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HepC Newsletter
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Dema-@aol.com
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Aug 03, 2009 13:05 PDT
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NATAP http://natap.org/
_______________________________________________
_Thyroid Dysfunction & Bone Disease in HCV & HIV_
(http://www.natap.org/2008/HIV/123008_04.htm)
Thyroid Dysfunction & Bone Disease in HIV & HCV; Thyroid Testing
Recommended by UK Group. NOF Osteoporosis Prevention - Risk Factors for
Osteoporosis ...
www.natap.org/2008/HIV/123008_04.htm
_Viral Hepatitis is Associated with Reduced Bone Mineral Density in ..._
(http://www.natap.org/2009/CROI/croi_143.htm)
In fact all HIV+ and certainly including HCV/HIV coinfected should
receive baseline bonedexas. A reason this is not supported by thought leaders in
HIV is ...
www.natap.org/2009/CROI/croi_143.htm
_Effects of chronic liver disease on bone mineral density and bone ..._
(http://www.natap.org/2005/HCV/110705_01.htm)
Nov 1, 2005 ... With the use of DEXA at four bone sites, we demonstrated
a higher prevalence (72 %) of osteoporosis in postmenopausal women with
chronic ...
www.natap.org/2005/HCV/110705_01.htm
Cirrhotics Have Low Bone Density & Low Vitamin D Levels
"Bone mineral density and disorders of mineral metabolism in chronic liver
disease"
"Patients with cirrhosis have low BMD. Contributory factors are reduced
physical activity, low lean body mass, vitamin D deficiency and hypogonadism
and low IGF-1 level.....Among the 63 patients, vitamin D values were < 10
ng/mL in 38 patients (60%), 10-20 ng/mL in 20 patients (32%), and > 20 ng/mL
in 5 patients (8%). Despite having a low vitamin D level in 92%, PTH was
within the physiological range in 87% of patients
Long-standing liver disease has long been recognized to result in fragile
bones with increased risk of fractures. In various international studies,
the overall incidence has varied from 11% to 48%, with a fracture rate of
3%-44%. The reason for this is poorly understood. With liver transplantation
becoming a viable option in liver disease and offering complete cure and
long-term survival, bone disease is becoming the major determinant of
survival and quality of life in these patients. The major influences on bone
metabolism are genetic, but also essential are mechanical stress (exercise and
muscle activity), good nutrition, adequate calcium and vitamin D, and a
normal hormonal environment. The patient with CLD could have any of these
factors acting alone or in concert, which potentially predispose him/her to
thin bones. Each of the above factors were assessed and compared between
patients with low and normal BMD. It was found that patients with CLD had all
the above and known risk factors: low sunlight exposure, reduced physical
activity, low lean body mass, vitamin D deficiency and hypogonadism. This
indicates that all patients with cirrhosis, unless prevented, will develop the
disease. In addition, although the calcium intake was adequate by ICMR
guidelines, it was well below the internationally accepted daily allowance. Our
results provide evidence of the key roles played by IGF-1 and estrogen in
this condition. Although risk factors are prevalent in all patients, the
severity of bone loss may be accelerated in patients with low IGF-1 level.
The present study also suggests a possible protective role for the high
estrogen level seen in cirrhosis.
World J Gastroenterol 2009 July 28; 15(28): 3516-3522
Joe George, Hosahithlu K Ganesh, Shrikrishna Acharya, Tushar R Bandgar,
Vyankatesh Shivane, Anjana Karvat,
Shobna J Bhatia, Samir Shah, Padmavathy S Menon, Nalini Shah
Joe George, Hosahithlu K Ganesh, Shrikrishna Acharya, Tushar R Bandgar
Vyankatesh Shivane, Anjana Karvat, Padmavathy S Menon, Nalini Shah, Department
of Endocrinology, Seth G.S. Medical College and KEM Hospital, Mumbai
400012, India
Shobna J Bhatia, Department of Gastroenterology, Seth G.S. Medical College
and KEM Hospital, Mumbai 400012, India
Samir Shah, Department of Gastroenterology, Jaslok Hospital, Mumbai
400026, India
Abstract
AIM: To estimate the prevalence and identify the risk factors for
metabolic bone disease in patients with cirrhosis.
