ANATOMIC PATHOLOGY
Original Article
H e p a t o c y t i c
Relationship
G l o b u l e s
to
in E n d - S t a g e
Alpha^antitrypsin
H e p a t i c
D i s e a s e
Phenotype
JULIA C. IEZZONI, MD, MICHAEL J. GAFFEY, MD, ELLEN K. STACY, MT(ASCP), AND DAVID E. NORMANSELL, PhD
Hepatic explant specimens from 171 patients with cirrhosis were
examined to determine the incidence of periodic acid-Schiff
(PAS)-positive diastase-resistant globules (PDRGs) in end-stage
hepatic disease and whether the globules bear a specific relationship to the alpha1-antitrypsin (A1AT) phenotype or to causes of
hepatic disease other than A^T deficiency. PAS-positive diastaseresistant globules were detected in 17 (10%) of the hepatic explant
specimens, and the globules in all of these cases were strongly
immunoreactive for AjAT. In the 17 patients with PDRGs, the cirrhosis was attributed preoperatively to AjAT deficiency (3
patients), ethanol abuse, viral hepatitis, or both (10 patients), cryptogenic cirrhosis (3 patients), and autoimmune hepatitis (1
patient). The AjAT isoelectric phenotypes classified according to
the protease inhibitor (Pi) nomenclature for 16 of these patients
were as follows: Pi ZZ (3 patients), Pi SS (1 patient), Pi MZ (8
patients), and Pi MM (4 patients). Because PDRGs were seen in a
variety of A1AT phenotypes, serum electrophoretic analysis, not
histologic examination, is required for the correct diagnosis of an
AjAT abnormality. Furthermore, although PDRGs were seen in a
variety of hepatic diseases, the majority of patients with globules
had an undetected A1AT abnormality. Accordingly, on identification of hepatocytic PDRGs, the clinician should be alerted to the
possibility of an unsuspected A1AT abnormality even in the
presence of other causes of hepatic disease. (Key words: Alpha1antitrypsin; Hepatic disease; Hepatic transplantation) Am J Clin
Pathol 1997;107:692-697.
are homozygous (Pi ZZ) or heterozygous (Pi MZ) for
this allele are at increased risk for the development of
chronic hepatitis and cirrhosis. 2
In the liver, homozygous Pi ZZ A ^ T deficiency is
characterized histologically by intracytoplasmic, variably sized, periodic acid-Schiff (PAS)-positive diastase-resistant globules (PDRGs) in the hepatocytes. 3
These globules, immunoreactive for A ^ T , result
from retention and accumulation of the abnormal
A a AT protein within the endoplasmic reticulum. 4
Specifically, the Pi Z variant folds in an abnormal
configuration that allows the AjAT molecules to
polymerize. The p o l y m e r i z e d protein cannot be
secreted, and intracellular retention of the protein
results. 5,6 The progressive cytoplasmic accumulation
of the polymerized A ^ T molecules results in globules that are detectable by light microscopy.
Although characteristic of A ^ T deficiency, hepatocytic PDRGs are not specific for this d i s e a s e .
Previous studies have described morphologically
identical globules associated with hepatic congestion
From the Department of Pathology, University of Virginia Health
or anoxia. 7-9 The globules in these conditions are cenSciences Center, Charlottesville, Virginia.
trilobular, in distinction from the predominantly periportal distribution of the globules in A : AT deficiency.
Manuscript received April 29, 1996; revision accepted
November 20,1996.
Other studies have documented PDRGs in alcoholic
Address reprint requests to Dr Iezzoni: Department of
cirrhosis; the patients in these studies had various
Pathology, Box 214, University of Virginia Health Sciences Center,
A ^ T phenotypes including Pi MZ, Pi MM, and Pi
Charlottesville, VA 22908.
A l p h a ^ a n t i t r y p s i n ( A ^ T ) is the major protease
inhibitor (Pi) in human plasma and protects tissues
t h r o u g h o u t the b o d y against d a m a g e by a w i d e
range of proteolytic enzymes. The predominant site
of synthesis of plasma AjAT is hepatocytes. Alpha^
antitrypsin is genetically heterogeneous; more than
75 allelic variants have been reported and classified
according to the Pi n o m e n c l a t u r e . 1 This system
assesses the mobility of a variant in isoelectric focusing analysis and assigns a letter to designate the variant according to its isoelectric point, the so-called Pi
p h e n o t y p e . The alleles are i n h e r i t e d as s i m p l e
mendelian traits, and in heterozygotes, the different
alleles are expressed codominantly. Most variants are
associated with quantitatively and qualitatively normal A ^ T , and Pi M is the most common of these
"normal variants." Pi Z is the most common allele
associated with a deficiency state, and persons who
692
IEZZONI ET AL
Hepatocytic Globules in
mtic Explant Specimens
MMmalton. 1 0 ' 1 1 In a recent abstract, Ferrell et al 1 2
reported the presence of A ^ T globules in a variety of
hepatic diseases and AjAT phenotypes, including Pi
MM. They postulated that the globule formation may
be the result of a variant allele undetectable by routine isoelectric focusing or a nonspecific reaction of
hepatocytes to injury.
