298 Brief Case Reports
1, 2000
Figure 1. (1) Occlusion of multiple ileal and jejunal branches at
origin of superior mesenteric artery. (2) Occlusion of ileocolic
artery with reconstitution via collateral. (3) Right colic artery
occlusion.
with positive celiac and renal angiograms, per the American
College of Rheumatology (ACR) criteria for the diagnosis
of PAN, with a sensitivity and specificity of 82% and 86%
respectively (5). However the presence of uveitis and the
positive C-ANCA make this case atypical of PAN and most
consistent with WG (4, 5).
Based upon the above clinical features, the positive se-
rology for C-ANCA plus angiographic findings, we believe
that this patient has an atypical presentation of WG. The
most important feature of this case is the morbidity experi-
enced by this patient as a consequence of his unusual,
indolent overlapping symptoms, which delayed his diagno-
sis of vasculitis and the appropriate treatment, which ulti-
mately was lifesaving.
This case serves as a reminder to remain vigilant to the
possibility of systemic vasculitis despite the atypical con-
stellation of the clinical and serological features.
Reprint requests and correspondence: Ya Ju Chang, M.D.,
Division of Rheumatology, Box 1244, Mount Sinai Medical Cen-
ter, 1 Gustave L. Levy Place, New York, NY 10029-6574.
Received Aug. 4, 1998; accepted Jan. 11, 1999.
REFERENCES
1. Jennette JC, Falk RJ, Andrassy K, et al. Nomenclature of
systemic vasculitides: Proposal of an international consensus
conference. Arth Rheum 1994;37:187–92.
2. Gross LR, Antineutrophil cytoplasmatic autoantibody testing
in vasculitides. Rheum Dis Clin North Am 1995;21:987–1011.
3. Lie JT. Illustrated histopathologic classification criteria for
selected vasculitis syndromes. Arth Rheum 1990;33:1088 –93.
AJG – Vol. 95, No.
4. Duna GF, Galperin C, Hoffman G. Wegener’s granulomatosis.
Rheuma Dis Clin North Am 1995;21:949 – 85.
5. Lhote F, Guillevin L. Polyarteritis nodosa microscopic poly-
angiitis, and Churg-Strauss syndrome. Rheum Dis Clin North
Am 1995;21:911– 47.
Precipitation of Iron Overload and
Hereditary Hemochromatosis After
Successful Treatment of Celiac Disease
Michael A. Heneghan, M.D., Kenneth M. Feeley, M.D.,
Fiona M. Stevens, M.D., Malcolm P. G. Little, M.D., and
Ciaran F. McCarthy, M.D.
Departments of Medicine and Pathology, Clinical Science
Institute, University College Hospital, Galway, Ireland
INTRODUCTION
Hereditary hemochromatosis (HH) is inherited as an auto-
somal recessive trait. It is characterized by increased ab-
sorption of dietary iron, resulting in excess iron deposition
in the parenchymal cells of the liver, heart, and certain
endocrine glands. Premature death can occur from compli-
cations of chronic liver disease, hepatocellular carcinoma,
and heart failure, whereas considerable morbidity is as-
sociated with nonspecific constitutional symptoms and
malaise. It is estimated that up to 5 persons per 1000 of
European descent are homozygous for the condition (1,
2). It is speculated that intact mucosal epithelium of the
proximal small bowel may be critical for the manifesta-
tion of the condition.
CASE REPORT
In February 1986, a 61-yr-old woman presented with weight
loss of 8 kg and malaise. She had a history of anemia for 30
yr and was treated with intermittent oral iron. A nonsmoker
and nondrinker, her family history was noncontributory.
Examination revealed a woman of 45 kg with clubbing but
an otherwise normal examination. Hemoglobin was 11.0
g/dl (normal range [NR] 12–16 g/dl), mean corpuscular
volume 94.9 fL (NR 77–91 fL), platelets 517 ⫻ 109/L (NR
160 – 440 ⫻ 109/L) with Howell Jolly bodies on blood film.
