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20. End-stage liver disease, HIV and liver transplantation
https://t.me/medicina_free
invasion or extrahepatic disease).
A new indication for LT in HIV positive patients was described in a
French study (Tateo 2008). Three patients underwent LT due to nodular
regenerative hyperplasia. LT is the only therapeutic option in cases of
severe portal hypertension caused by nodular regenerative hyperplasia,
and disease does not seem to recur ater LT (Sultanik 2013).
HIV criteria
Most LT groups from Europe and North America use similar HIV
criteria. These are summarised in Table 1 (Blumberg 2019, Morabito 2016,
Miro 2005, O’Grady 2005).
Table 1. HIV criteria for liver transplantation in HIV positive patients in Europe and the US
Spain
Miro
2005
Previous AIDS-defining events
Accepted
opportunistic
infections (OIs)
Neoplasms No Not defined No No**
CD4 cell count/mm
No previous
OIs
Previous OIs >200 >100*** >20 0 >200
Plasma HIV-1
RNA viral load
<50 copies/mL
on ART****
*Patient s with previous tuberculosis, Pneumocystis jirovecii pneumonia, or oesophageal
candidiasis can be evaluated for LT.
**Only progressive multifocal leukoencephalopathy, cryptosporidiosis, multidrug systemic
fungal infections, lymphoma, and visceral Kaposi’s sarcoma are exclusion criteria.
***Patients with CD4 < 100 cells/mm
****If HIV plasma viral load is detectable, post-LT suppression with cART should be expected
in all patients.
Some* Some* None in the
3
>10 0 >100*** >10 0 >200 or >100
Yes Yes Yes Yes Ye s
France
DuclosVallee 2008
3
were not excluded in France (case by case evaluation).
Italy
Morabito
2016
previous
year
UK
O’Grady
2005
None after
cART-induced
immune
reconstitution
if portal
hypertension
US
Blumberg
2019
Most**
>10 0
Clinical criteria
Some authors are in favour of waving exclusion criteria for some OIs that
can be efectively treated and prevented, such as tuberculosis, candidiasis,
and Pneumocystis jirovecii pneumonia (Nef 2004, Radecke 2005, Roland 2004).
In fact, the US NIH has updated the inclusion criteria and only untreatable
diseases continue to be exclusion criteria for LT (e.g., progressive multifocal
leukoencephalopathy, chronic cryptosporidiosis, multidrug-resistant
systemic fungal infections, primary CNS lymphoma, and visceral Kaposi’s
sarcoma) (Blumberg 2019).
Immunological criteria
All groups agree that the CD4+ T lymphocyte count should be above 100
cells/mm3 for LT (Nef 2004, Roland 2004). This igure is lower than that
for kidney transplantation (CD4 >200 cells/mm3), because patients with
cirrhosis oten have lymphopenia due to hypersplenism, which leads to a
lower absolute CD4 cell count, despite high CD4 cell percentages and good
virologic control of HIV. In Spain, Italy, and the US, the CD4 cell count must
be greater than 200 cells/mm3 in patients with previous OIs (Blumberg
2019, Morabito 2016, Miro 2005).
In Italy (Grossi 2012) and the UK (O’Grady 2005), the CD4 cut-of is
200 cells/mm3, unless patients have decompensated cirrhosis or portal
hypertension; in this situation, the CD4 cell count threshold is 100 cells/mm3.
Virologic criteria
The essential criterion for LT is that the patient must have the option of
efective, safe and long-lasti ng cAT dur ing the posttransplant period (Fung
2004, Nef 2004). The best situation is stable cAT before transplantation
with undetectable HIV viral load by ultrasensitive techniques (<50 copies/
mL). Currently, cAT is recommended for all HIV positive adults (Saag 2018).
However, in the limited number of patients in which the beneit of initiating
cAT is not clear (e.g., elite controllers), it is unknown whether and when
(pretransplant or posttransplant) it would be beneicial to initiate cAT in
order to reach an undetectable HIV plasma viral load. The proportion of
HIV positive patients are not admitted on the LT waiting list for reasons
related to their HIV (e.g., history of OIs or uncontrolled HIV infection) may
vary between 6% and 10% (Martel-Laferriére 2015, Gelu-Simeon 2015).
