Adrenal disease is an uncommon manifestation of hepatitis C infection and its related treatment regimen. This is a case of subclinical hypoadrenalism, probably induced by hepatitis C infection and further exacerbated by interferon-α2β and Ribavirin therapy. The adrenal deterioration during the treatment course was observed closely with 24-hour salivary profiles and 250 μg adrenocorticotropin stimulation tests using parallel serum and salivary cortisol concentrations. A number of possible pathogenic mechanisms are discussed, and the controversy over its management is emphasized

A De Bellis

B Wesche

C Betterle

G Coco

Glenn E Reeves

GS Eisenbarth

HA Tran

Huy A Tran

K Oshimoto

KP Batts

M Boscaro

P Restituto

PJ Tebben

RI Dorin

Robert J Lojewski

RS Patel

Shuzhen Song

English

PubMed

Crossref

Exacerbation of hepatitis C induced subclinical hypoadrenalism by Interferon-alpha2beta: A case report

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BioMed CentralCases Journal
ssOpen AcceCase Report
Exacerbation of hepatitis C induced subclinical hypoadrenalism by 
Interferon-alpha2beta: A case report
Huy A Tran*1, Shuzhen Song1, Robert J Lojewski1 and Glenn E Reeves2
Address: 1Department of Clinical Chemistry, Hunter Area Pathology Service, Locked Bag Number 1, Hunter Mail Region Centre, Newcastle, New 
South Wales 2310, Australia and 2Department of Immunopathology, Hunter Area Pathology Service, Locked Bag Number 1, Hunter Mail Region 
Centre, Newcastle, New South Wales 2310, Australia
Email: Huy A Tran* - huy.tran@hnehealth.nsw.gov.au; Shuzhen Song - ssong@hotmail.com; Robert J Lojewski - rlojewski@yahoo.com; 
Glenn E Reeves - greeves@hotmail.com
* Corresponding author    
Abstract
Adrenal disease is an uncommon manifestation of hepatitis C infection and its related treatment
regimen. This is a case of subclinical hypoadrenalism, probably induced by hepatitis C infection and
further exacerbated by interferon-α2β and Ribavirin therapy. The adrenal deterioration during the
treatment course was observed closely with 24-hour salivary profiles and 250 μg
adrenocorticotropin stimulation tests using parallel serum and salivary cortisol concentrations. A
number of possible pathogenic mechanisms are discussed, and the controversy over its
management is emphasized.
Case presentation
A 55 year old post menopausal Caucasian female pre-
sented with vitiligo on her face, arms and legs. Her past
medical history included only mild asthma requiring only
intermittent bronchodilators without glucocorticoids.
There was no other significant personal or family medical
history. Clinical examination showed a well woman,
weight of 69.1 kg, height 1.67 metre (body mass index
~25). Her blood pressure was 120/75 lying and 120/70
sitting with a regular pulse of 78 beats per minute. There
were 3 vitiligo patches each measuring approximately 3 ×
5 cm on her forehead, anterior abdomen and left cubital
fossa. No goitre or liver enlargement was detected. Bio-
chemical investigations are as follow: sodium 130 mmol/
L (reference range (RR), 136–146), potassium 5.4 mmol/
L (RR, 3.5–5.5), chloride 99 mmol/L (RR, 98–108), bicar-
bonate 21 mmol/L (RR, 24–30), urea 9.1 mmol/L (3.0–
7.0), creatinine 90 umol/L (RR, 40–90), bilirubin 18
μmol/L (6–10), alanine aminotransferase 105 IU/L (RR, <
50), aspartate aminotransferase 56 IU/L (RR, < 45), alka-
line phosphatase 136 IU/L (RR, < 110), γ-glutamyl trans-
ferase 40 IU/L (< 60), albumin 33 g/L (RR, 35–45),
plasma aldosterone 172 pmol/L (RR, 80–1040), plasma
renin activity > 35.7 ng/mL/hr (RR, 1.2–2.8). In essence,
they showed mild hyperkalaemic metabolic acidosis and
hepatocellular dysfunction. Because the latter persisted,
chronic hepatitis C was confirmed with positive serology
of genotype 1. The liver biopsy showed changes consistent
with chronic persistent hepatitis, the inflammatory and
fibrotic changes were both graded 1 according to the scor-
ing method [1]. Together with additional biochemical
and immunological studies, other causes of persistent
abnormal liver function tests were excluded. In view of her
vitiligo, hepatitis C and biochemical disturbance, the
Adrenocorticotropin (ACTH) stimulation test (AST), also
