Ch 58 Pathogenesis of HD Flashcards
hip dysplasia
most common orthopedic condition of the dog
- disease of complex inheritance, meaning that multiple genes, combined with environmental factors, can influence the expression of the condition
- etiology and pathogenesis of the condition remains unclear.
- most studies: hip joint laxity is key in the development of osteoarthritis of canine hip dysplasia
- understanding that hip dysplasia has a genetic basis, coupled with the clinical observation that hip joint laxity plays a role in disease expression, led to (screening) methods aimed at assessing hip joint laxity early in life with the hope that selecting the best candidates for breeding would lower the frequency
- Despite 75 years of observation and investigation, the diagnosis and treatment of hip dysplasia remains controversial.
Etiology (8) and Pathogenesis
manifestation of the disease phenotype occurs in genetically predisposed animals exposed to environmental factors that enhance expression
1. genetics
2. joint laxity
3. joint fluid
4. pelvic muscle mass
5. hormones
6. weight and growth
7. nutrition
8. environmental
Pathogenesis stems from a “varying degree of laxity of the hip joint, permitting subluxation during early life, giving rise to varying degrees of shallow acetabulum and flattening of the femoral head, finally inevitably leading to osteoarthritis
Hip Development
- At birth, canine hip joints are normal
- normal development if complete congruity between the femoral head and the acetabulum is maintained
- earliest dysplastic joint changes at 30 days (edematous ligament, torn fibers and capillary hemorrhage )
- increased volume of the ligament + synovial fluid volume
- studies in puppies
- first month of life, the ligament of the head of the femur > primarily responsible for maintaining hip joint stability
- After 2 weeks, the ligament slowly begins to lengthen
- in dysplastic dogs it is this excessive lengthening that permits lateral subluxation of the adult hip joint
- first radiographic signs of canine hip dysplasia, seen as early as 7 weeks of age, are subluxation of the femoral head and underdevelopment of the craniodorsal acetabular rim
- Gross pathology reveals thickening and stretching of the joint capsule
- articular cartilage is worn and roughened on the dorsal surface of the femoral head at its point of contact with the acetabular rim
- Evidence of palpable or radiographic laxity appears before degenerative structural change
- lab STUDY: subluxation as seen on the hip-extended radiograph occurred by 2 years of age; subluxation does not manifest thereafter
- Osteoarthritis is a progressive disease and with age will variably lead to clinical signs of pain and disability
When are the earliest gross changes of HD visible and what are they?
30 days
- Oedematous ligament of head of the femur with torn fibers and capillary haemorrhage
- Increased volume of ligament and of synovial fluid
When are the first radiographic signs of HD visible and what are they?
7 weeks old
- Subluxation
- Underdevelopment of craniodorsal acetabular rim
- From 60-90d the degree of subluxation increased
Biomechanics
congruent hip
- forces during weight bearing are distributed across the entire cartilaginous surface of the acetabulum.
- forces crossing the joint (joint reaction force) represent the vector addition of gravitational forces + muscle forces necessary to balance the moments of standing and locomotion
in subluxation
- periarticular muscle forces must increase to compensate for lateralization of the center of rotation of the joint
- cartilage stress (force divided by area of contact) is increased because forces acting are spread over a markedly reduced surface area> dorsal labrum of the acetabulum
- causes cartilage damage, joint inflammation, and ultimately osteoarthritis
weight bearing
- large gluteal muscles: extend, abduct and internally rotate the hip joint
- the adductor magnus et brevis muscles have compensatory adduction and external rotation
- co-contraction of these muscles + biceps, semimembranosus, and semitendinosus muscles forms a large resolved force tending to reduce (and stabilize) the femoral head
swing phase
- transarticular muscles acting to advance the pelvic limb for foot strike: rectus femoris, sartorius, and iliopsoas muscles.
- long muscle bellies, with lines of action more parallel to the axis of the femur.
- generate much lower loads than the muscles of weight bearing»_space;> orientation makes them prime candidates to cause subluxation in a lax hip joint
2 reasons biomechanics appears to support catastrophic reduction theory:
- in excessive joint laxity
still requires definitive proof
(1). femoral head subluxates during the swing phase of gate
- upon foot strike, the larger hip extensor muscles cause catastrophic reduction of the femoral head
- producing the characteristic cartilage erosion
(2). position of cartilage wear (dorsal fovea) suggest catastrophic reduction
What two destructive event accompany subluxation?
The forces crossing the joint increase as the force of the periarticular muscles increase to attempt stabilisation
The area over which the forces are transmitted decreased (abnormal forces within the joint)
What muscles help to reduce the femoral head when weight bearing?