These previous studies were performed on hepatic
biopsy or autopsy material, with varying attempts to
address the incidence or significance of A ^ T globules in cirrhosis in general, and no study reported in
the English language literature has examined specifically hepatic explant specimens for PDRGs. In the
c u r r e n t s t u d y , h e p a t i c e x p l a n t s p e c i m e n s from
patients with cirrhosis were systematically examined
to determine the incidence of PDRGs and whether the
presence of globules bears a specific relationship to
the AjAT phenotype or to causes of end-stage hepatic
disease other than A ^ T deficiency.
MATERIAL AND METHODS
The hepatic explant specimens from 171 consecutive
patients with end-stage hepatic disease and cirrhosis
who underwent orthotopic hepatic transplantation at
the University of Virginia Health Sciences Center
(Charlottesville) from 1990 to 1994 were reviewed.
Patients who underwent retransplantation secondary to
allograft failure were excluded from the study. Clinical
information was obtained by review of patient charts.
The h e p a t i c explant s p e c i m e n s w e r e fixed in
buffered aqueous zinc formalin, processed routinely,
and embedded in paraffin. Standard tissue sections,
5-|0.m thick, were stained with hematoxylin and eosin
(H&E) and PAS with diastase digestion (PAS-D) for
microscopic examination.
From each hepatic explant specimen, one H&Estained section and one PAS-D-stained section from
the same block were examined for the presence of
cytoplasmic globules in the hepatocytes. Each slide
was examined by two of us (J.C.I, and M.J.G.) for 5
minutes. The globules seen in the PAS-D-stained sections were assessed for the following: (1) overall
quantity (scored 1+ to 3+; 1+ = rare; 2+ = moderate;
3+ = abundant); (2) the percentage of regenerative
nodules with globules (scored 1+ to 3+; 1+ = <30%; 2+
= 30%-60%; 3+ = >60%); (3) the predominant pattern
of distribution of the globules within the regenerative
nodules (peripheral or central); and (4) the percentage
of globules that were large (>10 (im in diameter, measured with a micrometer; scored 1+ to 3+; 1+ = <10%;
2+ = 10%-50%; 3+ = >50%).
693
Immunohistochemical staining for A ^ T was performed in all cases with cytoplasmic globules detected
on the sections stained with H&E, PAS-D, or both.
These studies were performed on formalin-fixed,
paraffin-embedded tissue using a standard biotinstreptavidin-horseradish peroxidase method with 3'diaminobenzidine tetrahydrochloride (DAB) as the
chromogen. A polyclonal antibody for AjAT (1:7000,
DAKO, Santa Barbara, Calif) was used. Before incubation with the primary antibody, the tissue sections
were digested with 0.4% pepsin (Sigma Chemical, St
Louis, Mo) in phosphate-buffered saline, pH 7.4, for 30
minutes at room temperature.
The AjAT level and the electrophoretic phenotype were
determined on the pretransplantation serum from the
patients with cytoplasmic globules detected on the sections stained with H&E, PAS-D, or both. The pretransplantation serum level of AjAT was quantified by standard
rate nephelometric densitometry (Beckman Array Protein
System, Beckman, Brea, Calif). The electrophoretic A ^ T
phenotype was determined by a standard polyacrylamide
gel isoelectric focusing method,13 pH gradient 4 to 5, and
the gels were examined by two of us (E.K.S. and D.E.N.).
Control serum samples of Pi ZZ, Pi MM, and Pi MS sera
were run simultaneously with the test samples.
RESULTS
PAS-positive diastase-resistant intrahepatocytic
globules were identified in 17 (10%) of the 171 hepatic
explant specimens. In 14 of these cases, the globules
were detected on the H&E-stained sections. In three
additional cases, the globules were initially identified
on the PAS-D-stained sections (patients 9,13, and 17);
in one of these cases, globules were not detectable on
the H&E-stained section on re-review (patient 17).
