Bosch X. Hypercalcemia Due to Endogenous Overproduction of Active Vitamin D in Identical Twins With Cat-Scratch Disease. JAMA. 1998;279(7):532-534. doi:10.1001/jama.279.7.532
From the Internal Medicine Unit, Hospital Casa Maternitat, Corporació Sanitària Clínic, Barcelona, Spain.
Context.— The extrarenal synthesis of active vitamin D sterols has a central causative
role in the hypercalcemia associated with various granulomatous diseases.
Objective.— To study the calcium metabolism in patients with cat-scratch disease
who have hypercalcemia.
Design.— Case report.
Setting.— University hospital in Barcelona, Spain.
Patients.— Two identical twins who developed asymptomatic hypercalcemia during
the acute phase of cat-scratch disease.
Main Outcome Measures.— Serial measures of calcium homeostasis and metabolism over a 2-month
Results.— On admission and 6 and 7 days later, both patients were found to have
increased levels of serum and urinary calcium, serum phosphate, and serum
1,25-dihydroxyvitamin D [1,25(OH)2D], whereas they had normal values
of serum 25-hydroxyvitamin D and urinary cyclic adenosine monophosphate and
decreased serum concentrations of intact parathyroid hormone. Sixteen and
20 days after admission, these abnormalities had resolved without treatment.
A direct correlation was observed between the serum 1,25(OH)2D
levels and both the serum and 24-hour urinary calcium concentrations. Also,
the concentrations of calcium and 1,25(OH)2D paralleled the clinical
activity of the infectious disease over the period these parameters were measured.
Conclusions.— Our cases provide evidence that cat-scratch disease can produce hypercalcemia
through the unregulated production of the metabolite 1,25(OH)2D.
Cat-scratch disease should be added to the list of granuloma-forming diseases
that are responsible for 1,25(OH)2D-mediated hypercalcemia.
BARTONELLA henselae causes cat-scratch disease
(CSD), meningoencephalitis, endocarditis, and prolonged fever in immunocompetent
patients, and it causes bacillary angiomatosis and peliosis hepatis in patients
with human immunodeficiency virus infection.1
The classic clinical presentation of CSD is a self-limiting regional lymphadenopathy
usually caused by a cat scratch or bite. Antibiotic therapy has not been very
effective in treating the disease, and in most patients it resolves spontaneously
within several months.2 Results of routine
laboratory analyses are usually normal. Rare abnormalities discovered in laboratory
examinations include eosinophilia, anicteric hepatitis, and thrombocytopenia.
The latter constitutes a potentially serious event.3
Herein we describe 2 identical twin brothers who developed hypercalcemia,
hypercalciuria, and excessively high serum concentrations of the metabolite
1,25-dihydroxyvitamin D (1,25[OH]2D) during the acute phase of
CSD. The hypercalcemia in both brothers fulfilled the laboratory criteria
for the diagnosis of vitamin D metabolite–mediated hypercalcemia.4 Furthermore, the concentrations of calcium and 1,25(OH)2D in these patients paralleled the clinical activity of the infectious
disease over the period these parameters were measured.
Two identical twin brothers who were seen at our hospital in February
1997 received a diagnosis of hypercalcemia in association with CSD. Both conditions
were diagnosed simultaneously in each patient. Neither had taken calcium,
vitamin A, or vitamin D preparations previously. The monozygosity of the twin
pair was confirmed by a dermatoglyphic analysis of fingertip prints.5,6
An excisional lymph node biopsy was performed in each patient, and the
tissue specimen was divided into 2 samples for histopathologic examination
and microbiologic culture. Tissue samples were stained with conventional hematoxylin-eosin
as well as acid-fast, periodic acid–Schiff, and Warthin-Starry silver
stains. We attempted to isolate Bartonella species
from whole blood specimens and homogenized lymph node biopsy material. Specimens
were inoculated both onto 5% sheep blood agar (bioMérieux, Marcy-l'Etoile,
France) and into the human endothelial cell line ECV 304.7
Inoculated media were incubated at 37°C in a carbon dioxide atmosphere
for as long as 60 days. Any isolates were identified initially by colony morphologic
characteristics and negative results on tests for oxidase and catalase; identification
was confirmed by species-specific mouse polyvalent antisera8
and by gas chromatography of whole-cell fatty acids (Hewlett-Packard 5890
with Microbial Identification System software, version 3.0, Microbial ID Inc,
Newark, Del).9 Lymph node specimens were also
incubated for growing on conventional Lowenstein medium.
The initial serum specimen was drawn within 1 week of the reported onset
of illness in both patients. Serial serum samples from each patient were obtained.
