0021-972X/98/$03.00/0
Journal of Clinical Endocrinology and Metabolism
Copyright © 1998 by The Endocrine Society
Vol. 83, No. 1
Printed in U.S.A.
Hepatitis C-Associated Osteosclerosis: Late Onset after
Blood Transfusion in an Elderly Woman
JOSEPH L. SHAKER, WILLIAM R. REINUS,
AND
MICHAEL P. WHYTE
Department of Medicine, St. Luke’s Medical Center (J.L.S.), Milwaukee, Wisconsin 53215; and the
Departments of Radiology (W.R.R.) and Medicine (M.P.W.), Division of Bone and Mineral Diseases,
Washington University School of Medicine, Barnes-Jewish Hospital, St. Louis, Missouri 63110
ABSTRACT
A 69-yr-old woman with hepatitis C virus (HCV) infection from
blood transfusion 14 yr earlier was evaluated in 1997 for increasing
appendicular skeletal pain. Diffusely elevated radioisotope uptake on
bone scanning had appeared during the past 15 months. Radiographs
spanning 1978 –1997 showed remarkable restoration of bone mass
and a skeleton like that of a young woman. Bone mineral densities of
the femoral neck and lumbar spine were above the mean peak bone
mass of young women (T scores, 11.8 and 11.3, respectively) and
160% and 147% of mean values for age-matched female controls
(Z-score, 13.7 and 13.6, respectively). Biochemical markers of skeletal remodeling were substantially increased. Bone marrow biopsy
showed normal lamellar bone. Serum alkaline phosphatase activity
assays suggested that accelerated skeletal turnover began 6 –12
months before symptoms.
HC-associated osteosclerosis has been reported in nine individuals
27–73 yr of age, most with a history of iv drug abuse. Our patient
demonstrates that parenteral exposure to blood rather than illicit
drugs is the feature common to all affected subjects. Furthermore, we
document that there can be a long latency between HCV infection and
the development of skeletal abnormalities. We also find that bone
mass can be restored by this disorder in a postmenopausal woman.
Routine radiographs, however, may not show overt osteosclerosis in
the elderly. The precise pathogenesis of this disorder is unknown.
Understanding and control of the mechanism of HC-associated osteosclerosis could potentially lead to correction of low bone mass from
osteoporosis with good quality skeletal tissue. (J Clin Endocrinol
Metab 83: 93–98, 1998)
S
INCE 1992, nine patients with painful diffuse osteosclerosis and hepatitis C virus (HCV) infection have been
reported (1–9). Their ages range from 27–73 yr. Most had a
history of iv drug abuse. Each presented with limb pain,
usually associated with elevated serum alkaline phosphatase
(ALP) activity, and all had increased bone density. When
skeletal biopsies were performed, increased rates of bone
accretion and dense lamellar osseous tissue were described
(1–9).
We report an elderly woman with HC-associated osteosclerosis (HCAO) whose viral infection was acquired from
blood transfusion. Recent onset of appendicular symptoms,
serial measurements of ALP activity, and findings from two
bone scans indicated late onset of her skeletal disease. Radiographs and densitometry showed restoration of greater
than mean peak bone mass for young women.
She had undergone coronary artery bypass graft (CABG) surgery in
1983 and required blood transfusions. A total of 4 U packed red blood
cells and 8 U single donor plasma were administered. Abnormal
transaminase levels were present 3 yr later and led to diagnosis of HCV
infection in 1992. There was no history of iv drug abuse. She had worked
as a registered nurse, but could recall no accidental needle sticks. She did
not do phlebotomy and only rarely gave injections. She did not have
pierced ears or tattoos and knew of no other exposure to blood products.
Her past medical history was significant for type I diabetes mellitus
for 30 yr. She has neuropathy, albuminuria, and retinopathy, for which
she has had laser photocoagulation. She also has hypertension. Medications included human NPH and regular insulin, extended release
diltiazem, quinapril, isosorbide mononitrate, hydrocodone, and ibuprofen. She had been taking hormone replacement therapy with conjugated
estrogen and medoxyprogesterone since the age of 57 yr (2 yr after
menopause). A maternal aunt was reported to have osteoporosis. She
has two brothers, apparently without skeletal disease, and she has no
children.
