Primary liver Cancer and Survival in Patients
Undergoing Liver Transplantation for
Hemochromatosis
Kvis V. Kowdley, * Taveh Hassanein, # Sumanjit Kaur, # Fvanh]. Fawell, 3
David H. Van Thiel,# Emmet B. Keefle,§ Michael F. Sowell,II Bruce R. Bacon,#
Frederick L. WebevJv., # and Anthony S. TavilZ#
Cirrhotic patients with hereditary hemochromato-
sis (HHC) have an increased risk of primary liver
cancer (PLC). The purpose of this study was to
determine the prevalence of primary liver cancer
in patients with HHC undergoing orthotopic liver
transplantation (OLT). Five liver transplant cen-
ters were surveyed; clinical and pathological data
on 37 patients with HHC undergoing OLT were
retrospectively collected and analyzed. The diag-
nosis of HHC was established by a combination of
serum transferrin-iron saturation, hepatic iron in-
dex (HII), and/or pattern of liver iron staining. The
diagnosis of HHC had been unsuspected before
OLT in 13 of 37 (35%). Primary liver cancer was
found in the explants of 10 of 37 patients (27%)
and was unsuspected in 7 of 10 (70%); 8 were
hepatocellular carcinoma, and 2 were cholangio-
carcinoma; foci of hepatocyte dysplasia were
ereditary hemochromatosis (HHC) is the most
H common genetic disease in Caucasians, with a
prevalence of 3 to 5 per 1,000.’The complications of
HHC result from the deposition of iron in multiple
organs, leading to cirrhosis, cardiomyopathy, ar-
thropathy, hypogonadism, and diabetes mellitus.
There is a strong association between HHC and
primary liver cancer (PLC), particularly in HHC
patients with fibrosis or c i r r h o ~ i s .The
~ , ~ reported
prevalence of PLC in HHC ranges from 7.5% to
36%,4,5and PLC is reported to be the cause of death
in up to 45% of HHC patient^.^ However, there are
no data on the prevalence of PLC among HHC
patients undergoing orthotopic liver transplantation
(OLT) or the frequency with which a definite diagno-
sis of HHC is established before OLT. Therefore, the
primary purpose of this study was to examine the
prevalence of known and incidental PLC in HHC
patients undergoing OLT. Secondary goals were to
examine 1-year survival rate following OLT in HHC
patients, and to determine how often the diagnosis of
HHC was established before OLT.
Livw Transplantation and Surgery, Vol 1, No 4 (Jub), 1995:pp 237-241
found in 6 additional patients. Mean ( G E M ) he-
patic iron content and HI1 in 20 patients without
prior phlebotomy or bleeding were 17.2 mg/g dry
weight (k2.9) and 5.5 (+0.8), respectively. The
overall 1-year survival rate after OLT in the 37
HHC patients was 58% (v 55% for HHC patients
with PLC). We draw the following conclusions: (1)
the diagnosis of HHC is often unsuspected before
OLT, and HHC should be evaluated pretransplan-
tation by direct and indirect markers; (2) HHC
patients undergoing OLT have a high prevalence
of primary liver cancer, the majority being unsus-
pected; and (3) HHC patients have poorer than
average survival after OLT, which cannot be ex-
plained solely by the presence of concomitant
PLC.
Copyright 0 7995 by the American Association for
the Study of Liver Diseases
Materials and Methods
Five United States liver transplant centers were surveyed between
the period of July 1988 and January 1993. Clinical, biochemical,
and pathological information on patients with a known diagnosis
of HHC after OLT was retrospectively collected. The diagnosis of
HHC was made on the basis of the following: elevated serum
femtin ( > 400 pg/L1 and transfemn saturation (> 62961, hepatic
iron index (HI11 (hepatic iron concentration in prnol/g dry
weight/age in years) > 2 in the absence of prior phlebotomy
therapy or significant gastrointestinal bleeding6; and/or pattern of
significantly increased liver iron staining predominantly in hepato-
From the University of Washington, Seattle WAL; the University of
Pittsburgh, Pittsburgh, P A f ; Case Western Reserve University, Cleve-
land, OH#;Stanford Medical Center, Palo Alto, CAS; the University of
Nebraska, Omaha, NE/l; and St. Louis University, St. Louis, MO.#
Presented in part at the 44th Annual Meeting of the American
Association for the Study of Liver Diseases, Chicago, IL, November,
1993.
Address reprint requests to: Kris V. Kowdley, MD, University of
Washington School of Medicine, RG-24, Seattle, WA 981 95.
Copyright 0 1995 by the American Association for the Study of
Liver Diseases
1074-3022/95/0104-0006$3.00/0
237
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238 Kavdley et al