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Other criteria
To be included on the LT waiting list, HIV positive people must have had
a favourable psychiatric evaluation. Psychiatric problems are the reasons
for contraindication against LT in 3% of HIV positive LT candidates (GeluSimeon 2015).
Patients who use recreational or injecting drugs should not be placed on
the waiting list. In Spain, patients must undergo a two-year period without
using heroin and cocaine (Miro 2005), and six months with no consumption
of other drugs (e.g., cannabis, alcohol). A recent paper reported that 13% of
those HIV positive LT candidates were not enlisted due to active drinking
(Gelu-Simeon 2015).
Patients who are on stable methadone maintenance are accepted for
transplantation and can continue opioid maintenance ater transplantation
(Jiao 2010). Finally, as with other transplant candidate, HIV positive patients
must have an appropriate degree of social stability in order to ensure
adequate care in the posttransplant period. Around 20% of HIV positive
patients who are not enlisted for LT due to psychosocial reasons such as lack
of family/social support or toxic consumption (Martel-Laferriére 2015, GeluSimeon 2015).
Outcome of LT in HIV positive patients
Overall, mid- and long-term survival rates of HIV positive LT recipients
are comparable to HIV negative patients, except for HCV/HIV coinfection.
Survival rates in patients with HCV/HIV coinfection is lower compared to
HCV monoinfected LT recipients (Table 2) (see below) (Coin 2010, DuclosVallee 2008, Miro 2012, Terrault 2012, Locke 2016). However, with the high
HCV eradication rates currently seen with DAAs, life expectancy in HCVHIV LT recipients should be the same as in HIV negative recipients.
Most patients-maintained HIV viral suppression with good
immunological status ater LT (Miro 2015). Moreover, case reports of HIV
positive LT recipients receiving organs from HIV positive deceased donors
have been promising (Calmy 2016, Hathorn 2016). Studies under the HOPE
Act (Fishman 2016) will provide more robust evidence in the coming years.
are also needed. Additionally, some patients will receive treatment for
posttransplant complications such as de novo diabetes mellitus or arterial
hypertension. Patients who are receiving methadone treatment can restart
ater LT. As a general rule, HIV positive patients should follow the same
recommendations of care as any other LT recipient (Lucey 2013).
People living with HIV have not shown an increased risk of postoperative complications or a higher incidence of OIs or tumours than HIV
negative patients (Harbell 2013, Miro 2015, Samuel 2008).
Infectious complications
Posttransplant infections are a major cause of morbidity and mortality
in LT recipients who are HIV positive (Miro 2015). However, incidence
and aetiology of infections in HIV positive patients during the early
posttransplant period are similar to those reported in HIV negative patients
(Miro 2015). A high rate of severe non-opportunistic (43%) and opportunistic
(11%) infections in a cohort of 84 patients with HCV/HIV coinfection who
underwent LT has been reported (Moreno 2012): bacterial infections
occurred in 38 patients (45%), CMV infections in 21 (25%), uncomplicated
herpes virus infections in 13 (15%), and fungal infections in 16 patients (19%,
7 invasive cases). A pretransplant MELD score >15, history of category C
AIDS-deining events and non-tacrolimus-based immunosuppressive
regimens were factors independently associated with severe infections.
A French study found that 37% (40/109) of HIV positive LT recipients
developed at least one infection during the irst year ater transplantation
(Teicher 2015). Most were respiratory bacterial infections (45%) followed
by those afecting the biliary tract (20%). Three patients developed
CMV disease (colitis, pneumonia and hepatitis) and four developed an
opportunistic infection (two oesophageal candidiasis, one lymph node
tuberculosis and one atypical mycobacterial infection). The mortality
associated with infections was 21% (9/43). A MELD score > 17 points at the
time of LT was associated with a two-fold higher risk of developing severe
infections posttransplantation (Teicher 2015).