METHODS: The study was performed on 72 Indian patients with cirrhosis (63
male, 9 female; aged < 50 years). Etiology of cirrhosis was alcoholism (n =
37), hepatitis B (n = 25) and hepatitis C (n = 10). Twenty-three patients
belonged to Child class A, while 39 were in class B and 10 in class C.
Secondary causes for metabolic bone disease and osteoporosis were ruled out.
Sunlight exposure, physical activity and dietary constituents were
calculated. Complete metabolic profiles were derived, and bone mineral density (BMD)
was measured using dual energy X ray absorptiometry. Low BMD was defined as
a Z score below -2.
RESULTS: Low BMD was found in 68% of patients. Lumbar spine was the most
frequently and severely affected site. Risk factors for low BMD included
low physical activity, decreased sunlight exposure, and low lean body mass.
Calcium intake was adequate, with unfavorable calcium: protein ratio and
calcium: phosphorus ratio. Vitamin D deficiency was highly prevalent (92%).
There was a high incidence of hypogonadism (41%). Serum estradiol level was
elevated significantly in patients with normal BMD. Insulin-like growth
factor (IGF) 1 and IGF binding protein 3 levels were below the age-related
normal range in both groups. IGF-1 was significantly lower in patients with
low BMD. Serum osteocalcin level was low (68%) and urinary deoxypyridinoline
to creatinine ratio was high (79%), which demonstrated low bone formation
with high resorption.
CONCLUSION: Patients with cirrhosis have low BMD. Contributory factors are
reduced physical activity, low lean body mass, vitamin D deficiency and
hypogonadism and low IGF-1 level.
INTRODUCTION
Metabolic bone disease is a common complication of long-standing liver
disease, ranging from cholestatic disorders to alcoholic, autoimmune and
post-viral cirrhosis[1]. Often known as hepatic osteodystrophy (HO), it is
well-recognized among individuals with chronic liver disease (CLD). Its etiology
is poorly understood and is thought to vary according to the type,
severity and progression of the liver disease, along with a multitude of other
contributing factors including the ethnicity of the population studied. It can
result in spontaneous low-trauma fractures that significantly impact on
the morbidity, quality of life, and even survival, through pain, deformity
and immobility. With liver transplantation steadily taking the center stage
in treatment of end-stage cirrhosis of varying etiology and offering
long-term survival, bone disease has snowballed into one of the major determinants
of survival and quality of life in this cohort[1].
Keeping in view the numerous therapeutic options for bone disease[2]
already available and those under development, it is prudent to characterize
this condition in order to give these patients a better chance of survival.
The medical fraternity around the world has recognized this and has started
characterizing the disorder. In various international studies, the overall
incidence has varied from 11% to 48%[3], with a fracture rate of 3%-44%[3].
This has not been studied extensively in the Indian population[4].
RESULTS
BMD
Among the 72 patients, 49 (68%) had low BMD. There were no significant
differences in demography between the patients with normal and low BMD (Table
1). When patients were classified according to etiology of liver disease,
the incidence was 56.7% alcoholic, 72% hepatitis B, and 100% hepatitis C.
Incidence of low BMD was the same across all Child classes. Lumbar spine was
the most frequently and severely affected site. It was involved in all
patients with low BMD. Mean BMD at each site was: spine, -2.28 ± 1.1; hip,
-1.27 ± 0.74; trochanter, -1.3 ± 0.8; and femoral neck, 0.75 ± 0.86. Bone mass
loss in trabecular bone (lumbar spine) was more severe than that in
cortical bone (femoral neck). The percentage of patients with low BMD of the hip
was 14%, trochanter was 18%, and femoral neck was 7%.
Risk factors for low BMD
Patients were evaluated further for the possible predisposing factors for
low BMD. The following data pertain to the 63 men in the study. As there
were only nine women, they were analyzed separately. Patients were subdivided
into low BMD (Z score ≤ -2, 43 patients) and normal BMD (Z score > -2, 20
patients) groups and further analyzed.
