Porphyria cutanea tarda and liver transplantation. , 2012; 11 (6): 951-954
Porphyria cutanea tarda in an
HCV-positive liver transplant patient: a case report
Adriano M. Pellicelli,* Aldo Morrone,** Luca Barbieri,*** Arnaldo Andreoli*
* Liver Unit. ** Azienda Ospedaliera San Camillo Forlanini, Rome, Italy.
*** Struttura Semplice Dipartimentale Centro per le Porfirie e Malattie Metaboliche,
Ereditarie-Istituto San Gallicano, IRCCS, Rome, Italy.
Introduction. Porphyria cutanea tarda (PCT) is the most common type of porphyria. The strong association
between PCT and hepatitis C virus (HCV) infection is well established. Although antiviral treatment of chro-
nic hepatitis C may improve PCT in some cases, de novo onset of PCT has been observed in patients under-
going peginterferon/ribavirin treatment. We present a rare case of a genotype 3 HCV-positive liver
transplant recipient who developed PCT during antiviral treatment and discuss its probable etiopathogene-
sis. Case presentation. A genotype 3 HCV-positive liver transplant recipient, a 42-year-old man, was trea-
ted with peginterferon alfa-2a (180 µg/week) combined with ribavirin (1,200 mg/day) for recurrence of HCV
infection after liver transplantation. He presented with hyperferritinemia but tested negative for genetic
hemochromatosis (C282Y and H63D mutations). During antiviral therapy, he developed skin lesions on his
hands characterized by vesicles and erosions consistent with PCT. PCT was confirmed by skin biopsy and
elevated urinary uroporphyrin levels (1,469 mg/24 h). He was treated with chloroquine (200 mg) twice weekly,
resulting in gradual regression of the skin lesions. Antiviral treatment was stopped after 48 weeks, and the
patient achieved a sustained virological response. In conclusion, we report an extremely rare case of PCT
in a genotype 3 HCV-positive liver transplant patient treated with antiviral therapy. We believe that the
combination of HCV genotype 3 infection; hemolysis due to ribavirin treatment; and increased plasma le-
vels of cytokines, such as IL-6 and TNFα, could have altered the patient’ s iron metabolism and thus caused
Key words. Ribavirin. Hemolysis. Hyperferritinemia. Pegylated interferon.
Correspondence and reprint request: Adriano M. Pellicelli, M.D.
Via Terni 97, 00182, Rome, Italy
Tel.: +39-06-5870-3055. Fax: +39-06-5870-4343
E-mail: firstname.lastname@example.org; email@example.com
Manuscript received: January 26, 2012.
Manuscript accepted: April 09, 2012.
November-December, Vol. 11 No.6, 2012: 951-954
Porphyria cutanea tarda (PCT) is the most com-
mon type of porphyria and results from reduced acti-
vity of uroporphyrinogen decarboxylase (UROD), an
enzyme implicated in the heme biosynthetic
pathway. The strong association between PCT and
hepatitis C virus (HCV) infection is well established.
The percentage of PCT patients found to be antibo-
dy-positive for HCV ranges from approximately
50–90%.1 However, the percentage of HCV antibody-
positive patients who develop PCT is small, which
argues against HCV infection as a direct cause of
PCT.2 Although antiviral treatment of chronic hepa-
titis C may improve PCT in some cases,3-6 de novo
onset of PCT has been observed in patients under-
going peginterferon/ribavirin treatment.7-9 Other
factors that could be implicated in PCT are hemo-
chromatosis, alcohol consumption, and drug use.
Only one case of sporadic PCT in a liver transplant
recipient has been reported in the literature. Herein,
we describe the case of an HCV-positive liver trans-
plant recipient who developed PCT during antiviral
treatment and discuss its probable etiopathogenesis.
A 42-year-old man with a history of drug addic-
tion had been diagnosed with chronic hepatitis C
(genotype 3) in 1994. His medical history was not
significant except for alcohol intake. Diabetes melli-
tus was diagnosed in 2002, and the patient was star-
ted on insulin therapy. A liver biopsy examination in
2002 revealed liver cirrhosis (Ishak grade (G) 14,
Pellicelli AM, et al. , 2012; 11 (6): 951-954
stage (S) 6). In the same year, he was treated with
peginterferon alfa-2b (100 µg/week) and ribavirin
(800 mg/day) for 6 months, but his HCV infection
relapsed 2 months after suspension of antiviral
treatment. At that time, his ferritin level was found
to be 950 ng/mL, but tests for hemochromatosis
Figure 1. The patient pre-
sented with crusted lesions (A),
vesicles, and small bullae (B) on
his hands. After treatment, the
lesions regressed as previously
Figure 2. Hemolysis due to ri-
bavirin treatment, genotype 3
HCV infection, and increased
plasmas levels of the cytokines
IL-6 and TNFα could have contri-
buted to the development of
PCT by altering intracellular
iron metabolism. PCT: porphyria
cutanea tarda. OLT: orthotopic
liver transplant. UROD: uropor-
phyrinogen decarboxylase enzy-
me. TNF alpha: tumor necrosis
factor alpha. ↑: increase. ↓: de-
OLT with HCV recurrence
↑ TNF alpha
Porphyria cutanea tarda and liver transplantation. , 2012; 11 (6): 951-954
(C282Y and H63D mutations) were negative. The
patient was started on a new, 10-month course of
treatment with peginterferon alfa-2a (180 µg/week)
and ribavirin (800 mg/day) in 2004; however, as on
the previous occasion, HCV relapsed 2 months after
the end of treatment. The patient developed ascites
and experienced rapid deterioration of liver function
(MELD 18) in January 2006, and received a liver
transplant in July 2006. His immunosuppressive
treatment consisted of tacrolimus in combination
with mycophenolate. Due to persistent hypertransa-
minasemia, a liver biopsy was performed in June
2008, and active chronic moderate hepatitis C
(Ishak G8 S3) with grade II liver steatosis was re-
vealed. Positive Prussian blue iron staining was
observed in the Kupffer cells and scattered in the
hepatocytes. There were no signs of liver rejection.