Vitamin B12 and folate levels were normal. Serum iron was
11 (NR 11–26), iron binding capacity 39 ␮mol/L (NR
45–72 ␮mol/L), and serum ferritin 462 ng/ml (NR 10 –200
ng/ml). Celiac disease was confirmed on duodenal biopsy by
the presence of a flat mucosa, increased intraepithelial lym-
phocytes, and chronic inflammatory cells in the lamina
propria. Serum alkaline phosphatase was 167 u/L (NR
30 –115 u/L), with other liver function tests normal. The
patient was discharged from the hospital after 3 wk on a
gluten-free diet (GFD).
By November 1986, she was pigmented. Tests for Addi-
AJG – January, 2000
Figure 1. Liver: Perls reaction (400⫻) showing iron deposition
within hepatocytes and portal tracts.
son’s disease were negative. She weighed 53 kg and was
clinically well. Repeat duodenal biopsy showed improve-
ment in mucosal morphology. Serum iron was 50 ␮mol/L
with a normal iron binding capacity (48 ␮mol/L). Alanine
aminotransferase (ALT) was 114 u/L (NR 0 – 45 u/L) and
aspartate aminotransferase (AST) 54 u/L (NR 0 – 40 u/L).
The patient defaulted from clinic until 1989 and presented
with an ALT of 174 u/L, AST of 72 u/L, and bilirubin 24
␮mol/L (NR ⬍ 17 ␮mol/L). Hemoglobin was 15.6 g/L and
serum ferritin ⬎1000. HLA phenotype included HLA-A1,
A3, B7, B8, DR3, DR4, and DQ3. Liver biopsy showed iron
deposition within hepatocytes and in portal tracts (Fig. 1)
with mild fibrosis and fatty change. By 1993, after vene-
section of ⬎80 units of blood, ferritin was 185 with normal
liver function. Since then, liver function has remained nor-
mal with infrequent venesection. She has remained well on
a GFD without ill effects. The C282Y mutation was not
present.
DISCUSSION
Abnormalities of liver function such as elevation of AST,
ALT, and alkaline phosphatase have been reported as oc-
curring in association with or as a presenting feature of
celiac disease, with these abnormalities largely resolving
within 6 months to 1 yr of commencing a GFD (3, 4).
Treatment with GFD in this case resulted in improvement in
mucosal morphology of the small bowel, after which in-
creased iron was absorbed, as reflected by the rise in serum
ferritin and deterioration in liver function tests.
Class I HLA alleles such as HLA-A3, B7, A11, and B14
are found more often than would be expected by chance in
patients with HH, suggesting that an initial mutation causing
this condition occurred on a chromosome bearing these
alleles (5). Preservation of the HLA-A3 allele has occurred
because it may have conferred an advantage rather than a
liability (5–7). Recently, a molecular link between HFE and
a key protein involved in iron transport has been described
Brief Case Reports 299
(8, 9). The HFE protein, due to the Cys-282 3 Tyr (C282Y)
mutation, normally forms a stable complex with the trans-
ferrin receptor (TfR), the consequence of which is that the
receptor exhibits a lower affinity for transferrin. The C282Y
mutant protein forms only a trace amount of this com-
plex, allowing high affinity transferrin binding to the
uncomplexed TfR (9). Absence of the C282Y mutation as
in this patient does not, however, exclude HH. Most but
not all patients with HH in western Ireland have the
common mutation (Dr. Martin Cormacan, personal com-
munication, Department of Immunology, University Col-
lege Hospital, Galway, Ireland, 1998).
The recent findings of genes telomeric to the HLA class
I area in both celiac disease and HH is of interest in that
these two conditions are characterized by functional abnor-
malities involving the enterocyte (8, 10), one relating to
regulation of iron transport and the second relating to mu-
cosal morphology.