Relationship of BMD with physical activity, sunlight exposure and diet
Both groups showed considerable reduction in sunlight exposure and
physical activity after the onset of illness (Table 2). Past and present sunlight
exposure was lower in the group with low BMD, although it reached
significance (P < 0.05) only with present exposure. Low physical activity (defined
as < 600 MET.min/wk) was seen in 15 patients (23%) prior to disease onset
but in 76% after developing chronic liver disease. It can be seen that the
median activity level and sunlight exposure in the affected population was
zero, compared to some amount of activity (120 MET.min/wk) and sunlight
exposure (sun index of 0.15) in patients who were able to maintain their bone
strength.
Dietary intake was comparable between the two groups. Calorie and protein
intake were adequate. Calcium intake was also adequate according to the
Indian Council of Medical Research guidelines (ICMR)[6]. The calcium:protein
ratio (8.5-11.5) was much below the advocated range of 16-20[6]. The
calcium:phosphorus ratio (0.45) was also not in the recommended range of 1:1[6].
Relationship of BMD to hormone parameters
There was a high incidence of hypogonadism in patients with cirrhosis.
Twenty-six patients (41%) had low calculated free testosterone. This was
distributed equally between the low and normal BMD groups. Among the hypogonadal
patients, 18 (69%) had central hypogonadism and eight (31%) had primary
testicular failure. An FSH value of > 10 IU/L with normal free testosterone
was seen in an additional nine (14%) patients. Serum estradiol level was
significantly elevated (P < 0.05) in patients with normal BMD as compared to
those with low BMD (Table 4). Forty-six patients (73%) had a high estradiol
level, which was distributed unequally within the groups, with 90% of
patients with normal BMD and 65% in the group with low BMD having values above
the physiological upper range of 50 pg/mL.
IGF-1 levels were below the age-related normal range in both groups, but
significantly lower (P < 0.05) in patients with low BMD (Table 4). Forty-one
patients (95%) of patients in the low BMD group and 15 (75%) in the normal
BMD group had IGF-1 level below normal, which accounted for 89% of
patients with CLD. Low IGFBP3 was almost a universal finding in patients with CLD
(61 of 63 patients; 97%), although it did not differ significantly between
the groups (P = 0.071).
DISCUSSION
The purpose of the current study was to determine the prevalence of low
BMD, to estimate the bone turnover and hormonal status, and to identify the
factors associated with bone disease in patients with CLD. The only
available Indian data on this subject are those of Sachdev et al[4] from 1976. The
current study shows that patients with CLD have a high prevalence of
decreased BMD, with the lumbar spine being the most frequently and intensely
affected site. Furthermore, there was no relation between severity of hepatic
dysfunction (Child class) and incidence of low BMD. These factors point to
the need for early evaluation for HO in patients with CLD.
In the present cohort, low BMD was found in 68% of patients. This is
comparable to the only available Indian data of Sachdev et al[4], in which 64%
of cirrhotic patients had low BMD. The method of evaluation and diagnosis
differed greatly in that era. In the earlier study of 25 patients with
cirrhosis (all aged < 40 years), diagnosis of cirrhosis was made from liver
biopsy and osteoporosis from iliac crest biopsy. Scanning through western
studies has indicated marked heterogeneity in BMD findings in CLD, ranging from
no effect to a large BMD deficit. Leslie et al[7] have pooled the results
from uncontrolled and controlled studies of bone mineral content in CLD. They
have shown a Z score less than -2 in 21% of patients. Studies on patients
with end-stage liver disease of varying etiology confirm a high but
variable incidence of osteoporosis (11%-48%) and osteopenia (18%-35%)[3]. The
incidence of 68% in the present study is much higher than that in any previous
study. This may be because Indians have a lower BMD as compared to
Caucasians[8,9]. Thus, the use of Z scores based on a Caucasian database might have
resulted in overestimation of osteoporosis. However there are no published
data for BMD in healthy Indian populations.
The major influences on bone metabolism are genetic, but also essential
are mechanical stress (exercise and muscle activity), good nutrition,
adequate calcium and vitamin D, and a normal hormonal environment. The patient
with CLD could have any of these factors acting alone or in concert, which
potentially predispose him/her to thin bones. Each of the above factors were
assessed and compared between patients with low and normal BMD. It was found
that patients with CLD had all the above and known risk factors: low
sunlight exposure, reduced physical activity, low lean body mass, vitamin D
deficiency and hypogonadism. The presence of risk factors in the low and normal
BMD groups was probably the reason for the absence of a statistically
significant difference in risk factors between the normal and low BMD groups.