The globules in all 17 cases were variably sized, round
to oval, with a smooth, well-defined contour. PAS-D
staining typically identified many more globules than
seen with H&E staining, and the globules were more
readily apparent when stained with PAS-D (Fig 1).
There were no cases in which the globules detected on
the H&E-stained sections were PAS-negative.
The PDRGs were strongly immunoreactive for A ^ T
in all 17 cases, and A ^ T immunohistochemical staining detected more globules than seen on the H&E- or
PAS-D-stained sections. In addition to staining the
globules, immunohistochemical studies demonstrated
finely granular, A^T-positive material dispersed in the
cytoplasm of many of the hepatocytes. This material
was often seen in a morphologic continuum with the
AjAT-positive globules (Fig 2).
Vol. 107 No. 6
694
ANATOMIC PATHOLOGY
Original Article
FIG 1. A and B, Patient 7, with the isoelectric phenotype Pi MZ,
classified according to the protease inhibitor (Pi) nomenclature.
In comparison with hematoxylin-eosin staining (A), staining with
periodic acid-Schiff with diastase digestion (PAS-D; B) typically
identified many more cytoplasmic globules in the hepatocytes,
and these globules were more readily apparent when stained
with PAS-D (xl 25).
0.
Fie 2. Patient 16, with the isoelectric phenotype Pi MM, classified
according to the protease inhibitor (Pi) nomenclature.
Immunohistochemical staining for alphaj-antitrypsin (A^T)
showed that the globules were strongly immunoreactive for A^T.
In the cytoplasm of some of the adjacent hepatocytes, there was
variably sized, granular, AjAT-positive material in a morphologic
continuum with the A^T-positive globules (immunohistochemical
stain for A,AT with diaminobenzidine as the chromogen and
hematoxylin counterstain, x375).
During the routine surgical pathology examination
of the hepatic explant specimens, globules had been
identified on the H&E-stained sections in only four
(24%) of the 17 cases in which PDRGs were identified
in this study (patients 1 through 4). Preoperatively,
three of these four patients had been determined as
having cirrhosis secondary to severe Pi ZZ A t AT deficiency (patients 1 through 3); this clinical information
had been provided to the pathologist at the routine
examination of these hepatic explant specimens.
The clinical and pathologic features of the cases with
PDRGs are presented in the Table. At the time of transplantation, the median age of the patients with PDRGs
was 48 years (range, 8-64 years). Preoperatively, three
(18%) of these patients had been determined as A ^ T
homozygous ZZ with cirrhosis secondary to severe
AjAT deficiency (patients 1 through 3). The median
age of the remaining 14 patients was 49 years (range,
38-64 years). Of these patients, 10 (71%) had a clinical
diagnosis of cirrhosis secondary to ethanol abuse, viral
hepatitis, or both; three (21%) had cryptogenic cirrhosis, and one (7%) had probable autoimmune hepatitis.
Preoperatively, an AjAT abnormality was suspected in
none of these 14 patients.
Pretransplantation serum samples were available
for electrophoretic phenotyping of A ^ T on 16 of the
17 (94%) patients with PDRGs. The Pi ZZ phenotype
of the three patients with the pretransplantation diagnosis of AjAT deficiency w a s confirmed. Of the
remaining 13 patients, one (8%) was determined as Pi
SS, 8 (61%) as Pi MZ, and 4 (31%) as Pi MM phenotype (Fig 3).
Quantification of the pretransplantation serum
level of AjAT was available for all 17 of the patients
with PDRGs, and the average values grouped by Pi
phenotype were as follows: Pi ZZ 21 m g / d L (range,
17-24 mg/dL; median, 22 mg/dL); Pi MZ 108 m g / d L
(range, 48-156 mg/dL; median, 102 mg/dL); Pi MM
104 m g / d L (range, 92-126 m g / d L ; m e d i a n , 105
mg/dL). The one patient determined as Pi SS had an
AjAT serum level of 73 m g / d L . Of the 12 patients
with Pi MZ and Pi MM, 9 (75%) had an AjAT serum
level within normal limits (93-224 mg/dL).