Other complications
Complications after LT in HIV positive patients
Ater LT, patients and medical staf responsible for their care face a
complex clinical setting (Miro 2007, Miro 2015). Patients should continue
cAT while immunosuppressive agents and antibiotic prophylaxis for OIs
522 523
A high incidence of posttransplant hepatic artery thrombosis (HAT)
(12%, 3/24) was observed in one small cohort (Cherian 2012), while in HIV
negative people, HAT is reported in about 4.4% (Bekker 2009). However,
this inding was not conirmed in two other cohorts: the irst including 32
patients (none of whom presented with HAT) (Gastaca 2012) and the second
20. End-stage liver disease, HIV and liver transplantation
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including 125 HIV positive liver recipients which reported six (5%) cases
of HAT (Harbell 2013). Larger studies are needed in order to obtain more
robust data on this relevant complication.
Table 2. Liver transplantation in HIV positive patients: nationwide cohorts in the late cART
era (2003 to 2015)
Country Time
period
France
(DuclosValeè
2008)
Spain
(Miro
2012)
US
(Terrault
2012)
US
(Coffin
2010)
US
(Locke
2016)
1999–
2005
2002–
2006
2003–
2010
20 01–
2007
2002–
2011
Number and type
of patients
HIV+/HC V+ (n=44) – 73% - 51 % – 4
HIV-/HCV+ (n=35) – 91% - 81% –
HIV+/HC V+ (n=8 4) 88% 71% 62% 54% – 8
HIV-/HCV+ (n=252) 90% 81% 76% 71% –
HIV+/HC V+ (n=89) 76% 60% – 1
HIV-/HCV+ (n=235) 92% 79% –
HIV+/HBV+ (n=22) 85% 85% 85% – 0.09
HIV-/HBV+ (n=20) 100% 100% 100% –
HIV+ (n=149) 77% 62% 56% 39% 1
HIV- (n=1490) 88% 79% 72% 57%
Survival rates (years) p-value
1 2 3 5 10
Table 3. Posttransplant opportunistic infections (OI) in HIV positive patients who underwent
liver transplantation
Spain
(Moreno 2012)
Number of patients 84 109 125
Follow-up (months) 24 46 32
Number (%) of patients with at
least one OI
Type of OI
Tuberculosis 2 1 0
Pneumocystis jirovecii pneumonia 1 0 1
Esophageal candidiasis 2 2 3
Other invasive fungal infections* 3 0 0
CMV disease 2 3 0
Other OI 0 1
Neoplasms
Kaposi’s sarcoma 0 NR 1
Non-Hodgkin lymphoma 0 NR 0
NR: Not reported; *mucormycosis (2) and aspergillosis (1)
†
atypical mycobacterium; ‡ bronchial candidiasis
9 (11) 7 (6) 6 (5)
France
(Teicher 2015)
†
US
(Terrault 2012)
‡
1
Pharmacokinetic interactions in the posttransplant period
The risk of recurrent or de novo malignancy ater solid organ
transplantation in HIV positive patients is low (Nissen 2012). Ater a median
follow-up of 2.8 years posttransplant, 12 out of 125 (9.6%) liver recipients
developed 14 malignancies: 11 de novo malignancies (nine skin cancer, one
Kaposi’s sarcoma and one lymphoma) and three recurrences of pre-LT
malignancy: two HCC and one cholangiocarcinoma (Nissen 2012).
Aseptic osteonecrosis in three (12.5%) out of 24 patients who underwent
LT has been reported (Cocchi 2012). The incidence of this complication
should be analysed in future research.
524 525
Clinical management in the posttransplant period is complex, and
handling pharmacokinetic interactions is challenging (Primeggia 2013).