On physical examination, she was a thin woman (height, 164 cm;
weight, 49 kg) without skeletal deformity. Her blood pressure was
172/80 mm Hg, and her pulse rate was 100 beats/min. She had marked
diffuse tenderness to light palpation of all of her long bones. She was not,
however, particularly tender over the skull, ribs, pelvis, or spine.
Serum biochemical studies showed a creatinine level of 1.0 mg/dL
(normal, 0.6 –1.3), alanine transaminase (ALT) of 71 U/L (normal,
10 –50), aspartate transaminase (AST) of 72 U/L (normal, 10 –38), and
TSH of 3.8 mu/L (normal, 0.4 – 4.6). The creatinine clearance was 49
mL/min. Biochemical parameters of bone and mineral metabolism
are summarized in Table 1. They indicated accelerated skeletal remodeling. There was increased serum ALP activity as well as bonespecific ALP and osteocalcin levels reflecting enhanced bone formation (10), and increased urinary pyridinoline and deoxypyridinoline
levels reflecting enhanced bone resorption (10). However, her serum
calcium, phosphorus, and 25-hydroxyvitamin D levels were normal.
Intact PTH and 1,25-dihydroxyvitamin D levels were elevated (see
Discussion). The plasma fluoride level was 3.2 mmol/L (.15 is toxic),
and the plasma vitamin A concentration was 812 mg/L (normal,
360-1200). The angiotensin-converting enzyme level was 3.4 U/L
(normal, 6.1–21).
Case Report
A 69-yr-old Caucasian woman was evaluated in April 1997 because
of diffuse appendicular bone pain. She felt generally well until the
summer of 1996, when she developed arthralgias of her knees. Thigh and
hip discomfort began in the late fall and early winter of 1996. Her
symptoms worsened and extended during the ensuing 4 –5 months. Pain
involving her thighs, legs, elbows, upper arms, and, to a lesser extent,
forearms became severe and required narcotic analgesics. Although she
had been accustomed to walking 3 miles daily, ambulating even a short
distance was now difficult.
Received July 9, 1997. Revision received September 10, 1997. Accepted September 17, 1997.
Address all correspondence and requests for reprints to: Joseph L.
Shaker, M.D., Department of Medicine, St. Luke’s Medical Center, 2901
West Kinnickinnic River Parkway, Suite 503, Milwaukee, Wisconsin
53215. E-mail: [email protected].
93
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SHAKER, REINUS, AND WHYTE
TABLE 1. Biochemical parameters of mineral metabolism
Serum
Calcium (mg/dL)
Albumin (g/dL)
Phosphorus (mg/dL)
25(OH) vitamin D (ng/mL)
1,25(OH)2 vitamin D (pg/mL)
Intact PTH (pg/mL)
ALP (U/L)
Bone-specific ALP (ng/mL)
Osteocalcin (ng/mL)
Urine (24 h)
Calcium (mg/24 h)
Pyridinoline (nmol/mmol creatinine)
Deoxypyridinoline (nmol/mmol creatinine)
a
b
c
Patient
Normal range
9.1a
3.5b
3.3b
24
62
190b
821
138
71
8.8 –10.2
3.6 – 4.7
2.5– 4.8
9 –52
15–50
10 – 65
30 –120
,15
5.8 – 41
134b
116c
32c
50 –250
20 – 62
5–22
Mean of three values.
Mean of two values.
Elevated despite calcitonin treatment for 2 weeks.
HCV antibody, determined by enzyme immunoassay, was reactive.