A single report exists in the literature describing the
development of celiac disease in a patient with HH (11). It
is therefore worth bearing in mind that small intestinal
mucosal recovery, as in this case, although critical for symp-
tomatic and morphological improvement in patients with
celiac disease, may precipitate or exacerbate underlying
hemochromatosis.
Reprint requests and correspondence: Michael A. Heneghan,
M.D., Box 3923, Duke University Medical Center, Durham, NC
27707.
Received July 22, 1998; accepted Feb. 23, 1999.
REFERENCES
1. Edwards CQ, Griffen LM, Goldgar D, et al. Prevalence of
hemochromatosis among 11065 presumably healthy blood
donors. N Engl J Med 1988;318:1355– 62.
2. Leggett BA, Halliday JW, Brown NN, et al. Prevalence of
haemochromatosis amongst asymptomatic Australians. Br J
Haematol 1990;74:525–30.
3. Bardella MT, Fraquelli M, Quatrini M, et al. Prevalence of
hypertransaminasemia in adult celiac patients and effect of
gluten-free diet. Hepatology 1995;22:833– 6.
4. Hagander B, Brandt L, Sjolund K, et al. Hepatic injury in adult
coeliac disease. Lancet 1977;2:270 –2.
5. Simon M, Le Mignon L, Fauchet R, et al. A study of 609
HLA haplotypes marking for the hemochromotosis gene:
(1) mapping of the gene near the HLA-A locus and char-
acters required to define a heterozygous population and (2)
hypothesis concerning the underlying cause of hemochro-
motosis-HLA association. Am J Hum Genet 1987;41:89 –
105.
6. Crawford DHG, Powell LW, Leggett BA, et al. Evidence that
the ancestral haplotype in Australian hemochromotosis pa-
tients may be associated with a common mutation in the gene.
Am J Hum Genet 1995;57:362–7.
7. Bulaj ZJ, Griffen LM, Jorde LB, et al. Clinical and biochem-
ical abnormalities in people heterozygous for hemochromato-
sis. N Engl J Med 1996;335:1799 – 805.
300 Brief Case Reports
8. Feder JN, Gnirke A, Thomas W, et al. A novel MHC class
I-like gene is mutated in patients with hereditary haemochro-
matosis. Nature Genetics 1996;13:399 – 408.
9. Feder JN, Penny DM, Irrinki A, et al. The hemochromatosis
gene product complexes with the transferrin receptor and
lowers its affinity for ligand binding. Proc Natl Acad Sci USA
1998;95:1472–7.
10. Zhong F, McCombs CC, Olson JM, et al. An autosomal
screen for genes that predispose to coeliac disease in the
western counties of Ireland. Nature Genetics 1996;14:329 –
33.
11. Morris WE Jr. Hemochromatosis and celiac sprue. J Florida M
A 1993;243–5.
Cholangiopathy and
Intrahepatic Stones in
Sickle Cell Disease: Coincidence
or Ischemic Cholangiopathy?
S. Hillaire, M.D., Ph.D., C. Gardin, M.D., A. Attar, M.D.,
M. Attassi, M.D., B. Terris, M.D., Ph.D.,
J. Belghiti, M.D., Ph.D., C. Degott, M.D., Ph.D.,
S. Erlinger, M.D., Ph.D., and D. Valla, M.D., Ph.D.
Service d’Hépatologie et INSERM U-481, Service d’Hépatologie
Clinique, Service de Transfusion Sanguine, Service d’Anatomie
et de Cytologie Pathologiques, Service de Chirurgie Digestive,
Hôpital Beaujon, Clichy Cedex, France
ABSTRACT
Hepatic and bile duct involvement are common in sickle cell
disease. This article reports the case of a young woman with
cholangiopathy, homozygous sickle cell disease, and pro-
tracted anemia. We suggest that sickle cell disease was
directly responsible for ischemic cholangiopathy through
anoxia. (Am J Gastroenterol 2000;95:300 –301. © 2000 by
Am. Coll. of Gastroenterology)
INTRODUCTION
Hepatic involvement or bile duct stones are common in
sickle cell disease (1, 2). The aim of this article is to report
an unusual case of cholangiopathy accompanying homozy-
gous sickle cell disease in a young woman with marked and
protracted anemia.