Overall, the globules were more prominent in the
patients with at least one abnormal allele (Pi ZZ, SS,
or MZ) than in those who were phenotypically normal (Pi MM). In the former g r o u p , typically the
overall q u a n t i t y of g l o b u l e s , the p e r c e n t a g e of
regenerative nodules with globules, and the number
of large globules were greater than in the cases associated with a normal AjAT phenotype. Despite these
differences, however, the morphologic features of
AJCP • June 1997
IEZZONIET AL
Hepatocytic Globules in Hepatic Explant Specimens
695
Patient No. Age (ij)' Sex
1
8
M
2
48
M
3
19
M
4
56
M
5
40
M
6
38
F
7
54
M
8
44
F
9
51
F
10
48
M
11
47
M
12
64
M
13
41
M
14
41
M
15
63
M
16
53
M
17
50
F
Clinical
Diagnosis
Quantity
of Regenerative Overall
Pretransplantation A,AT
Quantity
A^AT Serum Electrophoretic Nodules
Level (mg/dL)f Phenotype* With Globules^ of Globules§
Cirrhosis due to
A, AT deficiency
Cirrhosis due to
AjAT deficiency
Cirrhosis due to
A^T deficiency
Cryptogenic
cirrhosis
Alcoholic
cirrhosis
Cryptogenic
cirrhosis
Alcoholic
cirrhosis
Cirrhosis due to
probable non-A,
non-B hepatitis
Cryptogenic
cirrhosis
Alcoholic
cirrhosis
Unknown, possible
alcoholic cirrhosis
Alcoholic
cirrhosis
Cirrhosis due to
alcohol, HBV,
and HCV
Cirrhosis due to
alcohol and HCV
Cirrhosis due to
probable autoimmune
hepatitis
Alcoholic
cirrhosis
Cirrhosis due to
probable HCV
2 a o »
CLINICAL AND PATHOLOGIC FEATURES OF PATIENTS WITH PAS-POSITIVE, DIASTASE-RESISTANT GLOBULES
22
ZZ
3+
3+
3+
24
ZZ
2+
2+
3+
17
ZZ
2+
2+
3+
73
ss
3+
3+
2+
48
MZ
3+
3+
2+
156
MZ
2+
2+
3+
94
MZ
3+
2+
2+
70
MZ
2+
1+
1+
147
MZ
1+
1+
1+
102
MZ
3+
3+
1+
126
MZ
3+
3+
3+
119
MZ
3+
3+
2+
92
MM
<1 +
Rare, <1 +
1+
126
MM
3+
2+
1+
94
MM
2+
1+
1+
105
MM
3+
2+
2+
112
NA
2+
Rare
1+
A, AT = alpha|-antitrypsin; HBV = hepatitis B virus; HCV = hepatitis C virus; NA = information not available.
*Agc at time of hepatic transplantation.
tNormal = 93-224 mg/c]L (at University of Virginia Health Sciences Center, Charlottesville).
^Isoelectric phenotypes classified according to the protease inhibitor nomenclature.
SScalc, 1+ to 3+; see text for definitions.
"Large defined as £10 mm in diameter.
the globules associated with the different phenotypes showed considerable overlap. Specifically, in
all phenotypes, the globules were distributed predominantly around the periphery of the regenerative nodules and all cases had small and large globu l e s . H e n c e , the A ^ T p h e n o t y p e could not be
distinguished based on the morphologic features of
the globules.
DISCUSSION
While the histologic hallmark of Pi ZZ A ^ T deficiency in the liver is PDRGs, 14 these globules are not
specific for A ^ T - r e l a t e d h e p a t i c d i s e a s e .
Morphologically identical globules have been reported
in various other causes of cirrhosis. 7-12 In the current
study, we systematically examined hepatic explant
Vol. 107 • No. 6
696
ANATOMIC PATHOLOGY
Original Article
specimens to determine the incidence of PDRGs in cirrhosis and whether the globules bear a specific relationship to the A7AT phenotype or to causes of endstage hepatic disease other than A ^ T deficiency.
PAS-positive diastase-resistant globules occurred in
10% of the hepatic explant specimens, a relatively frequent finding. These globules were seen in association
with a variety of A-[AT phenotypes and causes of
hepatic disease. Electrophoretic phenotyping of the pretransplantation serum samples in the patients with
PDRGs in their hepatic explant specimens demonstrated
various heterozygous or homozygous A ^ T abnormalities. In addition, 25% of the cases with globules had a
normal Pi MM phenotype. Thus, the presence of PDRGs
in the explant specimen was not indicative of a specific
A] AT phenotype or even an AjAT abnormality.
Although overall the globules associated with a Pi
MM phenotype were less prominent than those associated with an abnormal phenotype, there was considerable overlap of the morphologic features of the globules
associated with the different phenotypes. The different
phenotypes, therefore, cannot be distinguished solely
by morphology. This result concurs with the findings of
Ferrell et al, 12 who noted that the globules associated
with abnormal and normal p h e n o t y p e s were not
detectably different on blind review. Electrophoretic
analysis, not histologic examination, is required for the
correct diagnosis of an A1 AT abnormality.
