DISEASES OF BONE
AND CONNECTIVE
TISSUES
NOREEN BUKHTIARI
MECHANISM OF BONE FORMATION AND
BREAKDOWN
Key words
• Osteoblasts : cells that synthesize bone matrix
• Osteoid
: Unmineralized bone matrix
• Osteocytes : mature osteoblasts encased in bone
matrix.
• Osteoclasts: cells that resorb bone.
• Modeling : formation of bone
• Remodeling: breakdown and renewal of bone.
• Calcidiol : 25 (OH)2 D
• Calcitriol : 1, 25 (OH)2 D
OSTEOBLAST
• Synthesise and maintain bone matrix
•.Present on the surfaces of both cortical and trabecular bones.
•Originate from mesenchymal progenitor cells.
•Plasma membrane is associated with a very high activity of Alkaline
phosphatase.
•Osteoblasts express receptors for PTH, Calcitriol, Oestrogen,
growth factors and a number of cytokines.
•Cytokines and growth factors such as fibroblast growth factor (FGF)
and IGF-1 are regulators of formation of these cells.
•Mature osteoblasts change into osteocytes embedded in the bone
matrix they made.
OSTEOCLASTS
•
Derived from hematoprogenitor cells that also give rise to monocytes and
macrophages.
•
They are multinucleated, having large number of mitochondria and
lysosomes.
•
Cytokines (interlukin-1, IL-6, IL-11) and tumour necrosis factors (TNF) are
responsible for maturation of osteoclasts.
•
Activated osteoclasts possess a’ ruffled border’ which is delimited by a
‘sealing zone’ at which it is attached to the underlying bone.
•
Bone resorption occurs as a result of the secretion of protons and
proteolytic enzymes into the space between the ruffled border and the bone
surface.
•
Lysosomes dissolves bone crystals and their proteolytic enzymes digest
bone matrix.
BONE REMODELING
Components of bone
1.
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•
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Calcified matrix (90%),
composed of collagen fibres (type-1),
Glycosaaminoglycan containing ground substance,
Spindle shaped crystals of hydroxyapatite
2. Mineral Element
• Crystals of Calcium and Phosphate are arranged either
amorphously or as Hydroxyapatite Ca10 (PO4)6 (OH)2 on or
within the collagen fibres.
• Na, Zn, Mg, Pb, Cu and fluoride.
3. Non Collagenous Components (Proteins):
• Osteocalcein: protein produced by the osteoblasts
• α2 HS- glycoprotein: produced by the liver and absorbed by the
bone matrix
• Amino Acids: about one fourth of amino acids present in collagen
are proline and hydroxproline.
REMODELING OF BONE
 Maintenance of bone mass by replacing pockets of old and / or
microdamaged bone.
 Quiescent state:
bone surface is covered with lining cells.
 Resorptive state: excavation of a resorption pit by osteoclasts.
 Formation state of new bone matrix followed by mineralization.
 Osteoblasts then may turn into bone lining cells or survive as
osteocytes in bone lacunae.
 Osteoablasts provide much of the control as they receive signals
and release soluble mediators (signals) that induce osteoclastic
bone resorption.
•
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Formation and resorption are coupled. A critical mechanism by which
osteoblasts regulate bone resorption is via a system
‘ RANK/RANKL/OPG’
•
RANKL: Recetor activator of nuclear factor k-B ligand
•
OPG: Osteoprotegerin(cytokine), Inhibitor of osteoclastogenesis
•
RANKL &OPG regulate the development and function of osteoclasts and is
expressed on the surface of osteoblasts.
•
RANK: on the surface of osteoclast precursors

Remodeling can be controlled by systematic and local factors.

During growth bone formation exceeds, whereas In senescence resorption
increased due to deficiency of sex hormone, reduced physical activity and
various endocrine and inflammatory diseases.

Age related bone loss affects both cortical and trabecular bone.

After menaopause bone loss is from the axial skeleton which has greater
proportion of trabecular bone.
RANGE OF PATHOLOGIES
THAT IMPACT ON BONE AND
CONNECTIVE TISSUES
MALIGNANCY
HYPERPARATHYROIDISM
OSTEOPOROSIS
OSTEOMALACIA/RICKETS
MALIGNANT DISEASES WITH OR
WITHOUR BONE METASTASIS
NON-METASTATIC
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Due to the secretion of PTHRP by some tumours of non endocrine tissues.