Efavirenz is an inducer of CYP3A4, while ritonavir-boosted HIV protease
inhibitors (PIs) are CYP3A4 inhibitors. Ritonavir and a new selective
CYP3A inhibitor without intrinsic anti-HIV activity, cobicistat, have a
potent inhibitory efect (Deeks 2013). This fact has a considerable impact
on patient management (Frassetto 2013). Subjects taking concomitant
ritonavir- or cobicistat-boosted AVs (e.g., PIs, elvitegravir) will require
rapid and signiicant dose adjustments of both calcineurin inhibitors
and mTO inhibitors (Deeks 2013, Frassetto 2013). In the presence of HIV
PIs, the increase in the ciclosporin exposure could be two- to four-fold
(AUC) and for tacrolimus more than ten-fold. With a combination of an
HIV PI plus efavirenz, the interaction is complex and needs to be closely
monitored. Nevirapine has no signiicant efect on calcineurin inhibitor
pharmacokinetics (Frassetto 2013).
Raltegravir (RAL), which is mainly metabolised by uridine diphosphate
glucuronyltransferase, is not a substrate of CYP450 and can safely be used
in HIV positive LT recipients (Barau 2014, Tricot 2009). A study enrolling
13 HIV positive solid organ transplantation recipients (eight liver and ive
20. End-stage liver disease, HIV and liver transplantation
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kidney) on RAL, reported a lack of signiicant interaction between RAL and
calcineurin inhibitors (Tricot 2009). These indings were later conirmed
in a cohort of 16 HIV positive solid organ transplant recipients (Mirò 2013).
Therefore, the combination of two nucleos(t)ide reverse transcriptase
inhibitors (TDF/emtricitabine or abacavir/lamivudine) plus RAL is probably
the cAT regimen of choice in transplant recipients. The introduction of
dolutegravir (and probably bictegravir), which shares the same metabolic
pathway and has shown superior virological eicacy over RAL, will be
another option to safely treat LT recipients (Cahn 2013, Castellino 2013,
Waki 2011). Furthermore, previous reports have mentioned the hypothetical
anti-rejection and antiibrotic properties of the CC5 inhibitor maraviroc
(Haim-Boukobza 2013, Macias 2012). These indings remain preliminary
and the results of larger studies in humans are necessary to conirm these
interesting efects.
In addition, telaprevir and boceprevir (HCV PIs that are no longer used)
increase the drug levels of ciclosporin and tacrolimus to a magnitude
similar to that seen with HIV protease inhibitors. Management of drugdrug interactions is a challenging issue and is even more complex given
the higher incidence of chronic kidney disease observed in these patients
(Bahirwani 2014).
Finally, since this is an extremely rapidly evolving area, consultation of
up-to-date databases on drug interactions is mandatory. The interactions of
the antivirals used for the treatment of HCV can be found on the following
websites:
• https://www.hep-druginteractions.org
• https://app.hivclinic.ca
• https://www.hivmedicationguide.com
as well as in the product labels.
Immunosuppression and rejection in HIV positive LT
recipients
The optimal immunosuppressive regimen in HIV positive LT recipients
is currently not known. However, HIV positive coinfected patients
undergoing LT usually receive the same immunosuppressive regimens
used in LT recipients without HIV (Miro 2007, Miro 2015). In general, the
most commonly used immunosuppressive regimen combines a calcineurin
inhibitor with corticosteroids. Findings fr om the two major LT cohorts (Miro
2012, Terrault 2012) conirm that individuals with HCV/HIV coinfection are
more likely to have acute rejection than those with HCV monoinfection. A
38% acute rejection rate was reported in HIV coinfection compared to 20%
in HIV negative patients (p<0.001) (Miro 2012).
This higher rate of acute rejection may be due to diiculties in achieving
adequate serum levels of immunosuppressant agents due to drug-drug
interactions between AVs and calcineurin inhibitors. In addition, a higher
rate of misinterpretation of acute rejection (mainly versus recurrent HCV
infection) cannot be ruled out in HCV/HIV coinfection (Terrault 2012).
HCV recurrence after LT
For those patients with replicating HCV, the recurrence of HCV is
universal ater LT, regardless of HIV status. The impact of this fact on the
post-LT outcome of these patients has dramatically change since the advent
of DAAs.
Pre-DAAs era
Recurrence of HCV in patients with HCV/HIV coinfec tion was more severe
and occurs earlier (Antonini 2011, Castells 2006) than in HCV monoinfected
patients in the era of PEG-IFN plus RBV due to the low rate of SVR, impacting
on mid-term survival of HIV positive LT recipients (de Vera 2006).