CASE REPORTS
A 23-yr-old woman was admitted for upper abdominal pain,
fever, jaundice, and bloody diarrhea of 1 month duration.
Twelve years before, homozygous sickle cell disease had
been recognized. All medical care and follow-up had been
refused. She became asthenic 2 yr before admission and
began to lose weight. On admission, blood hemoglobin was
4 g/dl, hemoglobin S 97%, serum creatinine 99 ␮mol/L,
total serum bilirubin 70 ␮mol/L, unconjugated serum bili-
rubin 28 ␮mol/L, serum ALT activity 1.5-fold the upper
limit of normal values (ULN), serum alkaline phosphatase
AJG – Vol. 95, No. 1, 2000
activity 10 ULN, and serum albumin 2.8 g/dl. Hepatitis C
virus antibodies were found in serum. Serum HBs antigen
and anti-HIV antibodies were absent. Duplex Doppler ul-
trasound disclosed an enlarged left liver lobe, with cystic
dilation of the left hepatic duct filled with stones. There was
no dilation of the remaining bile ducts. There was one stone
in the gallbladder. The hepatic veins, portal vein, and he-
patic artery were widely patent. Endosonography showed
thickening of the common bile duct without any stone.
Colonoscopy showed diffuse edema and purpura without
ulcerations. Histological examination of the colonic mucosa
disclosed mild, nonspecific inflammatory lesions. Upper
gastrointestinal endoscopy showed a congestive gastric mu-
cosa with ulcerations of the antrum. For 1 month, the patient
refused blood transfusion. Thereafter, she was regularly
transfused; blood hemoglobin level was maintained ⬎7.5
g/dl and hemoglobin S ⬍20%. Renal function improved.
Diarrhea disappeared and bloody stools cleared. Endoscopy
showed a return of the colonic mucosa to a normal aspect.
Two months later, the patient was readmitted with fever,
jaundice (serum bilirubin 1431 ␮mol/L), and renal failure
(serum creatinine 224 ␮mol/L). Laparotomy was per-
formed. Operative cholangiography showed a normal com-
mon bile duct, stenosis at the distal end of the left and right
hepatic ducts, stenoses and dilations with numerous calculi
in the intrahepatic bile ducts (Fig. 1). Multiple pigment
stones were extracted; a Roux-en-Y biliary– enteric anasto-
mosis was constructed and intubated with a percutaneous
catheter introduced through the left liver lobe and left he-
patic duct. Peroperative liver biopsy showed normal liver
architecture, portal and perisinusoidal fibrosis, ductular pro-
liferation, normal small bile ducts, and iron overload. Sinu-
soids were dilated and contained sickle cells. Six months
later, percutaneous extraction of the remaining intrahepatic
stones was performed for recurrent symptomatic cholangi-
tis, and was followed by improvement in liver tests. The
subsequent course was marked by fluctuating fever and
jaundice and by recurrent bouts of hemolysis due to sickle
cell crises and to alloimmunization. The crises were asso-
ciated with recurrence of bloody diarrhea and renal failure,
and improvement of these symptoms after correction of
anemia. Multiorgan failure and death occurred in January
1996. Necropsy was not allowed.
DISCUSSION
The biliary lesions in our patient consisted of multiple
stenoses and dilations of the intrahepatic bile ducts, with
pigment stones in the saccular portions of dilated ducts.
There was no evidence of infection with liver flukes. Ac-
cording to current views (3), the association of bile stasis
and bile infection likely explains intrahepatic stone forma-
tion. There was no evidence of any immunodeficiency state
and no primary gallbladder or main bile duct calculi as a
potential cause of secondary cholangitis. Therefore, a for-
tuitous association of primary sclerosing cholangitis and