The patient’s HCV RNA level was 2,841,000 IU/mL
(TaqMan, Roche), and his ferritin level was 1,100
ng/mL. The patient was treated with peginterferon
alfa-2a (180 µg/week) (Hoffman-La Roche Ltd.-Ba-
sel) and ribavirin (1,000 mg/day) for 44 weeks but
again relapsed 2 months after the end of treatment.
A new course of treatment with peginterferon alfa-
2a (180 µg/week) and a higher dosage of ribavirin
(1,200 mg/day) (Hoffman la Roche, Basel) was ini-
tiated in March 2010. In April 2010, the patient
started on epoetin alfa (40,000 IU/week) for ribavi-
rin-induced anemia (Hb 10.5 g/dL). In July 2010,
the patient developed skin lesions on his hands cha-
racterized by vesicles and erosions consistent with
PCT (Figures 1A-1B). PCT was confirmed by skin
biopsy and elevated urinary uroporphyrin levels
(1,469 mg/24 h). At the time of the PCT diagnosis,
the patient’s hemoglobin level was 11.0 g/dL and his
ferritin level was 1,150 ng/mL. The plasma levels of
the cytokines IL-6 and TNFa were > 10 pg/mL and
21.2 pg/mL, respectively (Endogen Inc., Massachu-
setts) (normal value range for (IL)-6 is 3 ± 0.6 pg/
mL; normal value range for TNFα is 3.1 ± 0.2 pg/mL).
As the patient’s chronic ribavirin-induced anemia
did not permit phlebotomy, the PCT was treated
with chloroquine (200 mg) twice weekly, which allo-
wed gradual regression of the skin lesions (Figures
1C-1D). Antiviral treatment was stopped after 48
weeks, and the patient achieved a sustained virolo-
Herein, we describe the case of an HCV-positive
liver transplant patient who developed de novo PCT
during antiviral therapy. To our knowledge, this is
the first case of PCT reported in an HCV-positive li-
ver transplant patient treated with antiviral thera-
py. Huang, et al. have described another case of
post-liver transplant PCT in an HCV-positive pa-
tient with iron overload but not receiving antiviral
therapy. In that report, the patient developed an al-
cohol abuse habit after the transplant, which could
have contributed to increased hepatic iron deposits
and thus to the development of PCT. Our patient
had a high plasma ferritin level despite the absence
of genetic hemochromatosis. PCT is actually identi-
fied as the most frequent extrahepatic manifestation
of HCV infection in countries where the prevalence of
this viral infection is high, and HFE gene mutatio-
ns may be present in up to 73% of patients with
PCT. High ferritin levels are frequently reported in
chronic hepatitis C patients lacking an HFE muta-
tion. Sebastiani, et al. demonstrated that hepatic
iron deposits and liver steatosis in well-compensated
chronic hepatitis C infection were strongly associa-
ted with HCV genotype 3.10 Several studies have es-
tablished that there are increased serum prohepcidin
or hepcidin levels in chronic hepatitis C patients
with high plasma ferritin levels.11,12 This could be
due to inflammatory stimuli induced by the release
of a cytokine such as interleukin (IL)-6, which can
induce production of these 2 substances.13 At high
levels, hepcidin inhibits iron efflux from hepato-
cytes, macrophages, and enterocytes by binding to
ferroportin, which subsequently increases hepatic
iron deposits.13 Tumor necrosis factor alpha (TNFα)
is a proinflammatory cytokine that contributes to
the regulation of iron metabolism through several
mechanisms. TNFα has been reported to stimulate
the synthesis of ferritin and inhibit iron release
from macrophages. A transient increase in TNFα
gene expression during anti-HCV treatment has
been demonstrated; this may be connected with the
patient’s response to interferon α/ribavirin thera-
py.14 Our patient presented with high plasma levels
of TNFα and (IL)-6, which could have further con-
tributed to increased liver iron deposits. In addition,
the high dosage of ribavirin prescribed to our pa-
tient could have increased hepatic iron levels via
hemolysis and thus contributed to the de novo onset of
PCT. Five cases of porphyria cutanea tarda during
interferon and ribavirin therapy for chronic HCV
infection have been described in the literature.15 In
all 5 cases, the patients had clinical evidence of sys-
temic or hepatic iron overload. The excess of iron in
the cytosol of hepatocytes can damage UROD, redu-
cing the action of this enzyme and causing accumu-
lation of its precursor. In our case, we believe that
Pellicelli AM, et al. , 2012; 11 (6): 951-954 Download full-text
HCV infection was indirectly involved in the patho-
genesis of PCT and that altered iron metabolism ap-
pears to play the key role in triggering PCT. We
hypothesize that HCV genotype 3 infection, hemoly-
sis due to ribavirin treatment, and increased plasma
levels of cytokines such as (IL)-6 and TNFα could
have triggered the onset of PCT by altering the
patient’s iron metabolism (Figure 2).
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