The three major nationwide cohorts of LT recipients with HCV/HIV
coinfection (France, Spain and the US) showed, uniformly, that post-LT
survival rates are lower than those of HCV monoinfected patients (Table
2) (Duclos-Valeè 2008, Miro 2012, Terrault 2012). Survival rates vary from
76% to 88% in the irst year, 60% to 62% at three years, and 51% to 54% at
ive years in patients with HCV/HIV coinfection. On the other hand, HCV
monoinfected patients have survival rates of 90% to 92%, 70% to 76% and
71% to 81% in the irst, third- and ith-year post-LT, respectively. HIV was
independently associated with mortality (Miro 2012, Terrault 2012). Other
risk factors for death were HCV genotype 1 and a higher donor risk index
(DRI) (Miro 2012). By contrast, the absence of HCV replication was associated
with a signiicantly lower risk of death at ive years (H 0.23) (Mirò 2012).
Several studies have explored the efectiveness of treatment of HCV
recurr ence ater LT with PEG-IFN plus RBV (Castells 2015, Duclos-Vallee 2011,
Terrault 2014). They consistently found a very low SV rate. HIV infection,
donor age >60 years, HCV genotype 1 or 4 and severe histological hepatitis
were identiied as risk factors for virologic failure (Castells 2015). The main
results are summarised in Table 4. The US (Terrault 2014) and Spanish
(Castells 2015) cohort studies showed an SV of only 10% in patients with
genotype 1. In the Spanish study, a 59% rate of SV was obtained in patients
with genotypes 2/3 compared with only 7% in patients with genotype 1/4.
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DAA era
At the beginning of the era of DAAs, HIV positive patients were not
included in most studies in the setting of LT (Campos-Varela 2015) and data
on the eicacy of these drugs in this clinical scenario was derived from
case reports (Antonini 2015, Borentain 2014). However, current evidence
conirms the high eicacy of DAAs in the setting of LT recipients with HCV/
HIV coinfection (Campos-Varela 2016, Londoño 2016, Grant 2016, Fagiuoli
2016, Castells 2017, Manzardo 2018,) (Table 4). Most of these patients were
treated with sofosbuvir plus ledipasvir with/without ribavirin. Indeed,
SV at 12 weeks is similar in LT recipients both with and without HIV
infection (Manzardo 2018). The conclusion from these studies is that IFNfree regimens for post LT HCV recurrence in HIV positive individuals
were highly efective and well tolerated, with results comparable to HCV
monoinfection. In fact, current guidelines recommend DAAs regimens as
the only options in HCV/HIV-coinfected patients ater LT because of their
virological eicacy, safety and tolerability (EASL 2018). Therefore, the
post-transplant HCV recurrence and its fearful consequences seen until
a few years ago in the PEG-IFN plus RBV era have disappeared with DAA
treatment due to the high rate of virus eradication.
Table 4. Summar y of studies evaluating the efficacy of treatment of HCV reinfection in LT
Author + Year of
Publication
IFN-based regimens
Duclos-Vallée 2011 36 4 (11)
Terrault 2014 37 5 (14) – –
Castells 2015 78 16 (21) 176 64 (36%)
Tot a l 151 25 (17) 176 64 (36%)
IFN-free regimens
Grant 2016 8 7 (87.5)
Castells 2017* 6 6 (100) 16 16 (100)
Londoño 2016* 11 11 (100)
Campos-Varela 2016 20 16 (89)
Manzardo 2018 47 44 (94) 148 141 (95)
Tot a l 75 67 (89) 164 157 (96)
*Some of these patients may be included in the Manzardo study and were, therefore, not
considered for the overall response rate estimation.
HCV/HIV-coinfected
patients
N SVR n (%) n SVR n (%)
HCV-monoinfected patients
(Control Group)
HBV recurrence after LT
Cohorts of patients with HIV/HBV coinfection are not as large as those
with HCV/HIV coinfection. The outcome of LT is much better, as efective
control of HBV replication with anti-HBV hyperimmune globulin and HBV
polymerase inhibitors is almost always possible (Coin 2010, Tateo 2009).