This indicates that all patients with cirrhosis, unless prevented, will
develop the disease. In addition, although the calcium intake was adequate by
ICMR guidelines, it was well below the internationally accepted daily
allowance. This added to an unfavorable calcium:protein ratio of 8.5-11.5 mg/g,
and calcium:phosphorus ratio of 0.45 may have resulted in inadequate
recommended daily allowance of calcium in these patients.
Vertebrae consist of 50% trabecular bone, while other bones (hip, neck and
trochanter) consist mainly of cortical bone. Sites with a high proportion
of trabecular bone are affected earliest in diseases that produce increased
bone turnover[10]. In the present study, serum osteocalcin was low in 68%
and UDPD: creatinine ratio was high in 79% of patients, which indicated a
high resorptive state added to low formation. This suggests uncoupling of
bone remodeling as the cause of low BMD in CLD. This can explain the
predominant involvement of the spine in HO. This is also compatible with other
similar studies[11,12].
In the present study, 41% of patients were hypogonadal, although this
was not correlated with the severity of bone loss. Diamond et al[13] and
Monegal et al[11] have shown that hypogonadism is common in men with
cirrhosis but it is not correlated with osteoporosis. A particularly interesting
finding in the present study was the significantly elevated estradiol level
(P < 0.05) in patients with normal compared with low BMD. Estrogen is known
to have a positive influence on the male skeleton[14]. It is also known to
be increased in men with cirrhosis. Probably the anabolic and
antiresorptive qualities of estrogens in bone act as protective factors in preventing
bone loss in these patients with cirrhosis.
More than 90% of circulating IGF-1 is synthesized in the liver. It is a
proven early marker of hepatocellular functional capacity[15,16], and shows a
marked decline in the early stages of cirrhosis (Child-Pugh class A). It
starts decreasing before other liver-function parameters such as albumin,
bilirubin and prothrombin become involved[15]. GH levels are increased
correspondingly, which creates a state of IGF resistance[17]. IGF-1 is also a
major determinant of BMD in healthy men[18]. In the present study, IGF-1
levels were below the age-related normal range in both groups, and were
significantly lower (P < 0.05) in patients with low BMD. IGF-1 values were low in
89% of patients with CLD. Previous studies have shown IGF-1 levels to
correlate directly with BMD and inversely with disease severity[12,19,20].
Studies have described a role for decreased serum IGF-1, even in idiopathic
osteoporosis[21]. IGF-1 expression is increased during early osteoblast
recruitment, but declines as these cells undergo differentiation. It is known to
stimulate osteoblast proliferation[22] and play a key role in bone remodeling
and maintenance of bone mass. Simonet et al[23] have shown that low levels
of IGF-1 may lead to increased bone resorption. Thus, the link between
cirrhosis and bone loss also involves low levels of IGF-1. A significant
difference in IGF-1 level between normal and low BMD patients may be a pointer
to why some patients deteriorate faster, despite sharing equally all the risk
factors.
IGFBP3 play a very important role in bioavailability of circulating IGF-1.
It forms a stable ternary complex with an acid-labile subunit and IGF-1,
and binds > 95% of circulating IGF-1. In the present cohort, low IGFBP3 was
seen in 97% of patients with CLD, although this did not differ
significantly between the normal and low BMD groups (P = 0.071). This is plausible
because hepatocytes are the major site of IGFBP3 synthesis. This may have
further decreased the tissue bioavailability of IGF-1[24,25].
In conclusion, the present study confirms the high incidence of low BMD in
patients with CLD. Disease onset is early in the course of cirrhosis.
Decreased bone formation with increased bone resorption imply that uncoupling
of bone remodeling is the mechanism involved. Contributing factors are
inadequate sunlight exposure, reduced physical activity, low lean body mass,
vitamin D deficiency and hypogonadism. The presence of most risk factors in
low and normal BMD groups indicates that all patients with cirrhosis are
vulnerable, and unless prevented, will develop the disease. Our results provide
evidence of the key roles played by IGF-1 and estrogen in this condition.
Although risk factors are prevalent in all patients, the severity of bone
loss may be accelerated in patients with low IGF-1 level. The present study
also suggests a possible protective role for the high estrogen level seen
in cirrhosis.