cytes and bile duct cells characteristic for HHC in the absence of
other causes for liver iron overload.' Reports of explanted liver
pathology were reviewed for the presence of PLC and to determine
the size and location of the PLC; patient records were reviewed to
obtain levels of serum ferritin, iron, TIBC, and alpha-fetoprotein,
available radiological studies were reviewed to examine whether
the diagnosis of HHC was known or suspected prior to OLT or
made only retrospectively after OLT and to evaluate how often the
presence of PLC was known before OLT. The 1-year survival rate
after OLT for HHC was compared with overall survival data from
the United Network for Organ Sharing (UNOS) compiled from
United Stares liver transplant centers during 1987 to 1992.8
Results
Thirty-seven patients met criteria for the diagnosis of
HHC, as shown in Table 1. All but 2 patients with
HHC were Caucasian; 2 patients with HHC and
concomitant hepatitis B were Asian. Quantitative
hepatic iron concentration was available in 21 pa-
tients without prior gastrointestinal bleeding or phle-
botomy. Twenty of 21 patients had HI1 > 2; 1patient
had a hepatic [Fel of 5.5 mg/g dry weight, and HI1 of
1.94. This patient was assumed to have HHC, given
the lack of other causes for iron overload. Mean
hepatic iron concentration (kSEM) among these 2 1
patients was 16.6 mg/g dry weight (k2.9); mean HI1
was 5.3 (k3.8).
The diagnosis of HHC had been made before OLT
on the basis of serum femtin, transfemn-iron satura-
tion, as well as pattern of liver iron staining and HI1
in 13 patients; HHC was clinically suspected by
serum iron markers but not proven before OLT in 11
patients. HHC was clinically unsuspected before
Table 1. Characteristicsof Patients With HHC
UndergoingOLT
_ _
Characteristic
~
N Mean * SEM
~
OLT in 13 of 37 patients (32%). These 13 patients all
had a pattern of liver iron staining in the explanted
liver characteristic of HHC, with iron deposition
predominantly in hepatocytes and bile duct cells.
Quantitative hepatic iron concentration and HI1 were
available in 11 of these 13 patients; 10 of 11 had
HI1 > 2; 1 patient had hepatic iron concentration of
4.5 mg/g dry weight, HI1 of 1.6, serum transfemn-
iron saturation of 94%, femtin of 545 p.g/L, HLA A
and B haplotype of A3 B7, and had experienced
multiple episodes of gastrointestinal bleeding that
could have explained the low HlI. We thought that
there were sufficient data to support a diagnosis of
HHC in this patient. Two patients did not have HIIs
available. Both had a histological pattern of iron
staining characteristic of HHC. The characteristics of
the 13 patients unsuspected of having HHC until
OLT are described in Table 2. Nine of 37 patients
(24%) had concurrent liver histopathology (3 with
PAS-positive granules identified as a-1-antitrypsin, 3
with chronic hepatitis B, and 3 with chronic non-A,
non-B hepatitis).
A PLC was found in the liver explants of 10 of 37
patients (27%); 8 patients had hepatocellular carci-
noma, and 2 patients had cholangiocarcinoma. The
PLC was clinically unsuspected (incidental) in 7 of
10 patients (70%). All patients had undergone rou-
tine pretransplantation screening for PLC, including
abdominal ultrasonography and/or computed tomog-
raphy (CT) scanning. Foci of hepatocellular dysplasia
were present in an additional 6 patients. The distribu-
tion and features of PLC in this series are described in
Table 3. The mean size of the PLC was 2.3 cm in 8
patients with solitary nodules; 2 patients had diffuse
intrahepatic carcinoma. Serum AFP was markedly
elevated in only 1patient, and moderately elevated in
2 patients with HCC; both had incidental HCC.
Actual 1-year survival rate after OLT was 58% in the
37 HHC patients; however, survival rate in the