Probably due to the low incidence of HBV recurrence, survival rates in the
short and medium term in HIV/HBV coinfection LT recipients are similar
to those observed in HBV monoinfected LT recipients. A French study
that included 13 patients with HIV/HBV coinfection revealed 100% grat
and patient survival ater a mean follow-up of 32 months (Tateo, 2009).
Consistent with these indings, a US study enrolling 22 patients with HIV/
HBV coinfection and 20 HBV monoinfected patients reported a cumulative
patient and grat survival at three years of 85% in the HIV/HBV-coinfected
patients and 100% in the HBV-monoinfected group (p=0.08).
Hepatocellular carcinoma
Preliminary data from case series showed satisfactory outcomes in
people with HIV coinfection undergoing LT for HCC (Di Benedetto 2006,
Di Benedetto 2008). In 2011, a French study (Vibert 2011) observed a trend
towards a higher drop-out rate HIV positive patients with hepatitis B or C
compared to HIV negative controls (5/21, 23% versus 7/64, 10%, respectively;
p=0.08). From the time of enlisting, the survival rates at one and three
years were 81% and 55% in the HIV positive group versus 91% and 82% in
the HIV negative group (p=0.005). Moreover, the rate of HCC recurrence
was two times higher in the HIV positive group than in the control group
(30% versus 15%) (Vibert 2011). In contrast, an Italian study (Di Benedetto
2013) enrolling 30 HIV positive and 125 HIV negative LT recipients with
HCC, observed that the proportion of HCC recurrence was two-fold higher
in patients without HIV infection (2/30, 7% versus 18/125, 14%, respectively,
p=0.15). Moreover, survival rates at one and three years ater LT were
similar (77% and 65% versus 86% and 70%, respectively. These two studies
have two signiicant limitations: small sample sizes and limited follow-up
periods.
A Spanish report (Agüero 2016) compared the outcome of 74 HIV negative
patients undergoing LT for HCC with those of 222 LT recipients without
HIV infection. There were no statistical diferences regarding the baseline
characteristics of tumours in both groups. Survival rates at one, three, and
ive years for HIV positive versus HIV negative patients were 88% versus
90%, 78% versus 78%, and 67% versus 73% (p=0.779), respectively. HCV
infection (H 7.90) and maximum nodule diameter >3 cm in the explanted
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20. End-stage liver disease, HIV and liver transplantation
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liver (H 1.72) were independently associated with mortality in the whole
series. HCC recurrence occurred in 12 HIV positive patients (16%) and 32 HIV
negative patients (14%), with a probability of 4% versus 5% at one year, 18%
versus 12% at three years, and 20% versus 19% at ive years. Microscopic
vascular invasion (H 3.40) was the only factor independently associated
with HCC recurrence. HIV infection had no impact on recurrence of HCC or
survival ater LT. These results support the indication of LT in HIV positive
patients with HCC.
In addition, a Spanish study (Agüero 2017) showed that the incidence
and the histopathological features of incidental HCC in HCV infected LT
recipients being HIV positive or HIV negative were similar. Post-LT survival
was, however, lower in HIV positive patients, probably because of a more
aggressive HCV recurrence.
Liver retransplantation
Currently, in patients without HIV infection, liver retransplantation (reLT) accounts for approximately 10% of all liver transplants (Pitzmann 2007,
Reese 2009). Overall post-retransplant patient survival rate is between 15%
and 20% lower than the primary LT survival rate (Carrion 2010). This lower
survival is of concern due to the signiicant shortage of available organs.
In HIV positive patients, the frequency of re-LT is similar to the observed
LT recipients without HIV infection (6%) (Gastaca 2012, Agüero 2016). Overall
survival rates at one and three years ater re-LT for HIV positive (n=14) and
HIV negative (n=157) patients were 50% versus 72% and 42% versus 64%,
respectively (p=0.16).