COMMENTS
Background
Long-standing liver disease has long been recognized to result in fragile
bones with increased risk of fractures. In various international studies,
the overall incidence has varied from 11% to 48%, with a fracture rate of
3%-44%. The reason for this is poorly understood. With liver transplantation
becoming a viable option in liver disease and offering complete cure and
long-term survival, bone disease is becoming the major determinant of
survival and quality of life in these patients. The present study tried to
characterize the problem and identify contributing risk factors.
Research frontiers
Much work has been done and is still going on in the field of hepatic
osteodystrophy (HO). It is a hot topic of research, as liver transplantation is
improving survival of patients with end-stage liver disease, and bone
disease and fracture are limiting the survival and quality of life of these
patients. The medical fraternity has recognized that bone health has to be
taken care of to fully translate the benefits of modern treatment into patient
survival.
Innovations and breakthroughs
Most of the data obtained in this study conform to those in the
literature. Two significant findings of the study (that low levels of IGF-1 is a risk
factor for decreased BMD, and increased estrogen is protective) are
relatively new.
Applications
This article provide an entirely new frontier in research, namely, to look
forward to the therapeutic benefit of IGF-1 therapy in these patients.
Synthetic IGF-1 is available under the name mecasermin and is used currently
for the long-term treatment of growth failure in children with severe
primary IGF-1 deficiency.
Peer review
This work represents an original contribution regarding HO in patients
with advanced liver disease in India. The study was well-conducted. The
authors identified in cirrhotic patients that low levels of IGF-1 are a risk
factor for decreased BMD, while increased estrogens protect against osteopenia.
MATERIALS AND METHODS
Patients
The study was performed on 72 Indian patients with cirrhosis. The group
consisted of 63 men and nine women with a median age of 45 years (43.1 ± 7.4,
range 22-50 years). Twenty-five patients had hepatitis B (22 men and 3
women), 10 had hepatitis C (5 men and 5 women), and 37 had alcoholic cirrhosis
(36 men and 1 woman). A diagnosis of cirrhosis was confirmed
histologically or clinically if biopsy was not available. A clinical diagnosis was
established in patients who demonstrated a Child-Pugh index > 6 or ultrasound
findings suggestive of cirrhosis (the presence of at least two of the
findings of nodular irregular surface, distorted vascular pattern, or ascites).
Signs of portal hypertension (endoscopically proven esophageal varices or
dilated portal venous system with ultrasonography) were taken as additional
corroborative evidence. The etiology of post-viral cirrhosis was proven if any
of the serological markers were positive [hepatitis B surface antigen by
ELISA, anti-hepatitis C virus (HCV) by third generation ELISA, or HCV RNA].
Diagnosis of alcoholic cirrhosis was made with a positive answer to more
than one question in the CAGE questionnaire and a previous history of alcohol
intake of > 80 g/d in men and > 40 g/d in women for > 10 years. An
aspartate aminotransferase to alanine aminotransferase (AST/ALT) ratio of > 1.5
was taken as corroborative evidence. We selected only patients who had
abstained from alcohol for > 3 mo prior to the study.
All patients with acute exacerbation or flair of disease (suggested by a
bilirubin concentration > 5 mg/dL, AST > 2.5 times the upper limit of
normal, leukocytosis > 10 000/mm3, or diagnostic lesions of hepatitis on biopsy)
and those with recent gastrointestinal bleeding were excluded. Patients
with serum creatinine levels > 1.4 mg/dL were excluded, as were those with any
form of acute illness. None of the patients had a previous history of
chronic disorders associated with changes in mineral metabolism (thyroid
disorders, parathyroid disorders, Cushing’s syndrome, diabetes, immobilization in
the past, or renal failure). None had a family history of osteoporosis,
nor did they receive calcium, vitamin D or any medication which may have
influenced bone metabolism (corticosteroids, hormone replacement therapy,
calcitonin, bisphosphonates, cytotoxics, antimetabolites, anticoagulants,
anticonvulsants, thyroxine, interferon or lamivudine). Nineteen patients were
receiving spironolactone and 14 were receiving spironolactone and furosemide.