PTHRP induce osteoclastic activity and causes hypercalcaemia which is
not subject to normal feedback control. It may rise rapidly to dangerously
high level.
PO4 will be low relative to urea concentration.
Alk.Phos activity remains high either due to the secondary deposition on
bone or its impact on liver or on both.
Bony lesions are not present may be due to early diagnosis/treatment or
fatal underlying cause.
METASTATIC
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It occur in syndrome with multiple bony metastasis or myelomatosis
Plasma Ca and PO4 conc. Rise in parallel by direct bone breakdown.
Malignant deposits in bone stimulate osteoclastic reaction.
Alk.pos activity rise at early stage, later on it remains normal despite the
extensive involvement of bone.
In malignant diseases increase in osteoclastic activity is due to PTHRP, Vit.D
in lymphomas, and lymphotoxin in multiple myelomas etc.
HYPERPARATHYROIDISM
PTH: Cal/PO4 homeostasis, Vit.D synthesis and
osteoclastic activity etc..
Its secretion increase with age and in patients with
renal failure.
Inapropriate secretion of PTH
o Adenoma, hyperplasia or carcinoma of PT gland.
o Ectopic secretion - MEN e.g. pituitary and pancreatic adenoma and
carcinomas etc.
Complications
o Fluoride parathyroid Bone disease – an uncommon manifestation.
o Calcium related skeletal diseases become infrequent due to early
diagnosis / treatment.
o Mild hyperparathyroidism cause loss of cortical bone – increased risk
fracture
Overt Bone disease of P.
hyperparathyroidism
In severe hyperparathyroidism:
• P. Calcium >3.0 mmol/L and much higher level of PTH.
• Larger and growing tumours.
• Marked increase in bone resorption.
• Vit.D deficiency that occur due to accelerated hepatic
metabolism of 25(OH)D or hypercalcaemia
Treatment:
o Surgical correction of the cause & antiresorptive therapy to prevent
progressive bone loss.
o Hungry bone syndrome: After the surgical correction of underlying
cause patients may develop severe hypophosphataemia and
hypocalcaemia.
Investigation: Inter and post operative PTH level,
S. Cal ,and markers of bone resorption.
Osteitis Fibrosa
•
Histopatological bone lesion due to the excessive PTH secretion
due to P. hyperparathyroidism or Sec. HPT due to Renal failure.
•
Marked increase in the rate of bone resorption and formation.
•
Which result in the increased osteoid surface extent and marrow fibrosis.
•
Feautures and symptoms similar to Prim and Sec. HPT i.e. generalized bone
pain, bone tenderness, proximal myopathy and radiographic subperiosteal
erosions of bone.
•
Condition in P. hyperparathyroidism are not sever because of the surgical
removal of the underlying cause but Sec. HPT associated to renal disease
are less amiable to treatment.
•
Cystic lesions ( brown tumours) filled with osteoclasts and marrow fibrosis
are a frequent feature of severe P. hyperparathyroidism than ureamic
hyperparathyroidism.
•
Pathological fractures occur mostly at the site of brown tumour.
OSTEOPOROSIS
•
Reduction in bone mass density to the point that a minor trauma may result
in fracture.
•
Age and gender both reflects importance in its pathogenesis as the
incidence of hip and vertebral fracture increases later in life.
•
The fracture rate at these sites increase in men 10 years later in life.
•
Osteoporotic bone is normally mineralized but reduced in volume.
•
Using BMD criteria Osteoporosis is defined as a bone disease when BMD
T-score <-2.5. which means a BMD that is more than 2.5 standard
deviations below the mean value in the normal young population.
•
Common osteoporotic fractures of clinical consequence are hip, forearm,
vertebral body, humerus, ribs and pelvis.
Primary osteoporosis
Senile osteoporosis:
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Ageing – 50 yrs in women and 65-70 in men.
Hormonal alteration (PTH, oestrogen,)
Low synthesis of vit.D, and calcitonin
Nursing home residents
Decreased intestinal absorption of calcium.
Post menopausal: Oestrogen deficiency cause bone resorption
Release of Ca and PO4 in intra cellular spaces that in turn suppress PTH
secretion which result in decreased calcitriol synthesis and decreased
osteoblastic activity
Idiopathic juvenile osteoporosis:
•
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Recover at puberty, treatment with calcitriol reduce bone fracture.
Present in infants born with low birth weight.
