions of portal hypertension. Standard
in hepatocellular carcinoma or alcoholic biochemical indices of liver function tests
Pedijatrija danas 2005;1(2):73-80
are deranged, but with no clear pattern. 10 % in Southern and Western Europe (7).
One study has suggested that presence of Abnormal polymerisation of A1AT PiSS
cholestasis at six months of age indicates individuals has been demonstrated in vitro
a poor prognosis (1). (2), but does not appear to lead to its reten-
Abdominal ultrasound scan (USS) is tion in the hepatocytes and consecutive liver
usually unremarkable at presentation in in- damage in children.
fancy. Later, nonspecific abnormal appear-
ances of the liver parenchyma, abnormal
portal flow, splenomegaly and mild ascites, DIFFERENTIAL DIAGNOSIS
suggestive of CLD, can be observed.
Asymptomatic individuals with CLD At presentation in early infancy
can be detected on family screening, instituted A1ATD must be distinguished from non-
when the diagnosis is made in the proband. specific giant cell hepatitis, biliary atresia,
Homozygous and heterozygous neonatal sclerosing cholangitis, cystic
forms of PiZZ A1ATD are increasingly fibrosis and Alagille syndrome. Diagnosis
recognised in adults with cryptogenic cir- should be made by determining the A1AT
rhosis or CLD associated with alcoholism, phenotype, since blood levels of A1AT,
iron overload, autoimmunity or chronic an acute phase reactant, are often within
hepatitis B and C (12,13). It is conceiv- the normal range in deficient infants with
able that possession of a PiZ allele may inflammatory conditions. In the less com-
represent a co-morbidity element in the mon post-infantile presentation, the diag-
“multiple hit” theory of pathogenesis of nosis is often suggested by the presence of
the liver injury. The liver disease can re- PAS-positive, diastase-resistant material
main clinically silent for many years since on liver histology. Clinically, other causes
there are anecdotal reports of abnormal of CLD in childhood such as autoimmune
biochemical liver indices associated with liver disease, Wilson disease and storage
precocious emphysema as well as inciden- disorders need to be ruled out.
tal findings of cirrhosis at post mortem in
asymptomatic PiZZ adults.
Individuals with PiZZ A1ATD are DIAGNOSTIC METHODS
at an increased long-term risk of develop-
ing hepatocellular carcinoma or cholan- The diagnosis of A1ATD may be
giocarcinoma (14,15). Interestingly, some suspected on low serum levels of the pro-
of the patients with these malignancies tein or absent alpha-1 band on the agarose
have been non-cirrhotic and inconsistently gel serum protein electrophoresis, particu-
alpha-fetoprotein positive. larly in older children, but the abnormal
PiSS A1ATD has been detected phenotype should be confirmed by iso-
incidentally in children with various forms electric focusing on polyacrylamide gel,
of liver disorders (16), in keeping with the which is based on the different mobility of
estimated high PiS allele prevalence of 4- the A1AT variants (Fig. 4). Occasionally,
Pedijatrija danas 2005;1(2):73-80
in the jaundiced infants differentiation TREATMENT AND PREVENTION
between Z and S band may be difficult
on isoelectric phenotyping. Genotyping There is no effective way of modi-
by allele specific oligonucleotide probe fying the natural history of CLD in
hybridisation should be undertaken in se- PiZZ A1ATD. The only proven treatment
lected cases, such as antenatal diagnosis, for PiZZ A1ATD-related CLD is liver
presence of severe jaundice or history of transplantation. There are reports that
very recent blood transfusions. Parental transplanted patients with A1ATD may
testing to document their heterozigos- be more prone to develop hypertension in
ity is mandatory for confirmation of the the immediate postoperative period due to
diagnosis. subclinical renal involvement (3). Overall
survival rates in A1ATD are similar to
other indications for elective liver trans-
plantation. With a successful transplant
the phenotype is changed to the one of
the donor. It is yet unclear whether A1AT
transplant recipients have an increased
risk of developing post-transplant calci-
neurin inhibitor-related nephrotoxicity
and whether they are protected from lung
complications in adult life.
Avoidance of added risk factors
such as active and passive smoking or
heavy drinking is advisable in individu-
als with the PiZ allele, though there is no
clear evidence that this always prevents
liver and lung disease.
Genetic counselling is difficult
because of the varying clinical severity
Fig. 4.: A1AT phenotypisation using
and difficulty in predicting the progno-
isoelectric focusing (right to left): lane
sis. Early series have reported up to 75%
1: PiMM – normal; lanes 2 & 5: PiMZ
concordance in severity of liver disease
and PiMS heterozygous carriers; lanes
among siblings (9), though this should
3, 4 & 6: PiZZ, PiSZ and PiSS A1ATD
be confirmed in larger studies. Prenatal
(reproduced with permission from:
diagnosis can be made from genetic
Hadzic N. and Mieli-Vergani G. Alpha-
analysis after chorionic villi sampling at
1-antitrypsin deficiency in Weinstein
8-10 weeks’ gestation.
WM, Hawkey CJ and Bosch J (eds)
A better understanding of the
Clinical Gastroenterology and Hepatol-
pathogenesis of liver injury in A1ATD,
ogy, Elsevier Philadelphia, 2005)
in particular of the role of the abnormal
Pedijatrija danas 2005;1(2):73-80
folding of the PiZ variant and of the as- is good. Of these, 25% show no further
sisted export of the abnormal protein from evidence of liver disease, 25% develop
the hepatocytes, will hopefully lead to cirrhosis requiring transplantation before
effective treatment and/or prevention of the second decade of life, and the remain-
liver damage. der continue to exhibit biochemical and/or
clinical evidence of liver disease, which
may decompensate in adult life. The long-
COMPLICATIONS AND THEIR term susceptibility of children presenting
MANAGEMENT with liver disease in infancy for develop-
ing chronic obstructive lung disease is
Children with severe chronic liver yet unknown. PiZZ individuals, including
disease related to A1ATD can develop non-cirrhotic ones, have slightly increased
complications such as portal hyperten- lifelong risk of developing hepatocellular
sion, hypoalbuminaemia and ascites at carcinoma (15).
any time during childhood. Liver decom-
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Rad primljen 19.11.2005. godine. Zavr{ene recenzije 27.12.2005. godine. Kontakt adresa autora: dr. Nedim Had`i},
MD MSc FRCPCH, Consultant/Honorary Senior Lecturer in Paediatric Hepatology, Department Child Health/Institute
of Liver Studies, King’s College Hospital, Denmark Hill, London SE5 9RJ, UK

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