| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Original Studies |
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
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: jshaker{at}execpc.com
 |
Abstract |
|---|
 Top Abstract IntroductionCase ReportDiscussionReferences |
|---|
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.
|
Introduction |
|---|
|
TopAbstractIntroductionCase ReportDiscussionReferences |
|---|
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.
|
Case Report |
|---|
|
TopAbstractIntroductionCase ReportDiscussionReferences |
|---|
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 bone-specific 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
µg/L (normal, 360-1200). The angiotensin-converting enzyme level was
3.4 U/L (normal, 6.1–21).
|
-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 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).
|
, 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.
|
). 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).
|
|
Discussion |
|---|
|
TopAbstractIntroductionCase ReportDiscussionReferences |
|---|
-hydroxylase by PTH. Review of previous cases
Ours is the 10th patient reported with HCAO (1, 2, 3, 4, 5, 6, 7, 8, 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, 2, 3, 4, 5, 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 extremities). 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 increased in most, but not all, patients (1, 3, 5, 6, 7, 8, 9). When performed after two courses of tetracycline, bone biopsy shows accelerated rates of skeletal formation with normal lamellar bone (1, 2, 3, 4, 5, 6, 7, 8, 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).
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.
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 |
|---|
Received July 9, 1997.
Revised September 10, 1997.
Accepted September 17, 1997.
|
References |
|---|
|
TopAbstractIntroductionCase ReportDiscussionReferences |
|---|
This article has been cited by other articles:
 |
|
 |
|
  E. K. Chow, A. Castrillo, A. Shahangian, L. Pei, R. M. O'Connell, R. L. Modlin, P. Tontonoz, and G. Cheng A role for IRF3-dependent RXR{alpha} repression in hepatotoxicity associated with viral infections J. Exp. Med., November 27, 2006; 203(12): 2589 - 2602. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Khosla and C. A. Conover Insulin-Like Growth Factor (IGF)-II/IGF-Binding Proteins in Constitutionally Tall Children J. Clin. Endocrinol. Metab., April 1, 2003; 88(4): 1912 - 1913. [Full Text]
|
|
|
|
|
|
S. Khosla, F. J. Ballard, and C. A. Conover Use of Site-Specific Antibodies to Characterize the Circulating Form of Big Insulin-Like Growth Factor II in Patients with Hepatitis C-Associated Osteosclerosis J. Clin. Endocrinol. Metab., August 1, 2002; 87(8): 3867 - 3870. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. L. Shaker, B. P. Moore, and M. P. Whyte Hyperparathyroidism and Increased Serum IGF-Binding Protein-2 Levels in Hepatitis C-Associated Osteosclerosis J. Clin. Endocrinol. Metab., January 1, 1999; 84(1): 384a - 385. [Full Text]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Endocrinology | Endocrine Reviews | J. Clin. End. & Metab. |
| Molecular Endocrinology | Recent Prog. Horm. Res. | All Endocrine Journals |