known as the Cosyntropin or Short Synacthen test, was
performed which revealed the presence of subclinical
adrenal insufficiency (AI), additional file 1. Further inves-
Published: 18 September 2008
Cases Journal 2008, 1:157 doi:10.1186/1757-1626-1-157
Received: 5 June 2008
Accepted: 18 September 2008
This article is available from: http://www.casesjournal.com/content/1/1/157
© 2008 Tran et al; licensee BioMed Central Ltd. 
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), 
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Page 1 of 5
(page number not for citation purposes)
Cases Journal 2008, 1:157 http://www.casesjournal.com/content/1/1/157tigations for the causes of AI revealed positive adrenal cell
antibody (ACA) serology. Computerised tomographic
scan showed small adrenal glands bilaterally with normal
anatomy and appearance.
The patient underwent routine combination treatment of
Interferon-α2β (IFN) and Ribavirin (RBV) for 48 weeks
for her genotype 1 HCV infection. The patient's subclini-
cal adrenal disease was also followed closely using sali-
vary as well as serum cortisol levels to assess the
hypothalamo-pituitary-adrenal axis (HPA) every 12
weeks, starting at baseline, during treatment, 6 and 12
month follow-ups. The results suggested a progressive
decline of her adrenal function during the treatment
phase. Glucocorticoid replacement therapy was seriously
considered but with apprehension due to possible exacer-
bation of the hepatitis. The risks were discussed in detail
with the patient and her family and it was decided to con-
tinue with anti-viral therapy but without glucocorticoid
supplement. The patient and her husband were coun-
selled comprehensively regarding the emergency manage-
ment of Addisonian crisis, provided with a carrying note
and required to wear an alert bracelet. Other immediate
family members were also involved in her management
plan, with her consent. Her management plan was also
forwarded to the local hospital Emergency Department
and Hepatitis C Service. Fortunately, there was no crisis
other than the common side effects of the treatment regi-
men. Her pattern of steroid profile and ACA returned to its
pre-existing state and remained unchanged at 6 and 12
month follow-up after the cessation of therapy. The
patient has remained well since but her subclinical AI per-
sists.
Discussion
Hepatitis C is well-documented to be associated with
many auto-immune endocrinopathies, especially thyroid
but also including the hypothalamus, pituitary, renal
organs [2,3]. This is the first case to explore the challenge
of subclinical AI and the influence of interferon treatment
upon it. In the presence of positive ACA, it was very prob-
able that AI is the result of HCV infection and its immu-
nomodulating effect on adrenal tissue, as most alternative
causes are not apparent.
It was interesting that patient was found to have subclini-
cal AI in which the diagnosis was confirmed by the failure
to stimulate an adequate cortisol rise after 60 minutes of
Cosyntropin stimulation even though the baseline levels
were satisfactory throughout. In healthy subjects, there
must be an absolute increase of 300 nmol/L or more at the
60 minute sample [4]. Another definition of non-
responders has been suggested to be less than a 20%
increase compared with baseline value [5], directly rele-
vant to this patient. Additionally, the elevated ACTH and
renin levels and reduced aldosterone/renin ratio conclu-
sively indicated adrenal cortical failure. Various stages of
progressive adrenal failure have been described but this
case clearly does not fit into any of the prescribed catego-
ries [6]. According to this proposal, our patient belongs in
the 'Symptomatic Under Stress' category in which she satis-
fied all criteria except that her baseline cortisol was nor-
mal rather less than 83 nmol/L.
During IFN and RBV therapy, there was a steady and grad-
ual decline in baseline salivary and serum cortisol levels
prior to ASTs. Serum ACTH levels increased slightly
throughout the treatment course and returned to pre-
treatment level after. The failure of cortisol levels to rise at
60 minutes is consistent in both saliva and serum
throughout the 48 weeks of treatment. There was also a