HCV ribonucleic acid was detected by the Chiron branched DNA assay
(2.28 mEq/mL; normal, ,0.20; Mayo Medical Laboratories, Rochester,
MN). Sequential serum ALT, AST, and g-glutamyl transferase activity
values were obtained from review of her medical records (Fig. 1). The
transaminase levels were normal to slightly elevated and had been
essentially stable from 1986 to 1997, although there was an unexplained
flare shortly before referral. Of interest, her serum ALP activity, measured at the time of CABG in 1983 and regularly from 1986 –1997,
showed a remarkable recent increase (Fig. 1). ALP activity was only
high-normal to slightly elevated until 16 months before referral. At that
time, ALP activity increased to about 3 times the upper limit of normal
and was about 6 times the upper limit of normal upon referral. ALP
isoenzyme fractionation demonstrated predominantly ALP of skeletal
origin.
A bone marrow aspirate and biopsy in 1997 revealed normal findings.
Review of the specimen using polarized light microscopy showed that
cortical and trabecular bone were composed of normal lamellar osseous
tissue.
A total body bone scan (Fig. 2) showed diffuse enhanced uptake of
all major long bones (findings not present on a bone scan performed 15
months earlier because of increasing ALP activity).
We reviewed all available radiographs. Chest x-rays taken 5 yr before,
at the time of, and 14 yr after CABG documented changes in the thickness of the cortexes of her ribs (Fig. 3, a– c). Between 1978 –1983, there
appeared to be a slight decrease in the cortical thickness of her ribs by
approximately 0.2 mm, as determined by eye micrometer. However,
sometime during the interval between 1983–1997, rib cortices thickened
by approximately 0.6 mm. We were, however, unable to determine from
the available radiographs when this cortical thickening of her ribs had
occurred. Cortical thickening was confirmed by review of her pelvic
radiographs obtained 1 yr before and 14 yr after CABG (Fig. 3, d and e).
The thickness of the cortex of the medial aspect of the femoral neck
(calcar) had increased from a maximum of approximately 6 mm to a
maximum of 9 mm (i.e. 50%). Furthermore, sometime during these 15 yr,
the thickest portion of the cortex of the iliopectineal line had increased
from a maximum of approximately 3 to 6 mm (i.e. 100%). Multiple
radiographs of her extremities obtained 14 yr post-CABG showed cortical thickness and trabecular patterns that were subjectively those of a
much younger woman (Fig. 3f). The appearance of her skeleton was
consistent radiographically with accretion of normal osseous tissue in a
normal pattern of distribution. There was no evidence of focal sclerosis,
periosteal new bone apposition, pathologically thickened trabeculae, or
narrowing of the medullary canal to suggest abnormal skeletal
morphology.
Bone mineral density (BMD) of her lumbar spine and hip determined
by dual energy radiography (DPX-L, Lunar Corp., Madison, WI) was
distinctly elevated for a woman her age (Table 2). In fact, 5 months after
this initial dual energy radiography study, her BMD had increased 11.7%
in her lumbar spine (BMD in the proximal femur was difficult to compare because of differences in patient positioning).
FIG. 1. Serum levels of ALP and g-glutamyl transferase (gGT; upper
panel) and of AST and ALT (lower panel) from 1983–1997. Note that
only the ALP level begins to increase dramatically 16 months before
referral.
Discussion
Our elderly patient has HCAO. The clinical hallmarks of
this new disorder are generalized appendicular skeletal pain,
increased radioisotope uptake on bone scan, abnormally
high bone density, and biochemical parameters consistent
with rapid skeletal turnover developing after HCV infection
(11, 12). Although primary hyperparathyroidism can cause
osteosclerosis (12) and our patient’s serum PTH and 1,25dihydroxyvitamin D levels were elevated, her serum calcium
level was repeatedly normal. We cannot readily explain these
biochemical abnormalities, but do not conclude she has primary hyperparathyroidism. We do not believe the mild renal
insufficiency is a major factor in the hyperparathyroidism.
Indeed, elevations of serum PTH, perhaps secondary to avid
net bone formation, have been described in HCAO (1–3, 6, 9).
Hyperparathyroidism could, however, have contributed to
her osteosclerosis by increasing bone remodeling. The elevated 1,25-dihydroxyvitamin D level is presumably due to
stimulation of renal 25-hydroxyvitamin D-1a-hydroxylase
by PTH.
Review of previous cases
Ours is the 10th patient reported with HCAO (1–9). Of
the 10 cases, 7 are men, and 3 are women. All have been
from the United States, except for 1 Australian patient (6).