Secondary osteoporosis
Medication:
Glucocorticoids – induce resorption
Corticosteroid – exert inhibitory effect on bone formation
and reduce Ca. and PO4 intestinal absorption
Immunosuppressants , cytotoxic drugs, and Li increase
bone resorption.
TPN:
• Long term parenteral alimentation can cause demineralization of
bone and osteopenia
• Cyclic infusion of TPN solutions contain sulfur containing acidic
amino acids. Hypertonic dextrose infusions – hyperinsulinaemia
and acidosis.
• decrease tubular absorption of calcium.
• Main feature: hypercalciuria
Aluminium bone disease
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Al. is present in antacids, oral ingestion of aluminium
hydroxide as phosphate-binding agent, in dialysis fluids,
food and nutritional supplements.
It accumulate in bones, kidneys, brain and parathyroids.
Al. excretion reduced in patients with impaired renal
functions.
Its accumulation in bones increases the risk of fracture as it
accumulates at the bone-osteoid interface and exerts toxic
effects on osteoblasts.
It inhibits bone mineralization at higher concentrations.
MEDICAL CONDITIONS:
•
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Thyrotoxicosis - increase bone resorption
Hypogonadism - less bone mass
DIAGNOSIS
• Bone mass densitometry- assessment of bone mass
• In clinical context: Renal, liver and bone profiles, Growth
hormones, IGF-1, thyroid, PTH and Vit. D.
• Plasma and urine cortisol, serum and urine protein
electrophoresis, coeliac disease and full blood count.
•
X-ray and CT to scrutinize malignancy and bone biopsy
if required.
• Markers of bone (as shown on next slide).
TREATMENT
• HRT – increase BMD
• Calcium & Vit.D
• Biphosphonate – enhance Ca content of bone
• Calcitonin – effective for vertebral spinal crush
• Life style modification
• PTH – increase markers for formation and resorption
• Strontium – Antiresorptive and anabolic effects for skeleton
OSTEOMALACIA / RICKETES
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Normal amount of osteoid that fail to mineralize.
•
Rickets: Osteomalacia in children termed as ‘Rickets’.
•
In infancy
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Tetany and seizures
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Congenital, or fed on Vit.D deficient mother’s milk or acute infection.
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X-Ray : Earliest sign of rickets on wrist and knee.
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Rachitic Lung: weak rib cage resulting in secondary defective pulmonary ventilation.
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Beyond infancy
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Spinal and pelvic deformities: waddling gait, bowed legs and knock knees.
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Muscular weakness due to decrease uptake of calcium by myocytes.
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Hypotonia in proximal muscles also contribute in waddling gaitprotuberance of abdomen
and inefficient lung ventilation
Causes
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Inadequate supply of minerals – calciopenic and phosphopenic
osteomalacia.
Defective osteoblast function.
CALCIOPENIC RICKETS \ OSTEOMALACIA
•
Related with abnormal Vit.D metabolism.
1. Vitamin D deficiency
• Inadequate dietary intake or strict vegetarian diet or milk without
Vit.D.
• Less exposure to sunlight.
• Pigment in dark skin decrease the production of cholecalciferol
from 7- dehydrocholesterol
• Alteration of Vit.D metabolism in liver and / or kidney.
• Low calcitriol leads to hypocalcaemia which stimulate secretion of
PTH. Induce osteoclastic activity and mobilize calcium and PO4.
• Due to urinary losses of Cal and PO4, the biochemical response
will be hypocalcaemia, hypophosphataemia, increased activity of
alkaline phosphatase and hyper parathyroid, hyperphosphaturia,
aminoadicuria and rachitic bone disease
2.
Vit. D dependent OSteomalacia (Type I and Type II)
Type I: Similar abnormalities as of Vit.D deficient rickets
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S. calcidiol will be normal and calcitriol deficient.
Patients heal when physiological doses of calcitriol are administered.
Presumably it is 1 α hydroxylase which is either absent or deficient.
Type II: Normal 25(OH)D3 and 1, 25(OH)D3
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Resistant to physiological doses of calcitriol.
It is the end organ resistance to normal physiological dose.
Biochemical response: low Cal, PO4, raised PTH, and 1, 25(OH)D3 and
normal 25(OH)D3.
Both types are inherited as an autosomal recessive gene
Calcium deficiency rickets
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Features similar to Vit D deficieny osteomalacia as Vit. D
Bowed legs, knock knees, wind swept deformities but no muscular
weakness.