Serum samples were evaluated for immunoglobulin G antibodies to B henselae in an indirect immunofluorescent antibody assay. Antibody
screening was performed according to the manufacturer's instructions and interpreted
with previously published criteria.10,11
The serologic results were reported as an end-point dilution, with a titer
of 1:64 or greater considered positive (B henselae
antibody immunofluorescence test kit, BIOS GmbH Labordiagnostik, Munich, Germany).
The demonstration of seroconversion or an increase in titer of at least 4-fold
between the acute- and convalescent-phase serum specimens was considered supportive
evidence of current or recent B henselae infection.
According to the manufacturer's catalog, no defined cross-reactivity was found
when this assay was tested with serum containing antibodies to other organisms,
such as Afipia felis or Bartonella
Studies of hypercalcemia included measurements of serum levels of total
protein-corrected calcium, ionized calcium, serum phosphate, intact parathyroid
hormone, 25-hydroxyvitamin D, and 1,25(OH)2D. The 24-hour urinary
excretions of calcium and cyclic adenosine monophosphate were also determined.12 These parameters were measured at different intervals
over a 2-month period.
A previously healthy 18-year-old man was well until 5 days before evaluation,
when he noted the onset of tender right cervical and preauricular lymph nodes
and subjective fevers. He had purchased a 6-week-old kitten 3 weeks before
the onset of his symptoms and had received multiple scratches from it since
then. On physical examination his temperature was 38.3°C and he had a
5×5-cm tender right cervical lymph node as well as multiple loci of
smaller, axillary, supraclavicular inguinal and left cervical lymphadenopathy.
A diffuse maculopapular eruption was also observed. He had a 1.5-cm erythematous
pustule on his right hand at the site of a previous scratch. Apart from an
erythrocyte sedimentation rate of 64 mm/h and the abnormalities shown in Table 1, results of routine laboratory
examinations were normal. In addition, findings of blood cultures and serologic
tests for several bacteria and viruses, including human immunodeficiency virus
type 1, were negative. Antinuclear antibodies, anti–native DNA antibodies,
and rheumatoid factor were not detected. A chest roentgenogram and an abdominal
computed tomographic scan revealed no abnormalities. His symptoms abated spontaneously,
and he was discharged 8 days after admission free of symptoms with no antimicrobial
therapy. His cervical adenopathy resolved within 2 months.
The identical twin brother of patient 1 presented with a 1-week history
of low-grade fever, night sweats, fatigue, headache, and progressive enlargement
of bulky right axillary lymphadenopathy that became painful. These symptoms
began 10 days after the onset of his brother's symptoms. He had also received
several scratches from the same cat since it had been acquired. Examination
revealed a temperature of 37.7°C and a 6×5-cm, tender, firm right
axillary lymph node. Smaller adenopathies were found in other territories.
An inoculation papule or blister was not clearly seen. Results of laboratory
examinations were significant for an erythrocyte sedimentation rate of 50
mm/h, a leukocyte count of 13×109/L with a normal differential
count, and the abnormalities shown in Table
1. Results of serologic tests for several bacteria and viruses,
immunologic tests, and blood cultures were all negative. Findings of a chest
roentgenogram and an abdominal computed tomographic scan were normal. His
symptoms decreased over a few days, and he was discharged 5 days after admission
free of symptoms with no therapy. His axillary adenopathy had disappeared
3 months after admission.
Both patients had similar histologic findings in excised lymph nodes
(right cervical in patient 1 and right axillary in patient 2). Conventional
hematoxylin-eosin stains were interpreted as consistent with CSD. Changes
mainly consisted of lymphoid hyperplasia (that is, arteriolar proliferation,
reticulum cell hyperplasia, and widening of arteriolar walls), perivascular
lymphocytic infiltrates, and numerous scattered caseating granulomas containing
stellate areas of necrosis with large collections of macrophages, neutrophils,
and some multinucleated giant cells. No bacillary forms could be demonstrated
with Warthin-Starry staining in either patient. Results of the acid-fast and
periodic acid–Schiff staining procedures were also negative.
Microbiologic culture of a lymph node sample yielded growth of an organism
consistent with B henselae after 20 days in patient
1. An isolate was also obtained from the lymph node tissue of this patient
using endothelial cell coculture. Isolated colonies growing on blood agar
plates had irregular morphologic characteristics and adhered to the agar surface.
These colonies were small and white to gray. The identity of the isolate obtained
was confirmed using B henselae–specific mouse
polyvalent antisera and by gas chromatography of whole-cell fatty acids. Culture
of a lymph node sample from patient 2 as well as cultures of whole blood specimens
from both patients yielded no growth of any organism after 60 days. Finally,
no isolates were obtained in either patient from lymph node biopsy material
that had been incubated on Lowenstein medium after an appropriate period.