Age (yr) 37 55 '' 1.2

Male:female 37 34:3 patients with PLC was 55%, which is similar to the
Serum albumin (g/dL) 33 2.8 2 0.1 group as a whole (Fig 1).The reported cause of death
Serum bilirubin (mg/dL) 29 6.5 ? 0.9 was infection and/or sepsis in 10 of the 13 patients
Serum AST (IU/L) 36 131 2 2 6 who died (77%); the causes of death in the 3
Serum ALT (IU/L) 33 96 2 137 remaining patients were CMV pneumonia (l),intra-
Prothrombintime (sec) 32 16.9 0.5 * cranial hemorrhage and lymphoma (I),and cardiomy-
Alpha-fetoprotein(ng/mL) 25 112 2 90.5
Transferrin saturation (%) 15 89 ? 2.9 opathy (1). Mean survival in the 10 patients who died
Serum ferritin (pg/L) 22 2,172?802 was 2.9 months, and was less than 2 months in 8
Hepatic iron (mg/g, dry weight) 21 16.6 ? 2.9 patients, highlighting the high prevalence of severe
Hepatic iron index 21 5.3 0.8 postoperative infectious complications as the major
cause of mortality.
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Liver Transplantation in Hemochromatosis 239

Table 2. Characteristicsof Patients Not Diagnosed With HHC Until After OLT

Hepatic Iron
Patient No. (mg/g) HI1 Pre-OLT Diagnosis Pathology
3 10.58 3.8 Alcohol-inducedliver disease Micronodular cirrhosis/ + iron
4 5.47 2.3 Hepatitis C +
CAH/cirrhosis iron
7 13.88 5.8 Alcohol-induced liver disease Micronodular cirrhosis/ + iron
9 8.53 3.8 Alcohol-inducedliver disease Micronodular cirrhosis/+ iron
10 14.30 4.3 Hepatitis B & C Active cirrhosis + iron
11 12.60 3.7 Alcohol-inducedliver disease +
Cirrhosis iron
13 12.23 3.7 NANB hepatitis Micronodular cirrhosis/+ iron
14 6.32 2.6 Hepatitis C Active cirrhosis + iron
15 9.47 3.3 Alcohol-inducedliver disease +
Cirrhosis iron
17 4.52* 1.6* Alcohol-induced liver disease Micronodular cirrhosis +
22 8.29 3.4 Cryptogenic cirrhosis Cirrhosis + iron
31 N/A N/A NANB hepatitis Mixed cirrhosis + iron
33 N/A N/A Hepatitis B Micronodular cirrhosis/+ iron
Abbreviation: NA, not available.
*HI1 may have been lower than 2 because of recurrent gastrointestinal bleeding.

Discussion sizes the need for an increased awareness and earlier

diagnosis of HHC. Screening for HHC has been
In this series, 32% of the patients with HHC were not
shown to be cost-effective9and inexpensive.' Further-
diagnosed before OLT, highlighting the fact that
more, early histological evaluation as well as quantita-
HHC is often unrecognized and underdiagnosed
tion of hepatic iron is preferable for a number of
even in the setting of end-stage liver disease. Given
reasons. It is more likely to lead to a specific
the fact that HHC patients who are diagnosed before
diagnosis of HHC, because gastrointestinal bleeding
the development of cirrhosis and diabetes can avoid
most life-threatening complications of HHC and can
achieve a normal life expectancy,2 our study empha-