Biochemical response: Low S and urine Cal, normal 25(OH)D3, raised
alkaline phosphatase, 1, 25(OH)D3 and PTH.
Phosphopenic Osteomalacia
1.
Phosphate deficient
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Defect in reabsorption of PO4 in the proximal tubules result in
massive hypophastaemia and phosphaturia
Genetic (X- linked ) and / or acquired ( heavy metal or light chain
nephropathy)
Low PO4 stimulate the formation of calcitriol, theoretically S. calcitriol
should be high but on measurement it is low or low normal this might
be due to another defect in the functioning of 1α hydroxylase activity.
Biochemical response:
•
•
2.
Very low PO4, low S.Ca, raised or normal PTH and 1, 25(OH)D3.
Treatment : supplements of PO4 and Cholecalciferol.
Adult phosphopenic osteomalacia is due to mesenchymal tumours
•
•
These tumours secrete FGF23 that induce phosphaturia.
Lab investigation: hypophosphataemia, normal Cal., VitD, and PTH.
3. Osteomalacia secondary to gastrointestinal disease and Hepatic
Rickets
Serum 25(OH)D3 is low esp. in patients with hepatobiliary disease
Defective cholecalciferol or ergosterol absorption result in impaired
calcidiol production by liver or enhanced calcitriol metabolism
• Decrease enterohepatic circulation of 25(OH)D3
• due to low 1,25 hydroxylase activity , Vit. D malabsorption
• Biochemically there will be low S. 25(OH)D3, and 1, 25(OH)D3
4. Osteomalacia secondary to anticonvulsant medication:
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Phenobarbital and phynytoin induce mixed microsomal oxidase enzyme
system that convert 25(OH)D3 into polar inactive metabolites consequently
calcidiol deficiency.
Anticonvulsants inhibit calcitriol dependant intestinal calcium uptake.
Biochemical response: low Cal, low PO4, hypoclciuria, and elevated
alkaline phosphatase and PTH.
PAGETS’ DISEASE
.
Pathogenesis:
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Bone lesions on X-ray film and raised alkaline phosphatase
Giant Osteoclast with numerous nuclei, and cytoplasmic inclusion bodies
possibly of viral origin.
There is evidence for measles and canine distemper viruses but lab data is
still not conclusive.
Primarily a disorder of osteoclasts, causing increased resorption surfaces.
Bone formation will increase as well.
At very high rate of bone formation collagen fibers are laid down randomly
rather than in usual lamellar pattern. The resulting new bone with abnormal
structure known as ‘ woven bone ‘ (mosaic pattern) instead of lamellar bone.
Osteoblasts secrete collagen fibres into the marrow space, causing marrow
fibrosis.
Clinical features:
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Chronic and persistent bone pain, worse at rest and relieved by movement,
sec. osteoarthritis is common as well
very vascular and the high blood flow causes an elevation of skin temperature
over the affected bone.
Pagets’ Disease
Biochemical tests:
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Alkp and hydroxyproline: monitoring the progress of disease and response
to therapy. In monostotic pt. elevation may still be within the ref. range.
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All bone turnover markers will increase except osteocalcin.
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C- Telopeptides( CTX). α- CTX must be in large proportion than β – CTX
•
Skin temperature is a useful guide to disease activity affective area can be
u to 4°C warmer than unaffected area.
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Plasma and Urine calcium
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Usually normal but patients with very extensive and progressive pagetic
disease may develop hypercalcaemia and hypercalciuria.
Treatment:
• No cure, metabolic activity of diseased bone can be inhibited
•
Biphosphonate can reduce the metabolic activity of bone
Renal Osteodystrophy
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Associated with chronic renal failure
Ch. RF
Hyperphosphataemia and Hypocalcaemia
Secondary Hyperparathyroidism
a) Less excretion and
metabolism of PTH
b) Low or no alpha-1hydroxylation
c) Metabolic acidosis
Osteoclastic activity
Release of calcium hydroxyapetite
from bone
Osteomalacia
Osteitis fibrosa
Biochemical implications of
Arthritis and gout
KEY WORDS
SYNOVIAL MEMBRANE or SYNOVIUM
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One or two cell thick which secrete hyaluronate.
Phagocytose intra articular debris and
Secrete many components of synovial fluid that have immunological
properties.