A prospective international study which enrolled 37 HIV positive
patients undergoing re-LT found similar results (Agüero 2016). Five-year
survival probability in patients with a positive HCV RNA (n=22) at re-LT was
30% compared to 80% in patients with negative HCV RNA (n=10) (p=0.025).
HCV recurrence was the main cause of death (7/22 cases, 32%). Therefore,
the indication for re-LT in people with HCV/HIV coinfection with active
HCV replication at time of re-LT should be reassessed in the setting of the
widespread use of new DAAs.
Conclusions
ESLD is an increasingly frequent clinical scenario in the setting of HIV
coinfection with either HCV or HBV.
Early diagnosis of ESLD complications is particularly important and
should be actively monitored and treated. In general terms, the management
of ESLD in HIV positive patients should be the same as in those who are HIV
negative.
Physicians caring for ESLD patients should follow them prospectively
and promptly evaluate them for LT ater the irst clinical decompensation
of liver disease.
LT is a life-saving procedure in this population and is safe and efective
in patients with HBV infection. However, the recurrence of HCV infection
in HIV positive patients can afect both grat and patient survival in the
medium and long term. However due to the availability of efective and
interferon free DAA regimen this scenario is currently undergoing a rapid
change.
The members of the Hospital Clinic OLT in HIV Working Group are: JM Miró, F.
Agüero, J. Ambrosioni, G. Crespo, P. Ruiz, A Forner, M Laguno, M. Londoño, JL Blanco,
D. Nicolas, J Mallolas, M Tuset, M. Martinez-Rebollar, M Monras, A Ligoña, J Blanch,
P. Ruiz, D Paredes, M. Brunet, J Fuster, C Fontdevila, JC García-Valdecasas, JM Gatell,
A Moreno, A Rimola, (Hospital Clinic – IDIBAPS -CIBERehd, University of Barcelona,
Barcelona).
Dr. F. Aguero is currently working at Preventive Medicine Department, University
Hospital of Bellvitge, University of Barcelona, Bellvitge Biomedical Research Institute
(IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain.
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21. Metabolic liver diseases:
haemochromatosis
Claus Niederau
Definition and classification of iron overload
diseases
Hereditary haemochromatosis is classiied into 4 subtypes (Table 1).
Ty pe 1 is the well-k nown form of iron overload due to an autosomal recessive
genetic metabolic malfunction; the homozygous C282Y mutation of the HFE
gene on chromosome 6 accounts for more than 90% of clinical phenotypes
in populations of Caucasian origin (Feder 1996). This mutation leads to an
inadequately high intestinal iron absorption that ater decades may cause
iron overload and damage to various organs (Figure 1). Types 2a and 2b of
genetic haemochromatosis are juvenile forms of iron overload that lead to
a severe outcome prior to age 30, with cardiomyopathy and hypogonadism.
The corresponding mutations are located in the hemojuvelin and hepcidin
genes, respectively (Roetto 1999). Type 3 has mainly been described in
Italian families and refers to a mutation in the transferrin receptor 2
gene (Girelli 2002). Clinical consequences of type 3 haemochromatosis
are similar to type 1. Types 2 and 3 are autosomal recessive traits. The
mutations of the autosomal dominant type 4 haemochromatosis are located
in the gene coding for the basolateral iron transporter ferroportin 1 (Njajou
2001). In contrast to the other types, iron is accumulated in type 4 mainly
in macrophages; ferritin values are markedly elevated although transferrin
saturation is only slightly higher.
Secondary haemochromatosis is usually caused by multiple blood
transfusions in hemolytic anaemias such as thalassaemia, sickle cell
anaemia and myelodysplasia syndrome. Iron irst accumulates in RES
macrophages and is later transferred to parenchymal cells. With frequent
blood transfusions, iron may accumulate faster than with genetic
haemochromatosis; iron overload oten leads to severe cardiomyopathy
and liver cirrhosis, limiting efective prognosis. Therapy consists of iron
chelators because phlebotomies cannot be done due to the underlying
anaemia. This review will focus on type 1 HFE haemochromatosis, the most
prevalent genetic form in Germany. Most consequences of iron overload are
similar, whatever the cause. Thus, the pathophysiology of tissue and organ
damage by iron excess is discu ssed in detail only for HFE haemochromatosis.