Despite their relatively frequent occurrence, the
globules were often overlooked during the routine
surgical pathology examination of the explant specimens. Several reasons may account for this. Neither
the clinician nor the pathologist likely was suspicious
of an A ^ T a b n o r m a l i t y b e c a u s e m o s t of t h e s e
patients had normal serum A ^ T values or had other
risk factors for cirrhosis. Because the index of suspicion for an A ^ T abnormality was low or nonexistent,
globules probably were not sought at the time of routine histologic examination. Furthermore, the globules
are easily overlooked when scanning H&E stained
sections. The improved sensitivity and efficiency of
globule detection with PAS-D staining may justify the
expense of performing this test routinely on hepatic
explant specimens.
An additional finding of this study was that most
p a t i e n t s with PDRGs h a d an u n s u s p e c t e d A ^ T
abnormality. Nine patients with a previously undetected A ^ T heterozygous or homozygous abnormality were ascertained when electrophoretic phenotyping was performed after PDRGs were found in the
hepatic explant specimen. While the phenotype of the
serum A-[AT changes to that of the donor after hepatic
transplantation, 15 identification of an A ^ T abnormality in the recipient of a hepatic transplant has implications for the family members. Specifically, genetically
related relatives of the recipient also may have the
abnormal allele(s) and, if so, are at increased risk for
hepatic disease.
The globules in the apparent Pi MM cases may be
due to a variant allele undetectable by routine isoelectric focusing. PAS-positive diastase-resistant globules
have been reported in association with Pi Mmalton, a
recently described A^AT deficiency allele.11 This allele
M
M
MM
MS
zz
migrates to a position similar to the normal Pi M allele
Ctrl
Ctrl
Ctrl
Ctrl
in r o u t i n e isoelectric focusing gels a n d is electrophoretically indistinguishable from the normal phenotype unless special procedures are performed. 11 The
exclusion of a known deficiency allele such as Pi
Mmalton, however, does not rule out the presence of a
currently undescribed abnormal allele(s) that also electrophoretically colocalizes with the normal Pi M allele.
As described by Ferrell et al, 12 the relatively high incidence of globules in patients with the "normal" Pi M
phenotype indicates that such alleles may be common.
Analysis of AjAT on the genomic level to detect single-point mutations may identify variants that otherwise would be missed on isoelectric focusing. 16 ' 17
FIG 3. Isoelectric focusing of the pretransplantation serum samples
Alternatively, A ^ T globules in patients with a
from the patients with periodic acid-Schiff-positive diastase-resisnormal Pi MM phenotype may form as a nonspetant globules demonstrated a variety of alpha,-antitrypsin phenocific reaction of hepatocytes to injury. Normally, the
types classified according to the protease inhibitor (Pi) nomenclap
r o d u c t i o n of AjAT is met by the ability of the
ture. Lane 2, Pi MS; lane 4, Pi ZZ; lane 5, Pi MZ; lane 6, Pi ZZ; lane
hepatocyte
to secrete the protein, and there is no
8, Pi MM; lane 9, Pi ZZ; lane 10, Pi MM. Ctrl = control.
AJCP-June 1997
IEZZONIET AL
Hepatocytic Globules in ic Explant Specimens
n e t i n t r a c y t o p l a s m i c a c c u m u l a t i o n of AjAT.
Cellular injury, such as caused by alcohol, may
d a m a g e this s e c r e t o r y m a c h i n e r y a n d t h e r e b y
decrease the secretory capacity of hepatocytes. 1 8 If
A-jAT production then exceeds the capacity of the
injured hepatocytes to secrete the protein, the subsequent intracytoplasmic accumulation of A}AT
may result in globules visible by light microscopy.
This hypothesis is supported by our finding that
most of the patients with globules had underlying
hepatic disease, with alcoholic hepatitis and viral
hepatitis particularly prevalent. The association of
PDRGs with alcoholic cirrhosis was also observed
by Pariente et al, 10 who described a higher prevalence of globules in patients with, than in those
without, s u p e r i m p o s e d alcoholic hepatitis.
Furthermore, Pi MZ heterozygous patients with an
u n d e r l y i n g hepatic disease, such as alcoholic or
viral hepatitis, have expression of the a b n o r m a l
protein a n d h e p a t o c y t e d a m a g e . These p a t i e n t s
m i g h t h a v e an i n c r e a s e d p r o p e n s i t y to f o r m
PDRGs, b e c a u s e they have two risk factors for
globule formation.