SYNOVIAL FLUID
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Ultrafiltrate of plasma with additional components secreted by synovium.
Most important is hyaluronate which is important for smooth movement.
Articular surfaces: The bone ends that move against each other.
SYNOVIAL JOINTS
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Synovial fluid (90-4ml) to lubricate joint.
Cartilage and synovial fluid together maintain coefficient of friction.
PATHOLOGIES
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Over a hundred rheumatic disorders with different underlying causes, different treatments
and different outcomes.
CLASSIFICATIONS:
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Inflammatory- Rheumatoid arthritis, SLE, and ankylosing spondylitis
Non-inflammatory- Osteoarthritis etc.
OSTEOARTHRITIS:
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Causes: Inherited tendency, frequency increase with age, and trauma.
The articular cartilage fissured and gradually weared away.
Joint forms bony outgrowth (osteophytes) in order to heal.
Hip and Knee are affected- Treatment is replacement of joints.
CRYSTALS ARTHRITIS:
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The body response to crystals varies. Crystals in joints may provoke a severe
inflammatory reaction. Or may just accumulate asymptomatically.
Different crystals tend to favour different sites.
Monosodium urate deposited in cartilage and synovium
CPP in articular fibrocartilage
And basic calcium phosphates in tendons and hyaline cartilage.
Inflammatory Arthritis
The major class of articular diseases is inflammatory arthritis. Group of
systemic immunological diseases that focus their attention on the synovium
of the joint.
Rheumatoid Arthritis: Archetypical form of inflammatory Arthritis.
•
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The inflammation of synovium, causing pain, tenderness, heat, and stiffness
in joint, and systemic reaction causing malaise and fatigue.
Synovial cells are in increased size and number and develop the changes of
chronic inflammation with infiltration by macrophages and lymphocytes, and
cause alterations in the small blood vessels.
The thickened synovium will spread over the cartilage and erode it and the
neighbouring bone. This results is joint damage, deformity and disability.
Ankylosing Spondylitis: mainly affects the small joints of the spine.
•
The ‘reactive’ arthritis ‘ associated with psoriasis and in response to certain
intestinal or genitourinary infections.
Treatment
Day to day basis:
Acute part of inflammatory process can be relieved by anti inflammatory
drugs like ibuprofen, celecoxib and diclofenac.
Long term:
Chronic inflammation results in the joint damage and disability. Several
drugs can slow down the process eg. methotrexate and sulfasalazine.
The side effects of these drugs are liver damage or bone marrow
suppression.
Cytokines such as tumour necrosis factor α (TNF α ) are closely involved in the
rheumatoid process so the recently introduced biological drugs designed to
block the effects of TNFα has revolutionized the RA.
These drugs effect greatly on the synovial thickening and symptoms of RA.
Laboratory Testing in Articular Disease.
• Normochronic, normocytic anaemia is frequent.
• Anaemia secondary to chronic diseases.
Iron is present in bone marrow but can not be utilized in
erythropoiesis.
• Hypochromic microcytic anaemia (reduced Hb, MCV and MCH).
Anti –inflammatory drugs have a tendency to cause erosions and
ulcers in the stomach, duodenum or small bowel resulting in blood
loss and iron deficiency.
• In RA patients it is often tricky to separate two anaemias, and is
made more difficult by the behaviour of ferritin in inflammatory
disease.
Ferritin
It is a measure of iron deficiency and an acute phase reactant as well.

In RA patients results should be interpreted with caution.

Usually a conc. <12ug/L is taken as diagnostic of iron
deficiency but in RA, rheumatologists take a conc. Of 30µg\L
to indicate iron deficiency.

Iron deficiency can exist with higher concentration of Ferritin.

Presence of microcytosis favours iron deficiency, but some
times examination of bone marrow for iron stores is the only
reliable way to differentiate between iron-deficiency anaemia
and anaemia of chronic disease.
The Acute Phase Response
ESR:
CRP:
Traditionally used for diagnosis and monitoring the activity
of the disease
Correlate better with disease activity
In SLE the CRP is often normal. Raised conc. suggest infection
rather than disease activity.
Examination of Synovial Fluid
• Gram staining will show bacterial infection
• Polarizing light microscopy will demonstrate the crystals
Rheumatoid Factors
 RF are antibodies directed against the Fc portion of IgG and are
present in 75-80% of patients with RA.