Seroconversion was observed in patient 1 as late as the 12th day after
onset of illness (seventh hospitalization day), with a titer of 1:256. Antibody
titers rose to 1:2048 at day 16 after admission and declined thereafter to
1:512 at 2 months after admission. Patient 2 was also seropositive for B henselae, with a titer of 1:64 on admission. Serial serum
specimens obtained from this patient revealed a 6-fold rise in antibody titers
6 days after admission; titers continued to rise to 1:4096 at day 20 after
admission. Forty-five days after admission, serum titers had decreased to
1:1024. Serum titers of both patients observed for more than 3 months remained
elevated but stable.
On admission and 6 and 7 days later, both patients had increased levels
of serum and urinary calcium, serum phosphate, and serum 1,25(OH)2D,
whereas they had normal values of serum 25-hydroxyvitamin D and urinary cyclic
adenosine monophosphate and decreased serum concentrations of intact parathyroid
hormone (Table 1). Neither patient
had hypercalcemia-related symptoms at any time. Sixteen days after admission
in patient 1 and 20 days after admission in patient 2, these abnormalities
were all resolved (Table 1). No
medications were administered that could have affected calcium metabolism.
In these patients a direct correlation was observed between the serum
1,25(OH)2D levels and both the serum and the 24-hour urinary calcium
concentrations. This fact supports the hypothesis that excessive serum 1,25(OH)2D was responsible for the development of hypercalcemia-hypercalciuria
in both patients.
The 3 most frequent causes of human hypercalcemia are primary hyperparathyroidism,
malignant neoplasms, and granulomatous diseases.4
Deregulated production of 1,25(OH)2D by macrophages that are activated
appears to be the pivotal causative factor for the abnormalities of calcium
metabolism that may occur in some granulomatous diseases, especially sarcoidosis.4,13 Overproduction of 1,25(OH)2D
may cause increased intestinal absorption of calcium, enhanced bone resorption,
and resultant hypercalciuria with or without hypercalcemia.13
The extrarenal synthesis of active vitamin D sterols has a central causative
role in the hypercalcemic-hypercalciuric state associated with sarcoidosis,
tuberculosis, disseminated candidiasis, leprosy, silicone-induced granulomatous
disease, Wegener granulomatosis, and Nocardia asteroides infection, whereas the circulating vitamin D metabolite status of
patients with hypercalcemia who have other granuloma-forming diseases, such
as coccidioidomycosis, histoplasmosis, berylliosis, and eosinophilic granuloma,
has not been carefully studied.4,12,14
To the best of our knowledge, our 2 cases are the first instances of hypercalcemia
reported in patients with CSD.
Stellate caseating granulomas, usually with microabscess formation,
are widely thought to be the characteristic distinguishing histopathologic
feature of CSD.3,15 Of interest,
our patients had numerous necrotizing granulomas in their lymph node biopsy
samples. The fact that they were monozygotic twins and that 1,25(OH)2D-mediated hypercalcemia developed in the setting of a well-established
diagnosis of CSD reinforces the possibility of a cause-effect relationship
and suggests the existence of a genetically determined unusual susceptibility
for the state of disordered calcium homeostasis that occurred in these cases.
Because urinary excretion of calcium, especially 24-hour excretion,
is probably not routinely evaluated in most patients with CSD, one might speculate
that abnormalities in calcium metabolism may have been underdiagnosed in other
patients with CSD. In fact, the prevalence of hypercalciuria in patients with
sarcoidosis is much higher than that of hypercalcemia.4
There are now at least 3 major lines of clinical evidence to demonstrate
that the extrarenal, macrophage-dependent synthesis of an active vitamin D
metabolite in hypercalcemic-hypercalciuric patients with sarcoidosis is not
subject to control by those factors that normally regulate renal 1α-hydroxylase.4,13 First, hypercalcemic patients have
a frankly high or inappropriately elevated serum 1,25(OH)2D concentration,
although their serum intact parathyroid hormone level is suppressed and their
serum phosphate concentration is relatively elevated. Second, the serum concentration
of 1,25(OH)2D is exquisitely sensitive to an increase in the availability
of substrate. Third, the serum calcium and 1,25(OH)2D concentrations
are positively correlated to indices of disease activity; patients with sarcoidosis
who have widespread disease and high angiotensin-converting enzyme activity
are more likely to be hypercalciuric or frankly hypercalcemic.4
Most of these features can be extrapolated to the present cases of CSD.
Of importance, we decided not to treat hypercalcemia in our patients
because it caused no symptoms. Also, no antibiotic therapy was administered.
This allowed us to observe the natural evolution of the infectious disease,
including both clinical and serologic evolution as well as the natural evolution
of calcium metabolism abnormalities.
Our cases provide evidence that CSD, like other granulomatous diseases,
can produce hypercalcemia through the unregulated production of the metabolite
1,25(OH)2D. Furthermore, in view of these 2 cases, we believe that
CSD should be added to the list of granuloma-forming diseases that are responsible
for 1,25(OH)2D-mediated hypercalcemia.