697
REFERENCES
1. Massi G, Chiarelli C. Alpha-1-antitrypsin: Molecular structure
and the Pi system. Acta Paediatr. 1994;393(suppl):l-4.
2. van Steenbergen W. Alpha-1-antitrypsin deficiency: an
overview. Acta Clin Belg. 1993;3:171-189.
3. Sharp HL. The current status of alpha-1-antitrypsin, a protease
inhibitor, in gastrointestinal disease. Gastroenterology.
1976;70:611-621.
4. Perlmutter DH. The cellular basis for liver injury in alpha-1 antitrypsin deficiency. Hepatology. 1991;13:172-185.
5. Lomas DA, Evans DL, Finch JT, Carrell RW. The mechanism of
Z alpha-1-antitrypsin accumulation in the liver. Nature.
1992;357:605-607.
6. Lomas DA. Loop-sheet polymerization: the structural basis of Z
alpha-1-antitrypsin accumulation in the liver. Clin Sci (Colch).
1994;86:489^95.
7. Reintoft I. Periodic acid-Schiff-positive non-glycogenic globules in hepatocytes. Acta Pathol Microbiol Scand.
1978;86:325-329.
8. Carlson J, Eriksson S, Hagerstrand I. Intra- and extracellular
alpha-1-antitrypsin in liver disease with special reference to
Pi phenotype. / Clin Pathol. 1981;34:1020-1025.
9. Qizilbash A, Young-Pong O. Alpha-1-antitrypsin liver disease
differential diagnosis of PAS-positive, diastase-resistant
globules in liver cells. Am ] Clin Pathol. 1983;79:697-702.
10. Pariente E-A, Degott C, Martin J-P, et al. Hepatocytic PAS-positive diastase-resistant inclusions in the absence of alpha-1 antitrypsin deficiency: high prevalence in alcoholic cirrhosis.
Am ] Clin Pathol. 1981;76:299-302.
Although the mechanism of globule formation in
11. Roberts EA, Cox DW, Medline A, Wanless 1R. Occurrence of
non-Pi ZZ livers is still s p e c u l a t i v e , all h e p a t i c
alpha-1-antitrypsin deficiency in 155 patients with alcoholic
explant specimens should be examined closely for
liver disease. Am ] Clin Pathol. 1984;82:424-427.
12. Ferrell L, Steinkirchner T, Sterneck M, et al. Alpha-1-antitrypsin
hepatocytic globules regardless of the clinical history.
globules in cirrhotic livers. Mod Pathol. 1993;6:110. Abstract.
Because PDRGs were seen in normal and abnormal
13. Jeppsson J-O, Franzen B. Typing of genetic variants of alpha-1A ^ T phenotypes, serum electrophoretic analysis,
antitrypsin by electrofocusing. Clin Chem. 1982;28:219-225.
14. Sharp HL. Alpha-1-antitrypsin deficiency. Hosp Pract.
not histologic examination, is required for the correct
1971;6:83-96.
diagnosis of an AjAT abnormality. Furthermore,
15. van Furth R, Kramps JA, van der Putten ABMM, et al. Change
while PDRGs were seen in a variety of hepatic disin alpha-1-antitrypsin phenotype after orthotopic liver transeases other than A ^ T deficiency, most patients with
plant. Clin Exp Immunol. 1986;66:669-672.
16. Dahlen P, Carlson J, Liukkonen L, et al. Europium-labeled
globules had an undetected A a AT abnormality. Thus,
oligonucleotides to detect point mutations: application to Pi Z
on identification of hepatocytic PDRGs, the clinician
alpha-1-antitrypsin deficiency. Clin Chem. 1993;39:1626-1631.
should be alerted to the possibility of an unsuspected
17. Gunneberg A, Scobie G, Hayes K, Kalsheker N. Competitive
assay to improve the specificity of detection of single-point
A 1 AT abnormality even in presence of other causes of
mutations in alpha-1-antitrypsin deficiency. Clin Chem.
hepatic disease.
1993;39:2157-2162.
18. Baraona E, Leo MA, Borowsky SA, Lieber CS. Pathogenesis of
Acknmvlecigments: We thank Ursula W. Miller for her photographic
alcohol-induced accumulation of protein in the liver. ] Clin
expertise and Jim Sullivan for graphic arts assistance.
Invest. 1977;60:546-554.