 In selected population of patients with polyarthritis its positive
predictive value is over 80% and a negative predictive value over
95%.
 In unselected population its predictive value is low (20%).
 Very high value of RF are strong confirmatory evidence of RA
but a poor prognostic marker.
Anti-CCP
Antibodies to cyclic citrullinated protein are more specific (96-98%)
test for diagnosing RA than RF.
AUTOANTIBODIES
• Produced in connective tissue diseases and some cases of
vasculitis.
• Most autoantibodies occur in several conditions and in normal
individuals as well.
• Valuable in confirming suspected diagnosis.
• Negative tests are useful to rule out diagnoses.
• Should not be used for screening purposes or in cases without
clinical features suspicious of connective tissue disease.
CONNECTIVE TISSUE DISEASES (CDTs)
•
In CDTs the person’s ability to recognize their own tissue goes awry and
they form antibodies against their own tissues (autoantibodies).
In some cases, these are responsible for the clinical manifestation of the
disease.
In others they are a peripheral effect of the underlying disease process.
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Systemic Lupus Erythematosus (SLE)
Features:
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Mainly affects younger women
Can involve one or more of the bodily systems. Characterized by the
formation of autoantibodies against the cell’s nucleus, or part of the
nucleus, which are believed to be responsible for many of the
manifestations of the disease;
In others they are peripheral effect of the underlying disease.
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Joint pains is common, it is unusual to see joint damage such as
occurs in RA.
SLE can result in a variety of manifestation in other systems, for
example a variety of rashes, haemolytic anaemia, glomerulonephritis
leading to renal failure, as well as cerebral, and lung and heart
problems. Some of them are life threatening.
Autoantibodies against cell nuclei (anti nuclear factor ANF) are
present in almost every case of SLE. However they are also
frequently present in other CDTs.
Antibodies to specific components of the nucleus are more diagnostic
for example antibodies against double – stranded DNA are strongly
suggestive of SLE.
Treatment:
•
Chloroquine, and / or low doses of prednisone.
•
Serious cases require high doses of corticosteroids with
immunosuppression using clyclophosphamide or azathioprine.
OTHER CTDs
For example:
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Sjogren’s syndrome,
Polymyositis,
Scleroderma
Primary biliary cirrhosis
Common Features:
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•
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Associated with autoantibody formation
Disease is not believed to be caused by specific antibody-antigen complexes
as in SLE.
There is often a cross-over of antibodies in the various diseases and the
antibodies are by no means seen in every case.
Concerns over antibody testing:
•
•
Low specificity of antibodies triggers inappropriate alarm in patients and
increased workload of Rheumatologist and biochemists/immunologists.
These are often positive in normal people, especially low positive e.g. Low titer
of TNF is widespread, False positive RF and slightly raised ESR.
GOUT
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Gout has prevalence of 3 per 1000 of the general population of which 90 to
95% are men.
•
Caused by deposition of Monosodium Urate (MSU) crystals in articular
tissues (cartilage and synovium).
•
Hyperuricaemia without attacks of gouty arthritis is common and sometimes
plasma UA concentrations are normal during an acute attack of gout.
•
Uric acid is end product of Purines, they metabolized to UA via
hypoxanthine and xanthine.
•
The final step being catalyzed by xanthine oxidase.
•
Two – thirds of the urate excreted through kidneys and remainder via the
bowel where it is broken down into carbon dioxide and ammonia by
bacterial action.
Risk factors:
– Hyperuricaemia, obesity, hypertension, age, alcohol
consumption, renal insufficiency, and family history (New
Zealand Maori).
– Several drugs particularly diuretics, low dose aspirin,
ciclosporin, and lead poisoning.
– conditions with high purine turnover, such as leukaemia and
lymphoma and their treatment with cytotoxic drugs, can cause
gout by increasing the urate load.
Lesch-Nyhan Syndrome:
 A very rare disorder due to inherited abnormality in urate
metabolism.
 Deficiency of hypoxanthine – guanine phosphoribosyl transferase.
Acute gout
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Usually strike on first metatarso-phalangeal joint at night (about 70%).
Crystal formation is more likely at colder temperatures and this joint is
cooler than more proximal joints.
Joint rapidly become swollen, red and exquisitely tender to touch. There is
often a systemic reaction with fever and an acute phase reaction.
Examination of synovial fluid show many MSU crystals. Left to itself acute
gout may subside within ten days or so.