Patients with major sclerosis of the aorta, osteophytes, or scoliosis on X-
ray, which precluded accurate measurements of lumbar bone mineral density
(BMD) by dual energy X ray absorptiometry (DXA), and those who had the
criteria for more than one etiology of chronic liver disease were also
excluded. All patients signed informed consent and the protocol was approved by the
institutional ethics committee.
Methods
Demographic and disease-related data including anthropometry at the time
of enrollment were captured. Each subject was interviewed to characterize
sunlight exposure, physical activity and dietary intake.
Sunlight exposure was calculated in terms of length of usual weekly
outdoor activity, sunscreen use, and usual outdoor attire. The “rule of nine”
was adapted to estimate the fraction of body surface area (BSA) exposed to
sunlight by each subject’s usual outdoor attire[5]. With this, sun index was
calculated as the product of hours of sun exposure per week and fraction of
BSA exposed to sunlight. Mumbai is at latitude 18° 56’ North and all of
the study population were from areas below 37° latitude. Only sunlight
exposure between 8 am to 5 pm in summer and 9 am to 3 pm in winter was measured.
All our patients belonged to the same ethnicity and were of skin type 5.
Physical activity was assessed using the Global Physical Activity
Questionnaire (GPAQ) developed by WHO (www.who.int/chp/steps). Nutritional intake was
calculated using a questionnaire with specific reference to calorie,
protein, calcium (dairy and non-dairy), phosphorus and salt intake. These
parameters were calculated in two different periods of life; prior to illness (5
years prior to patient perceived onset) and present state of illness.
Biochemical and hormonal determinations
Blood samples were drawn in the morning after an overnight fast. In
addition to standard liver function tests, serum levels of calcium, phosphate,
magnesium, alkaline phosphatase, and creatinine were measured on the same day
with an auto analyzer (Biosystems S.A., Barcelona, Spain). The rest of the
sample was centrifuged immediately and stored at -70℃ for measurement of
hormonal parameters, which were analyzed in a single batch. Serum was
assayed using commercially available kits for 25 hydroxy vitamin D [25 (OH)D;
radioimmunoassay (RIA); DiaSorin Inc., Stillwater, MN, USA], 1,25, dihydroxy
vitamin D [1,25 (OH)2D; enzyme immunoassay; Immunodiagnostic Systems Inc,
Fountain Hills, AZ, USA], parathyroid hormone (PTH), osteocalcin, follicle
stimulating hormone (FSH), luteinizing hormone (LH), estradiol (E2),
testosterone (RIA; Diagnostic Products Corp., Los Angeles, CA, USA), sex hormone
binding globulin (SHBG), free T4 (FT4), thyroid stimulating hormone (TSH),
insulin like growth factor 1 (IGF-1) and IGF binding protein 3 (IGFBP3). Free
testosterone was calculated from total testosterone, SHBG and albumin
concentration (www.issam.ch). All hormonal investigations except testosterone,
25 (OH)D and 1,25 (OH)2D were done by chemiluminescent immunometric assay
with Immulite 1000 systems (Diagnostic Products Corporation). Serum
testosterone, estradiol, FSH and LH were estimated from pooled sera collected three
times at 20-min intervals. The morning second void urinary sample was used
for urinary parameters. Urine was analyzed for calcium, creatinine and free
deoxypyridinoline (UDPD). UDPD was expressed as the ratio to creatinine.
BMD and X-ray measurements
BMD of the lumbar spine (L1-L4) and proximal femur (femoral neck and
trochanter) was measured by DXA (Delphi W 70460; Hologic Inc., USA). All scans
were carried out on the same machine by the same operator and were analyzed
with the same software. BMD was expressed as g/cm2 as well as Z score,
compared to reference data for Caucasian populations. As there are no normative
data available for the Indian population, no such comparison could be
made. Low BMD was considered to be a Z score of -2 or less obtained at any site.
X-ray analysis of lumbosacral spine (lateral view) and pelvis
(antero-posterior view) was done to rule out any fracture. Lean body mass was also
assessed by DXA.
Statistical analysis
Statistical analysis was done using SPSS version 14 software (Chicago, IL,
USA). All results are expressed as means ± SD and median. The statistical
significance between means was calculated by Student’s t test, analysis of
variance (ANOVA), or Mann-Whitney U test when appropriate. Differences
between proportions were assessed by the c2 test. P < 0.05 was considered
significant.
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