significant decrease in cortisol levels during therapy (addi-
tional file 1). At 12 months following the end of IFN ther-
apy, the baseline cortisol levels returned to their pre-
treatment levels.
The longitudinal 24-hour salivary cortisol profile
throughout the course of treatment is rewarding and
revealing. The normal physiological diurnal pattern has
been lost with the deletion of the second late-afternoon
cortisol peak. Although the first morning peak was
retained, it was significantly attenuated to a mean of 6.2
nmol/L followed by a gradual decline to an undetectable
nadir at midnight. The effect and influence of IFN on the
24-hour salivary profile also paralleled that observed in
serum. There was a distinct difference in salivary cortisol
concentrations during therapy in comparison to levels
before and after. Following the completion of therapy,
adrenal function recovered and returned to pre-treatment
level, i.e. subclinical hypoadrenalism where the second
afternoon cortisol peak was lost (additional file 1, Figure
1). In this case, salivary cortisol levels appear to be an
additionally useful tool in the assessment of HPA axis. In
ASTs, it compares satisfactorily with serum cortisol in
detecting AI. Although AI is best assessed by serum corti-
sol dynamics, this report strongly suggests that salivary
concentration dynamics are a reliable and dependable
tool in the diagnosis of AI. It is additionally convenient
for patients, especially in the ambulatory setting. This
assay is not widely and routinely available however. The
loss of diurnal variation in salivary concentration also
remains to be validated but is also indicative of AI. Our
testing frequency may not have detected the second diur-
nal peak which may occur anywhere between 15:00 and
18:00 hours. Frequent samplings may be more revealing
but at the risk of non-compliance. The absolute morning
salivary cortisol concentrations of less than 3.8 nmol/L is
a good indicator of (impending) adrenal failure [7,8].
This level declined steadily following IFN therapy indicat-
ing a continuing decrease of adrenal reserve where it isPage 2 of 5
(page number not for citation purposes)
Cases Journal 2008, 1:157 http://www.casesjournal.com/content/1/1/157maximally stimulated by ACTH as indicated by the ACTH
failure to rise further with progressive hypoadrenalism.
The ACA titres peaked at the 48th week. Thereafter, it
returned to pre-treatment titre, paralleling the cortisol
profiles.
The pathogenesis of HCV associated adrenal disease
remains unknown and the molecular basis by which this
occurs is undelineated. Normal CT imaging excluded ana-
tomical causes such as haemorrhage, disseminated carci-
noma or rarely antiphospholipid syndrome [9]. In
autoimmune adrenal disease, it is thought that there must
be an antigen presented on the adrenal cortical cells to
stimulate the immune response. This response includes
both T and B cells although the major determinant is in
the former. The immune system is often stimulated by
HCV infection, further amplified by IFN therapy. This is
reflected by the positive but low titre of ACA at baseline,
peaking at the nadir of adrenal function. This observation
is consistent with a previous report [10] although our case
additionally details the effect of the rise in ACA titre on
cortisol metabolism. It is possible that IFN directly inhib-
its the synthetic function of adrenal cells and the swinging
cortisol dynamics before and during treatment represents
a balance between the inhibiting effect of IFN and the
trophic effect of ACTH. Alternatively, the IFN may act by
stimulating the T cells to destroy more adrenal cortical
cells. ACTH was almost at its peak level pre-treatment and
consequently failed to rise adequately to counter the
adrenalytic effect of IFN. Other case report suggested an
increase in cortisol consumption in AI proper [11]. Fur-
thermore, the natural history of adrenalitis is unknown
including its reversibility, the influence of IFN therapy
Twenty-four hour salivary cortisol profiles before, during and after the patient underwent combination Interferon-α2β and Rib-aviri  therapyFigure 1
Twenty-four hour salivary cortisol profiles before, during and after the patient underwent combination Inter-