Some may never have another attack; there are usually further sporadic
attacks.
May become more frequent with involvement of other areas (polyarticular
gout ) as the urate load increases.
Chronic Tophaceous Gout
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Continuous inflammation of many joints with associated pain, tenderness
and immobility
Masses of urate crystals deposit as chalky material called tophi, which
some times ulcerate and discharge through the skin. Often seen over joints
and bony prominences such as the points of elbows.
Can occur in joints and inside bone causing permanent damage, pain,
deformity and disability.
Urate nephropathy and renal calculi of uric acid.
Diagnosis and Treatment
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•
•
Gout presents in the classic manner. (However infection also presents with
painful, swollen, red, hot joints with fever , leukocytes and acute phase
reaction.
Reliable diagnosis is by the examination of synovial fluid with Polarizing light
microscopy for crystal and Gram staining for bacterial infection.
Only very high UA conc. are convincing, and sometimes helpful in making
decision for drug treatment.
Two strands of treatment:
o Anti-inflammatory drugs such as diclofenac, indometacin or naproxen.
Colchicine can be used when anti-inflammatories are not advisable.
o long term to reduce the urate load by allopurinol. Allopurinol is xanthine
oxidase inhibitor, which block the conversion of xanthine into urate.
Xantine is souble and is excreted renally.
o Failure of treatment is seen when there is non-compliance with medication.
Often seen in male patients.
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Treatment of complicated gout is very difficult e.g. Patients with renal failure
and or heart failure often require diuretic which provoke gout.
In transplant patients because of gout inducing anti –rejecting drugs.
Calcium Pyrophosphate Deposition (CPPD)
• Common form of crystal arthritis less frequent and less understood.
• CPP crystals deposited in articular cartilage and calcification can be
seen on X-rays (chondrocalcinosis).
• Knee and wrist are most affected.
• Symptoms and diagnosis are same as gout. However chronic
involvement of several joints can confuse it with other inflammatory
articular diseases.
• Chondrocalcinosis increase with age, could be triggered by a
trauma like surgery.
• Familial CPPD is well recognized - a genetic abnormality on the
short arm of chromosome 5p has been identified.
• Associated with several metabolic diseases e.g.
haemochromatosis, hyperparathyroidism, hypomagnesaemia,
hypophosphataemia, alkaptonuria and Wilson's disease.
• Treatment is with anti-inflammatory drugs and corticosteroid
injection of affected joint if required.
Basic Calcium Phosphate Deposition
Disease (BCP)
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BCP crystals include hydroxyapatite, octacalcium phosphate and
tricalcium phosphate.
Often difficult to identify.
Sometimes deposited on soft tissues outside the joint or in tendons.
Tend to occur in young females and affects the shoulder, wrist and even
the great toe.
Can cause large effusions and joint resorption in the shoulders of elderly
women (Milwaukee shoulder).
Interest in BCP increases as they appear to involve in the process of
osteoarthritis.
– Injection of corticosteroid often results in dramatic improvement.
Other Crystals:
• Crystals of cholesterol, lipids are seen in patients after trauma.
• Crystals of oxalic acid are seen in patients of renal failure on
dialysis or of primary oxalosis. These can provoke a chronic
polyarthritis in the small joints of the hand.
Articular involvement in systemic
diseases
Diabetes Mellitus:
• Disabling and painful hands and /or shoulders are present in about
30% of diabetics .
• Dupuytren’s contracture: thickening of the palmer fascia and
increasing contracture of fingers is common is diabetes.
• Diabetic cheiroarthropathy or diabetic hand syndrome: thickening of
skin and underlying tissues causing limited range of movement of
the hands and fingers. Often tendons are affected. Changes are
mistaken for rheumatoid arthritis.
• Biopsy shows excessive fibrosis and increased deposition of dermal
collagen. It is suggested that increases tissue glycation may result in
diminished collagen breakdown.
• Charcot’s joint or Charcot’s arthritis. Due to the peripheral nerve
damage ( a complication of diabetes) usual sensations of joint
position and joint movement are lost. Repeated trauma and
painless destruction of the joint and bony resorption of large areas of
bone may occur in the affected joint.
HAEMOCHROMATOSIS:
•
Deposition of iron in synovium, loss of joint space and characteristic hook
osteophyte formation in these joints. No inflammatory reactions.
ALKAPTONURIA:
•
•
•
•
•
•
Rare autosomal disorder caused by a deficiency of the enzyme
homogentisic oxidase.
