Journal of the Egyptian National Cancer Institute (2015) xxx, xxx–xxx

Cairo University

Journal of the Egyptian National Cancer Institute

www.elsevier.com/locate/jnci
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Review

Radiation induced liver disease: A clinical update

R. Benson a, R. Madan a,*, R. Kilambi b, S. Chander a

a
Department of Radiation Oncology, All India Institute of Medical Sciences, New Delhi 110029, India
b
Department of Gastrointestinal Surgery and Liver Transplant, All India Institute of Medical Sciences, New Delhi 110029, India

Received 3 June 2015; revised 26 July 2015; accepted 4 August 2015

KEYWORDS Abstract Radiation-induced liver disease (RILD) or radiation hepatitis is a sub-acute form of liver
Radiation induced liver dis- injury due to radiation. It is one of the most dreaded complications of radiation which prevents
ease; radiation dose escalation and re-irradiation for hepatobiliary or upper gastrointestinal malignan-
Patho-physiology; cies. This complication should be kept in mind whenever a patient is planned for irradiation of these
Risk factors; malignancies. Although, incidence of RILD is decreasing due to better knowledge of liver tolerance,
Management improved investigation modalities and modern radiation delivery techniques, treatment options are
still limited. In this review article, we have focussed on patho-physiology, risk factors, prevention
and management of RILD.
Ó 2015 The Authors. Production and hosting by Elsevier B.V. on behalf of National Cancer Institute,
Cairo University. This is an open access article under the CC BY-NC-ND license (http://creativecommons.
org/licenses/by-nc-nd/4.0/).

Contents

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
Patho-physiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
Risk factors. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
Prevention. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
Dose volume constrains for prevention . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
Role of radio protectors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
Onset and symptoms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
Investigation and diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
Conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
Disclosure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

* Corresponding author. Mobile: +91 9868597027.