Most were in their 3rd and 4th decades of life, ranging
from 27–73 yr. Six of these individuals had a history of iv
drug abuse (1– 6, 9). In one patient, the mode of transmission of HCV was not reported (7). Two men, however,
appear to have acquired HCV infection from blood transfusion (8, 9).
The clinical presentation of the disorder is an acquired
deep bone pain of the limbs (especially the lower extremi-
HEPATITIS C-ASSOCIATED OSTEOSCLEROSIS
95
FIG. 2. Total body bone scan (anterior view) from December 29, 1995 (A) demonstrates moderately increased activity in the ankles and hind
feet, but is otherwise normal. A similar view scan from March 11, 1997 (B) shows diffusely increased radionuclide activity in the long bones
with deficient activity in the soft tissues, a finding consistent with markedly increased bone turnover.
ties). Fractures have not been reported, and it has been speculated that discomfort is from the periosteal stretching by
new bone apposition (1).
Radiographs show generalized cortical thickening and a
trabecular pattern of coarsened normal bone. The skull may
be spared (3, 5, 6, 9). Bone scintigraphy typically reveals
diffusely increased radioisotope uptake, and bone density
measurements are elevated.
Laboratory findings include normal serum calcium and
phosphorus levels. Markers of bone formation, such as serum ALP activity, and/or markers of bone resorption, such
as urinary hydroxyproline or deoxypyridinoline, are in-
creased in most, but not all, patients (1, 3, 5, 6 –9). When
performed after two courses of tetracycline, bone biopsy
shows accelerated rates of skeletal formation with normal
lamellar bone (1–9).
Therapy with calcium and calcitriol or drugs that inhibit
osteoclast function may decrease serum ALP activity (1, 3, 6,
8, 9); however, subjective response to pharmacological treatment appears to vary. One patient may have benefited from
calcium and calcitriol therapy (3). Clinical improvement with
calcitonin injections (1) or pamidronate infusions (6, 9) has
been reported, whereas other patients have not improved
with antiresorptive therapy (8, 9).
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HEPATITIS C-ASSOCIATED OSTEOSCLEROSIS
97
TABLE 2. Bone densitometry
Site
Spine (L2–L4)
Femur
Neck
Wards
Trochanter
BMD
(g/cm2)
% Predicted
Z-score (SD mean for age,
sex, race)
t-score (SD mean for young adult,
sex, race)
1.36
147
13.6
11.3
1.19
1.06
1.03
160
175
158
13.7
13.5
13.4
11.8
11.2
12.2
Bone densitometry was performed using dual energy radiography (DPX-L, Lunar Corp., Madison, WI).
Etiology and pathogenesis
Including our patient, three individuals have now been
described who almost certainly acquired HCV infection from
blood transfusion rather than from iv use of illicit drugs (8,
9). Accordingly, illegal drugs or a contaminant (2) is not the
cause of HCAO (4). Instead, parenteral exposure to blood is
the history common to all patients.
All 10 reported cases with this syndrome have been infected with HCV. Although another unidentified parenterally transmitted agent cannot be excluded, the invariable
presence of HCV infection strongly suggests that this virus
causes this syndrome. Documentation of similar patients
without HCV infection would be particularly important. Although infection with HCV appears to be the etiology of
HCAO, the pathogenesis of the dense bone is unknown.
Indeed, the syndrome is uncommon in patients with HCV
infection. Fully 1.4% of Americans are believed to be seropositive for HCV (13), yet HCAO is rare. Beyer and colleagues reviewed skeletal radiographs of 107 HCV-positive
patients and found no radiographic evidence of osteosclerosis (2).
Our patient provides new insight into the temporal relationship between exposure to tainted blood and onset of
HCAO. She almost certainly acquired HCV during blood
transfusions in 1983. Nonetheless, her serum ALP activity
did not become markedly elevated until late in 1995, and
her skeletal symptoms began approximately 6 months
later. In fact, a bone scan about 6 months before symptoms
began was essentially negative. Subsequently, another
scan revealed diffusely increased radioisotope uptake.