Result in the build up of homogentisic acid - an intermediate product in the
metabolism of phenylalanine and tyrosine.
Excess homogentisic acid oxidized, polymerized and form a blackish
pigment “alkapton”, which deposits in cartilage and can be easily seen in
the cartilage of ear.
Its deposition in articular cartilage make the joint susceptible to mechanical
stress and degeneration. Result in the arthritis of hip, knees and shoulders.
It also deposits in intravertebral discs in the spine, which become calcified.
Diagnosis is made by its characteristic X-ray appearance and estimation of
homogentisic acid in urine.
MECHANISMS OF KIDNEY STONE
FORMATION AND THEIR
INVESTIGATION
Predisposing factors:
 Increased concentration of stone constituents due to the excessive
production or decreased excretion of stone forming substances.
 Changes in urine pH, decreased urine volume, bacterial infection.
 Increased urine calcium, urate and oxalate, and decreased Mg, and
citrate excretion.
Metabolic Disorders:
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Primary hyperparathyroidism,
Renal tubular acidosis type 1
Hereditary hyperoxaluria
Medullary sponge kidney
Cushing’s disease
Milk-alki syndrome
Postulation
Patients with hypercalciuria, hyperoxaluria, and hyperuricosuria do not form
stone; conversely may form calculi in the absence of risk factors. It is there
fore postulated that:
“ Stone formation occur due to the absence or deficiency in inhibitors
of crystal formation in urine”
Inhibitors:
•
Magnesium, Pyrophosphate, diphosphonate, citrate, Osteopontin,
glycosaaminoglycan , and nephrocalcin.
Initiation:
• There are many causes for initiatin and propagation of stone
• the most determinant is the increased urinary concentration of the stone
constituents, such that they exceed their solubility in urine.
• Crystals formed spontaneously at supersaturation or a preexisting nuclei
can provoke their formation.
Stones and Pathogenesis
Calcium oxalate Calculi:
•
•
•
•
•
Majority (70 %) of stones are calcium containing, mostly of calcium oxalate
alone or mixed with phosphate.
Calcium containing stones are radio opaque.
Hypercalciura with hypercalcaemia; may be due to primary
hyperparathyroidism, sarcoidosis,or neoplastic bony metastases.
Hypercalciuria with normocalcaemia may be idiopathic or due to increased
gastro intestinal absorption.
Hypercalciuria in RTA – persistent loss of calcium.
Calcium oxalate and UA Calculi:
•
•
•
•
As many as 20% calcium oxalate stones are associated with increased uric
acid excretion with or without hypercalciuria (hyperuricosuric calcium
nephrolithiasis).
The stone formation occurs with nucleation of calcium oxalate by uric acid
crystals in the collecting ducts.
Hyperoxaluria can occur in vegetarians and enteric patients due to the over
absorption of oxalate by intestine.
Hypocitraturia associated with acidosis and chronic diarrhoea.
Stag horn calculi (Triple stone or Struvite stone 15%)
•
•
•
•
Composed of MG, NH4 and PO4
Formed largely after infection of urea splitting bacteria (e.g.
staphylococcus and proteus). They convert Urea to Ammonia the
resultant alkaline urine causes the precipitation of Magnesium
ammonium phosphate salts.
Form largest stones as urea excreted in large amount.
Occupy large portion of renal pelvis.
Uric acid Calculi
•
•
•
•
Uric acid stone are radioluscent and present in 5-10% patients.
Common in patients with hyperuricaemia such as gout and diseases
involving rapid cell turnover like leukaemia.
More than half of the patients have neither hyperuricaemia nor increased
urinary uric acid excretion.
It’s the tendency of the patients to produce urine with pH lower than 5.5
as uric acid is insoluble at lower acidic pH.
Cystine 1-2%
•
Genetic defect in the renal reabsorption of amino acids including cystine
leading to cystinuria and stone formed at lower urinary pH.
INVESTIGATIONS
Biochemical investigations involve:
• Chemical analysis of calculus (if available)
• Plasma PTH
• Plasma/serum estimation for calcium , albumin, phosphate,
bicarbonate and urate.
• Urine estimation for
– pH (must be very fresh)
– qualitative test for cystine
– Excretion of calcium, oxalate, urate and citrate in 24 hour urine
collection.
– Microbiology for the evidence of infection.