E-mail address: renumadan10@yahoo.com (R. Madan).
Peer review under responsibility of The National Cancer Institute,
Cairo University.
http://dx.doi.org/10.1016/j.jnci.2015.08.001
1110-0362 Ó 2015 The Authors. Production and hosting by Elsevier B.V. on behalf of National Cancer Institute, Cairo University.
This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Please cite this article in press as: Benson R et al. Radiation induced liver disease: A clinical update, J Egyptian Nat Cancer Inst (2015), http://dx.doi.org/10.1016/j.
jnci.2015.08.001
2 R. Benson et al.
Acknowledgment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
Introduction
Radiation induced liver disease (RILD) is one of the important
complications of radiation therapy (RT). RILD typically
occurs 4–8 weeks after completion of RT but has been
described as early as 2 weeks and as late as 7 months after radi-
ation. It is a major factor that limits radiation dose escalation
and re-irradiation for tumors that are situated in the close
vicinity of the liver. However; in recent years, modern radia-
tion treatment planning has allowed modest dose escalation
for these tumors. Various dosimetric constrains have been
given to predict toxicity. Mean dose of 30 Gy is usually consid-
ered as safe but radiation tolerance of the liver is lesser in
patients with deranged liver function. These patients are more
susceptible for development of RILD. Clinical manifestations
of RILD are non-specific. There are two types of RILD, clas-
sical (patients without underlying liver disease) and non-
classical (patients with underlying liver disease). Patients with
classical RILD usually present with fatigue, abdominal
pain, increased abdominal girth, hepatomegaly, anicteric
ascites and isolated elevation of alkaline phosphatase out of
proportion to other liver enzymes. In contrast, patients with
non-classical RILD present with jaundice and markedly ele-
vated serum transaminase. Non-invasive imaging findings are
nonspecific. RILD is a diagnosis of exclusion and other com-
mon causes must be ruled out first. Computed tomography
(CT) may reveal well demarcated area of reduced enhancement
as compared to surrounding normal liver [1]. However,
recently it has been reported that functional imaging tech-
niques like single photon emission computed tomography
(SPECT) are more reliable options to detect RILD [2]. There
are no specific guidelines for the management of RILD and
patients are managed in the same way as non irradiated
population.
Patho-physiology
Reed and Cox were the first to describe the patho-physiology
of RILD and suggested that retrograde congestion is the
main culprit [3]. Liver biopsy of a patient with RILD may
show endothelium swelling, terminal hepatic venule narrow-
ing, sinusoidal congestion, parenchymal atrophy of zone
and proliferation of collagen [4]. These abnormalities are sim-
ilar to that of veno-occlusive disease and are predominantly
evident around the central vein. Formation of micro thrombi
due to hepatic venule endothelial damage also contributes to
the outflow obstruction. Animal studies have shown dose
dependent increased expression of transforming growth
factor-beta 1 (TGF-ß1) in the liver of irradiated rats which
may be an important factor in the development of RILD in
humans also [5]. Hepatic stellate cells are responsible for
regeneration of hepatocytes, secretion of lipoproteins and
growth factors. Activation of these cells may be an early
event in patients with severe congestive changes of classic
RILD [6].
Please cite this article in press as: Benson R et al. Radiation induced liver disease: A clinical update, J Egyptian Nat Cancer Inst (2015), http://dx.doi.org/10.1016/j.
jnci.2015.08.001
Risk factors
The risk of developing RILD is about 5–10% when the whole
liver is irradiated up to 30–35 Gy. But the radiation dose to
control most of the solid malignancies is around 50–70 Gy.
Thus the use of radiation for management of upper gastroin-
testinal (GI) and hepatobiliary malignancies may result in high
chance of RILD. Dawson et al. tried to evaluate dose-volume
tolerance for RILD using the Lyman–Kutcher–Burman nor-
mal tissue complication probability model in their study
involving 203 patients treated with conformal liver radiother-
apy and concurrent hepatic arterial chemotherapy [7]. They
found that no cases of RILD were observed when the mean
liver dose was kept below 31 Gy in partial liver irradiation.
It was concluded that the liver exhibits a large volume effect
for RILD and partial liver irradiation is feasible by keeping
the liver mean dose within tolerance limits [8]. Xu et al. com-
pared the Michigan model and the modified Lyman NTCP
model for predicting the risk of RILD [9]. The study included
109 patients of primary hepatocellular carcinoma (HCC) trea-
ted with hypofractionated 3-dimensional conformal radiother-
apy (3D-CRT). They found that the Michigan model was
probably not good to predict RILD and the modified Lyman
NTCP model for RILD should be used instead.
With the availability of Intensity modulated radiotherapy
(IMRT), stereotactic body radiotherapy (SBRT) and image
guidance in radiation treatment planning, high tumor ablative
doses of radiation can be delivered to the tumors without com-
promising normal liver functions [10].
The baseline liver function, background hepatic cirrhosis
and volume of liver in the PTV are important factors for devel-
oping RILD [11]. The Child-Pugh Grading is useful in assess-
ing the baseline liver function in patients with chronic liver
disease [11]. However, Indocyanine green clearance test is a
more sensitive test than Child-Pugh grading in assessing liver
functions. Indocyanine green is delivered systemically and
the hepatic retention is measured at 15 min. When the reten-
tion rate is 10–19%, the function of liver is considered very
well and even a lobectomy can be done. Though most of the