feron-α2β and Ribavirin therapy. There is a significant difference between the IFN-treated vs. non-IFN treated groups.
0.0
1.0
2.0
3.0
4.0
5.0
6.0
7.0
8.0
9.0
10.0
0:00 6:00 12:00 18:00 24:00 hrs
Baseline 12 wk 24 wk 36 wk
48 wk 6 mth 12 mth
Salivary cortisol (nmol/L)
p = 0.0011
p = 0.0042
IFN-treated group
Non IFN-treated groupPage 3 of 5
(page number not for citation purposes)
Cases Journal 2008, 1:157 http://www.casesjournal.com/content/1/1/157and response to glucocorticoid supplement. Reversible
autoimmune adrenalitis treated with high dose glucocor-
ticoid associated with Graves' disease was previously
described but this was distinctly different from our case
[12]. The ACA titres parallel the dynamic of cortisol levels,
peaking at the nadir of adrenal function although the
absolute titre is modest. Nevertheless, this observation
lends strong evidence to the immunopathogenesis of this
condition.
Although the entity of subclinical AI has been well
described [13], its management remains controversial. In
de novo autoimmune situation, its progress depends on a
number of factors such as ACA titres, the degree of adrenal
gland failure, age and gender of the patient [14,15]. In the
presence of hepatitis C infection, the progress is unknown
although it can be surmised that the risk is higher due to
the presence of ACA antibodies and subsequent interferon
therapy. It is debatable as to the true 'subclinical' state of
the condition given the presence of vitiligo. The patient
however, had no other adrenal related symptoms
although admittedly in the presence of HCV and IFN ther-
apy, the clinical symptoms of adrenal failure can be very
hard to elicit.
It was both tempting to treat this patient with replacement
hydrocortisone given the biochemical results and the dif-
ficulties in separating adrenal failure symptoms and treat-
ment related side effects. The latter made it very difficult
to determine the active component of the symptomatol-
ogy due to adrenal insufficiency. Treatment with supra-
physiological corticosteroid has been reported to reverse
the condition in a similar clinical scenario but in the
absence of HCV infection [12]. Physiological replace-
ment, which was non-immunosuppresive, was not
required as the patient has adequate baseline cortisol, but
emergency supraphysiological supplement was made
available in the contingency plan.
Conclusion
This case explores the immunopathogenic effect of hepa-
titis C virus and IFN therapy on the adrenal cortex. It is
made more interesting by the presence of incidental and
subclinical AI. Whilst clinically silent, the clinical scenario
allows for the exploration of the use of salivary cortisol
levels which appears to be a useful tool in detecting AI,
either in a AST or a 24-hour profile.
Competing interests
The authors declare that they have no competing interests.
Authors' contributions
HAT provided the clinical case, consented the patient,
conceived the study, participated in its design, assisted
with data collection and statistical analysis, and coordi-
nated and helped to draft the manuscript. SS and RJL ana-
lysed, provided the data, and participated in the
discussion and drafting of the manuscript. GEMR contrib-
uted to the statistical and statistical analysis, participated
in the discussion and drafting of the manuscript. All
authors read and approved the final revised manuscript.
Consent
Written informed consent was obtained from the patient
for publication of this case report and biochemical data. A
copy of the written consent is available for review by the
Editor-in-Chief of this journal.
Additional material
Acknowledgements
We are very much indebted to Geoffrey M Kellerman for his constructive 
and analytical comments on this manuscript.
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Hepatitis C infection, treatment regimens, and thyroid function abnormalities. The Endocrinologist

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http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2556317

Exacerbation of hepatitis C induced subclinical hypoadrenalism by Interferon-alpha2beta: A case report

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