Longitudinal biochemical information is not available in
prior case reports of HCAO; however, in one patient,
skeletal symptoms first occurred 13 yr after non-A, non-B
hepatitis was diagnosed (1), and symptoms developed 8 yr
after transfusions in another individual (8). Our patient
documents that the pathogenetic process may indeed begin many years after acquiring HCV infection. Accordingly, the skeletal symptoms can be the result of rapid
bone accretion over a relatively short period of time, rather
than the result of many years of slow but steady excessive
bone formation.
To fully understand HCAO, we will need to explain the
long latency period in some cases and the predisposition of
only a small minority of HCV-positive patients. Perhaps a
triggering event occurs in a genetically predisposed individual with HCV infection. We could not discern such a factor
in our patient.
There are several plausible explanations for HCAO. The
HCV could infect bone cells or bone cell precursors in susceptible individuals. This theory is not without precedent.
Paget disease of bone, a condition associated with focal acceleration of bone turnover, may be caused by paramyxovirus infection of osteoclasts in genetically predisposed subjects (14, 15). Like Paget bone disease, HCAO could reflect a
slow virus infection of bone cells. Alternatively, the HC virus
within the liver or other tissues could lead to the production
of cytokines or growth factors that indirectly increase bone
remodeling (16, 17). Our patient had no biochemical evidence of a flare of her hepatitis until 15 months after her
serum ALP activity had begun to increase. However, serum
transaminase levels can fluctuate in some patients with HCV
infection and may not correlate with the severity of the liver
disease (18). It is possible that hepatic inflammation results
in the release or increased production of factors that stimulate bone turnover. In a preliminary report, however,
Cheng and co-workers were unable to establish the presence
of a circulating osteoinductive factor in patient serum (19).
Finally, it is possible that another infectious agent is transmitted together with HCV and causes HCAO.
Implications for osteoporosis
Patients with HCAO have a dramatic increase in bone
mass. Indeed, their BMD can be more than twice the mean
values predicted for age and sex (1, 5). Prior osteopenia in an
elderly patient who develops HCAO could mask osteosclerosis. In our elderly patient, recent radiographs suggested
that she had the skeleton of a young woman. Restoration of
bone mass in this syndrome is in contrast to current antiresportive therapies for osteoporosis that result only in stabilization or modest increases in bone density (20). Although
speculative, understanding HCAO could result in an effective treatment for osteoporosis.
FIG. 3. Coned down views of the postero-lateral left sixth rib from April 9, 1978 (A), June 24, 1983 (B), and March 19, 1997 (C) show that the
maximal cortical thicknesses (curved arrows) measure approximately 1.1, 0.9, and 1.5 mm, respectively. The change between 1978 and 1983
is consistent with postmenopausal bone loss. The 67% increase in cortical thickness sometime between 1983 and 1997 is consistent with marked
bone apposition. Similarly, coned down views of the left hip obtained 1 yr before CABG (D) and 14 yr after CABG (E) show marked increases
in the thickness of the calcar of the femoral neck (short arrow) and the iliopectineal line (long arrow). An antero-posterior view of the knees
(F) at age 69 yr shows normal bone morphology, but an appearance and density that are subjectively consistent with the skeleton of a young
woman.
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SHAKER, REINUS, AND WHYTE
Conclusion
Our patient demonstrates three important findings for
HCAO. The disorder is acquired from parenteral exposure to
tainted blood, not from illicit drugs. The onset of the skeletal
disease can be delayed many years after HCV infection is
acquired. Substantial augmentation of bone mass can occur
in affected elderly postmenopausal women. Because the
bone formed in HCAO appears to be good quality lamellar
bone, elucidation of the pathogenesis of this syndrome and
control of the mechanism could lead to improved therapy for
osteoporosis.
Acknowledgments
The authors thank Drs. Scott Magee and Jack Anderson for referral
of the patient, Dr. Steven L. Teitelbaum for reviewing the bone marrow
biopsy specimen, and Virginia Wiatrowski and Darlene Harmon for
preparation of the manuscript.
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