data on Indocyanine green clearance test is on liver resection,
it can be helpful in considering patients for liver irradiation
also. Some studies have shown that Child-Pugh class may be
a more important parameter than Indocyanine green retention
test for predicting RILD [12].
Dose per fraction is another important factor in the devel-
opment of RILD. The tolerance of liver parenchyma to hypo-
fractionated and accelerated radiotherapy is much lower than
that of conventional 2 Gy per fraction. This must be kept in
mind especially when planning hypo fractionated regimens
for the treatment of liver malignancies.
There is an additional risk of RILD by concurrent
administration of hepatotoxic chemotherapy to radiation and
irradiating a patient who has already received hepatotoxic
chemotherapy prior to radiation. Though there are no specific
guidelines, this factor should be considered whenever a patient
Radiation induced liver disease
is planned for radiotherapy. Care must be taken in patients
receiving other hepatotoxic drugs also.
Other risk factor that may be associated with a higher risk
of RILD includes prior trans-catheter arterial chemo-
embolization presence of portal vein tumor thrombosis, tumor
stage and male sex [13–15]. Patients with primary hepatobil-
iary malignancies have a lower tolerance to liver radiation than
the patients with liver metastases.
Prevention
Since there is no effective treatment for RILD, the most effec-
tive measure is prevention. Appropriate assessment of the
patient before starting the radiation treatment is very
important.
The functional reserve of liver can be assessed by Child-
Pugh Grading and Indocyanine green clearance tests. The
development in treatment delivery has led to better sparing
of the normal liver while providing the desired dose to the
tumor. Image guided radiotherapy and stereotactic targeting
are useful in reducing setup uncertainty [16]. Regular breathing
can result in liver tumor displacement up to 2 cm. Use of res-
piratory motion management techniques (abdominal compres-
sion, shallow breathing, breath holding, gating and tracking)
can be useful in reducing the volume of liver irradiated and
there by the incidence of RILD [17]. During radiation treat-
ment, patients should be monitored by physical examination
and blood chemistry every week. After completion of the radi-
ation, these examinations should be repeated every 2 or
3 months.
Dose volume constrains for prevention
Investigators from the university of Michigan are one of the
pioneers in the work related to dose constrains and incidence
of RILD. When the whole liver is irradiated by conventional
fractionation, a dose of 30 Gy is likely to produce a 5% risk
of RILD [18]. The threshold dose for RILD may be lower in
hypo-fractionated or accelerated radiotherapy. The incidence
of RILD was 10% in a RTOG study where accelerated hyper
fractionated hepatic radiotherapy of 33 Gy (1.5 Gy separated
by 4 h or longer) was given for the management of liver metas-
tasis [19]. There are some clinical situations where the entire
liver receives the prescribed dose of radiation and these are
whole abdominal irradiation for advanced stage Wilms tumor,
some ovarian malignancies and total body irradiation. The
radiation dose for Wilms tumor is within the tolerance limit
for the whole liver. Whole liver irradiation can also be used
in a palliative setting in patients with multiple incurable liver
metastases, especially in palliation of pain [20]. The above dose
limits must be kept in mind when whole liver irradiation is
planned for these patients.
Radiobiologically, liver parenchyma has parallel architec-
ture in which individual functional units work independently.
This allows for high-dose treatment to small volumes of the
liver as long as the mean dose of the normal liver is kept within
tolerance limit. The tolerance of partial liver volumes can be
higher (up to 80 Gy). The two main constrains that must be
kept in mind are the mean dose to the liver and volume of liver
receiving 30 Gy. The volume that must be taken should be liver
minus gross tumor. The mean dose should be kept below
Please cite this article in press as: Benson R et al. Radiation induced liver disease: A clinical update, J Egyptian Nat Cancer Inst (2015), http://dx.doi.org/10.1016/j.
jnci.2015.08.001
3
28 Gy and 32 Gy in conventional fractionation for primary
HCC and liver metastases respectively [15,17]. The volume of
liver receiving 30 Gy should be less than 60% of the liver vol-
ume [21].
Liang et al. investigated for dosimetric predictors for RILD
after hypo fractionated conformal radiotherapy [22]. The
study included 114 patients of primary HCC (with Child-
Pugh Grade A cirrhosis) treated with hypo fractionated con-
formal radiotherapy. They found that the volume receiving
20 Gy (V20) was a unique significant dosimetric predictor for
RILD in these patients.
The dose constrains are different when SBRT is used. The
mean dose must be kept less than 13–18 Gy for three fractions
and less than 15–20 Gy for six fractions SBRT. Another
important constrain that may be used is to keep the volume
of liver receiving 15 Gy to less than 700 mL in three to five
fractions SBRT. Jung et al. investigated the clinical and dosi-
metric parameters that predict the risk of RILD for patients
with HCC treated with SBRT [23]. They found that Child-
Pugh B class was a significant parameter for predicting grade
2 or higher RILD. Son et al. evaluated the incidence of hepatic
complications in 47 patients treated with SBRT for small unre-
sectable primary HCC using Cyber Knife [24]. They found that
the factors associated with significant hepatotoxicity were
Child-Pugh class and total liver volume receiving a dose less
than 18 Gy.
Radio-embolization with yttrium-90 (90Y) is a popular
method of treating extensive liver metastasis and HCC.
Young et al. investigated the clinical and dosimetric parame-
ters that predict the risk of liver injury in patients of HCC