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association between special HLA haplotypes and haemochromatosis which
recognised the genetic nature of the disease was described (Simon 1975).
The mode of inheritance was identiied as an autosomal recessive disorder
(Simon 1977). Finally, the major mutation on the HFE gene associated with
clinical manifestations was identiied (Feder 1996).
Figure 1. Scheme of natural histor y of type 1 genetic haemochromatosis
Table 1. Classification of haemochromatosis
I) Genetic haemochromatosis
Types Gene defect on Affected gene Inheritance High prevalence
Typ e 2 a Chromosome 1 Hemojuvelin Autosomal
recessive
Typ e 2b Chromosome 19Hepcidin Autosomal
recessive
Typ e 3 Chromosome 7 Transferrin
receptor 2
Typ e 4 Chromosome 2 Ferroportin 1 Autosomal
Neonatal Unknown Unknown Unknown Ver y ra re
Others Unknown Unknown Unknown Of non-Caucasian origin
II) Secondary haemochromatosis
a) Chronic anaemias (thalassaemia, sickle cell disease, MDS, other rare hemolytic anaemias)
b) Multiple blood transfusions in general
c) Long-term oral intake of high amounts of iron (diet-related or intravenous)
III) Non-classified, ill-defined iron overload syndromes
a) iron overload in Bantu Africans
b) iron overload in aceruloplasminaemia
Autosomal
recessive
dominant
Juvenile form
Juvenile form
Italy
Italy
Type 1 HFE haemochromatosis
History
The association between liver cirrhosis, pigment deposits in the liver,
and diabetes mellitus was recognised over a century ago (Trosseau 1865,
Troisier 1871, Hanot and Schachmann 1886). The term haemochromatosis
was irst introduced in the 19th century (Recklinghausen 1889), but was not
generally accepted until used as the title of a classic monograph (Sheldon
1935). The controversy over whether haemochromatosis was merely a
form of alcoholic liver cirrhosis (MacDonald 1960) or a genetic error of iron
metabolism (Sheldon 1935, Crosby 1966) lasted almost a century until the
Epidemiology
Type 1 haemochromatosis is probably the most prevalent genetic
metabolic error in Caucasian populations (Adams 2005). The prevalence
of C282Y homozygotes is approximately 0.5% in central Europe and in
the Caucasian population of North America; the prevalence of C282Y and
H63D heterozygotes approaches 40% in similar populations (Adams 2005).
Phenotypic expression also depends on several non-genetic factors such the
amount of dietary iron and blood loss (Figure 2). For example, due to menses,
females develop clinical consequences of iron overload 5–8 times less
frequently and 10–20 years later than males. It is now widely accepted that
not all C282Y homozygous men will develop the full clinical manifestation
of haemochromatosis. It also remains unclear how many men will show
clinical disease during their lifetime and what factors determine that
phenotype.
As mentioned previously, the homozygous C282Y mutation accounts for
more than 90% of the clinical phenotype in Caucasian populations (Feder
1996, Adams 2005) (Table 2). A point mutation at H63D is also frequently
identiied in the HFE gene as well as other less frequent mutations. None of
these gene alterations or polymorphisms, found in up to 40% of Caucasians,
correlates with the phenotype. A subject with a C282Y variation on one
allele and a H63D variation on the other is called a “compound heterozygote”
(Table 2). Only a small percentage of such compound heterozygotes are at
risk for clinical consequences of iron overload (Gallego 2015). A recent metaanalysis showed a positive association between compound heterozygosity
for C282Y/H63D and the risk of NAFLD and HCC, but not liver cirrhosis (Ye
et al. 2016). C282Y and H63D heterozygotes are at no risk of iron overload
(Table 2). In non-Caucasian populations other genes may be involved in
causing iron overload.
Aetiology and pathogenesis
Intestinal iron absorption and iron losses are inely balanced under
physiological conditions. Approximately 10% of the total daily intake of iron
(10–20 mg) is absorbed by the small intestine (1–2 mg). However, subjects
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