Table 3. Distribution and Featuresof PLC in HHC

Patient Incidental/ Size AFP

No. Known (cm) Type (ng/mL)*
5 Incidental 3 HCC N/A
10 Incidental 2.1, 1.9 HCC 112
12 Incidental Diffuse Cholang CA 4.6
24 Known > 7 c m HCC 2,228
25 Known 4.5 CholangCA N/A
29 Incidental 1.8 HCC 167
33 Incidental 1.5 HCC N/A HHC HHCPLC UNOS
34 Incidental 1.0 HCC 7 (n=37) (n=11) 1987-92
36 Incidental 1.3 HCC 2
Fibrolamellar Figure 1. Actual 1-year survival rate for HHC
37 Known 3.0 hepatoma 3
patients undergoing OLT; the bars represent the
actual 1-year survival rate for the overall group of
Abbreviation: NA, not available. 37 patients, HHC patients with a PLC, and overall
*Normal range for serum a-fetoprotein (AFP) < 5 I-year survival rate among US liver transplant
ng/mL. centers during the years 1987 to 1992 as reported
by UNOS.8

240 Kowdley et nl
or other causes for relative iron depletion may occur
in end-stage liver disease, and confuse the clinical
picture. Moreover, earlier diagnosis of fibrosis or
cirrhosis because of HHC might alert the clinician to
the need for closer surveillance for PLC.
Most large series of patients with miscellaneous
causes of liver disease undergoing OLT have found
< 5% prevalence of incidental PLC,l0J1 compared
with 18.9% in the current report among patients with
HHC. The combined prevalence of dysplasia and/or
PLC was 43% in this series, confirming the observa-
tions of a number of authors that patients with HHC
are at significantly increased risk of malignant trans-
formation in the l i ~ e r .However,
~-~ the high rate of
PLC does not appear to be responsible for the
decreased 1-year survival rate observed in our series,
because patients with PLC had survival rates similar
to those of the overall group. Recent Medicare data
from the Health Care Financing Administration
(HCFA) also reported a decreased 1-year survival rate
of 54% after OLT in 56 patients with HHC, compared
with an overall 1-year survival rate of 79%.'* De-
creased survival after OLT for HHC appears to be
primarily related to an increased risk of postoperative
cardiac and infectious complications.'3%14 A recent
report by Farrell et al, which included some of the
patients in the current series, concluded that cardiac
and infectious complications were primarily respon-
sible for the disappointing outcome after OLT for
HHC.l4 Their findings support an earlier preliminary
report from the University of Pittsburgh, which also
included some of the patients in this series, that
HHC patients have an increased risk of infectious
complications after OLT.13 As Farrell et a1 have
suggested, HHC patients may have clinically silent or
subtle cardiac dysfunction that might nevertheless
increase the rate of arrhythmias and other cardiac
complications p0st-0LT.'~These investigators have
recommended vigorous iron depletion by either
phlebotomy or chelation therapy before OLT to
decrease the risk of cardiac complications. l4
The current study confirms previous reports of
associations between HHC and heterozygous a-l-
antitrypsin deficiency,15 and between HHC and
chronic viral hepatitis.I6 Given the fact that HHC is
an uncommon indication for OLT despite its report-
edly high prevalence among Caucasians, one may
speculate that a concurrent cause for liver injury such
as alcoholism or viral hepatitis is needed in many
patients with HHC to cause end-stage liver disease
requiring liver transplantation.
In conclusion, our results emphasize the need for
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increased awareness and earlier diagnosis of HHC.
The diagnosis of HHC might possibly be elusive in
patients with end-stage liver disease, given the lack of
specificity for HHC of increased serum transfenin-
iron saturation in these patients. Furthermore, com-
plications such as gastrointestinal bleeding and con-
comitant transfusions may make interpretation of
hepatic iron concentration and HI1 difficult. The
optimal management of patients with HHC is early
diagnosis by the performance of liver biopsy and
determination of quantitative hepatic iron concentra-
tion, institution of phlebotomy therapy, family screen-
ing, and genetic counseling. Prevention of PLC has
not been shown once cirrhosis has developed.2
Removal of excess tissue iron before the development
of cirrhosis may be the only way to reduce the
incidence of PLC in this condition. Whether aggres-
sive therapy with phlebotomy or chelation therapy
can decrease the cardiac and infectious complica-
tions leading to the currently disappointing results of
OLT for HHC in this and other recent series1'J2
should be examined prospectively.
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