undergoing radio-embolization [25]. They found that com-
pared to Okuda stage II, stage I patients tolerate higher cumu-
lative radiation dose with 90Y and liver toxicity increases with
an increase in dose: 222 Gy (no toxicity) versus 390 Gy
(>or = 1 toxicity, p < 0.005).
Role of radio protectors
Animal studies have shown that the use of amifostine protects
hepatocytes from ionizing radiation without compromising
tumor control [26]. In a phase I study, Feng et al. evaluated
the role of amifostine as a radio protector in dose-escalated
whole liver radiation therapy [27]. The study included 23
patients and a maximum dose of 40 Gy was used. This was
compared with previously treated patients by logistical regres-
sion model. It was observed that the use of amifostine
increased the liver tolerance by 3.3 +/ 1.1 Gy. Animal studies
have also shown that antioxidant a-tocopherol (Vitamin E)
may reduce the incidence of RILD by reducing liver lipid per-
oxidation and maintaining the endogenous liver antioxidant
defense [28]. But the use of these radio protectors in routine
clinical practice is still investigational due to lack of clinical tri-
als. The question of whether or not these agents reduce the
tumor control also needs to be tested before its use as radio
protectors.
Onset and symptoms
Symptoms of RILD usually occur 2–8 weeks after completion
of radiation treatment [29]. A high index of clinical suspension
is very important in early diagnosis. The symptoms are usually
4 R. Benson et al.
non-specific with fatigue and right upper quadrant pain being
the most common symptoms. Examination findings may
resemble Budd-Chiari Syndrome with massive ascites and hep-
atomegaly. Jaundice is unlikely to be present in a patient with
RILD. If jaundice develops during or following radiotherapy
treatment, ascending cholangitis must be considered as a pos-
sible cause. Profound thrombocytopenia may be seen which is
caused by splenic sequestration from portal hypertension due
to the obstruction of the hepatic veins. The irradiation of the
liver may also lead to the reactivation of hepatitis B.
Investigation and diagnosis
In classical RILD, alkaline phosphatase increases more than
two times the normal level but level of transaminase, bilirubin
and ammonia remain normal. In contrast to classical RILD,
patients with underlying liver disease present with jaundice
and markedly elevated serum transaminase (more than five
times the upper limit of normal) [22]. Common toxicity criteria
for adverse events (CTCAE) criteria for elevations of aspartate
aminotransferase, alanine aminotransferase, alkaline phos-
phatase, bilirubin should be used to report toxicity. Hepatic
viral markers, serum bilirubin, serum protein and prothrombin
time should be investigated.
Ultrasound of the abdomen reveals massive ascites and
hepatomegaly. It may also help in excluding other causes of
ascites. Doppler studies may show the direction of flow in
the portal vein, and any possible thrombosis. Contrast
enhanced computed tomography (CT) usually reveals a sharp
demarcation line between the normal enhancing lesion and the
hypo attenuation [‘‘straight-border” sign,] along the trajectory
of the radiation beam [30]. RILD may present as demarcated
areas of hypo or hyper attenuation in a non-anatomic distribu-
tion [31]. One of the limitations of dynamic CT is that even
though it may show blood flow, it gives very little idea of the
hepatocellular function [32]. Magnetic resonance imaging usu-
ally shows low signal intensity on T1-weighted images and
high signal on the T2-weighted image as it has increased water
content [33].
Paracentesis of ascites may be useful in the diagnosis of
RILD as it rules out other possible causes of ascites (RILD
is a diagnosis of exclusion) [11]. Cytopathologic evaluation
of the ascitic fluid is usually negative for malignancy. The anal-
ysis of the fluid generally shows features of transudate with the
serum-ascites albumin gradient > 1.1. Diagnostic laparoscopy
may reveal mottled appearance of the liver with bluish and
dark areas [4]. Liver biopsy helps in confirming the diagnosis
of RILD.
Acute hepatic toxicity may also occur during radiation.
Patients may present with elevated transaminases. Usually
no severe long term consequences are seen if appropriate ther-
apy is given on time. Radiation discontinuation may be
required in some cases.
Treatment
No therapy has been shown to prevent or to modify the natu-
ral course of the disease. Treatment is mainly directed at con-
trol of symptoms. The drugs used for supportive care include
diuretics for fluid retention, paracentesis for ascites, correction
Please cite this article in press as: Benson R et al. Radiation induced liver disease: A clinical update, J Egyptian Nat Cancer Inst (2015), http://dx.doi.org/10.1016/j.
jnci.2015.08.001
of coagulopathy, and steroids to reduce hepatic congestion
[32].
The use of anticoagulants and thrombolytics may be help-
ful in relieving hepatic vein thrombosis. Other agents that have
been approved for the management of hepatic veno occlusive
disease may be tried in RILD also.
Conclusion
Radiation induced liver disease is a diagnosis of exclusion.
Indicators of liver function status like Child-Pugh score and
Indocyanine green clearance test are important parameters to
predict the toxicity. Mean radiation dose of 30 Gy is consid-
ered as safe but radiation tolerance of liver decreases in the
presence of deranged liver functions. Prevention is the key as
there are no specific treatment guidelines. Attempt should be
made to keep the mean dose below tolerance level. Role of
radio-protectors is doubtful. Although newer techniques of
radiation have reduced the incidence of RILD, more extensive
research is required to structure guidelines for prevention and
management.
Conflict of interest
None.
Disclosure
None.
Acknowledgment
None.
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