Gluteals
Adductor magnis et brevis
hip laxity biomechanics
- origin of the cascade leading to hip osteoarthritis is functional hip joint laxity; accordingly
- mechanical testing of cadaver hips (Heyman et al) laxity is at its maximum when the joint is placed in a neutral weight-bearing position
- Pulling the pelvic limbs into extension (i.e hip screening) produce a windup of the joint capsule, which severely limits the lateral movement of the femoral head
- degree of lateral femoral head displacement is not directly proportional to the applied force
- hip joint can be modeled as a ball on a rope (biphasic behavior)
- displacement of the femoral head from the acetabulum was maximized in the neutral position and was largely independent of the distraction force above a minimum force> basis for [PennHIP]
diagnostic tests assess hip joint laxity in a variety of positions
What is the neutral stance of the hip?
- 10-15 deg of extension
- 10 deg of abduction
- 0 deg of rotation
Hip joint laxity is at its maximum when at a neutral stance
What is a luxoid hip?
A hip showing the most severe phenotypic characteristics of HD
For such hip joints, reduction cannot occur, and the joint is permanently subluxated (or luxated) during all phases of the gait cycle
Genetics
- low progress in reducing the incidence of canine hip dysplasia via conventional hip-extended radiographic phenotypic testing has fueled research to develop a genomic test
- some techniques and research results have produced molecular/DNA tests for predicting canine hip dysplasia susceptibility in young dogs
- quantitative trait loci (QTLs), which are regions on a chromosome containing a gene or a group of genes influencing the phenotypic expression of a quantitative trait
- QTL on CFA11 explained less than 18% of the total variance in hip joint laxity, as measured by the distraction index.
- a genome-wide study of different dog breeds reveals multiple different genes and associated single nucleotide polymorphisms locations, often only explaining a portion of phenotypic variance> suggesting that many other genes must contribute
- demonstrate challenge of interpreting the many rather disparate findings reported in the literature.
- most studies on genotype neglect to account for the age dependence of hip dysplasia onset
- More precise phenotypic definitions, high genome coverage, large sample meta-analyses, and more accurate phenotype-genotype correlations are needed
(Illumina CanineHD BeadChip)
- STUDY: Genomic methods resulted in similar or higher accuracies than pedigree-based hip scoring methods
- criticism is that the test applies only to Labrador Retrievers
- variability of the phenotype to which genotypic association was mad (young only used, when known labs can develop OA at any age)
- at 6 years of age, 45% of the dogs scored as normal were actually false-negative diagnoses
- may reflect gene loci more related to the severity rather than the genomic cause
- test may lessen the severity of canine hip dysplasia / delay its onset in subsequent generations; however, its impact on disease incidence may be negligible
- Making genomic association to hip scores at 8 months of age, or 1 year, 2 years, or even 6 years, has questionable relevance given the known age-dependent behavior of canine hip dysplasia expression
What is considered a normal Norberg angle?
over 105
Norberg angle (NA) is a measure of hip joint laxity. It is derived from the hip-extended radiograph and is calculated by drawing a line connecting the centers of the femoral heads and one from the center of each femoral head to its ipsilateral craniolateral acetabular rim
Joint laxity
- measured by distraction index
- shown to be the primary risk factor for the development of hip joint osteoarthritis in all breeds studied
- Passive hip joint laxity is an estimation of functional hip joint laxity
- subluxation of the femoral head > resulting in abnormal force distribution > premature wear of the articular cartilage and microfractures > osteophyte formation and osteoarthritis
- higher degrees of joint laxity are at greater risk for developing osteoarthritis
- risk for osteoarthritis increases as the distraction index increases beyond 0.30
- Subluxation, a subjective assessment of hip joint laxity derived from the hip-extended radiograph, is another risk factor for osteoarthritis
- life span STUDY: however, 98% of dogs in that study developed osteoarthritis by the end of life, whether or not they had radiographic evidence of subluxation
- it is unclear what actually causes joint laxity. Several causes have been proposed
subluxation of the femoral head during the gait cycle, resulting in abnormal force distribution across the joint. This leads to premature wear of the articular cartilage and microfractures in the subchondral bone and ultimately progresses to osteophyte formation and osteoarthritis
What did the lifelong Labrador study highlight regarding age of HD?
- 98% of dogs in that study developed osteoarthritis by the end of life, whether or not they had radiographic evidence of subluxation
- Only 55% of those whom would eventually develop HD, showed radiographic evidence by 6yo
- meaning 45% of the dogs scored as normal were actually false-negative diagnoses
What distraction index is considered low chance of developing OA?
under 0.3
Joint Fluid
- experimental addition of fluid to the hip joint caused an increase in passive laxity; similarly, removal of excessive joint fluid reduced joint laxity
- uncertain whether these changes are the primary cause of hip joint laxity, or secondary changes
- ## Homeostatic mechanisms to regulate hip joint synovial fluid volume have not been identified
Synovial fluid production is primarily mediated by dialysis of blood from the intracapsular vessels, whereby the endothelium, connective tissues, and synoviocytes modify the plasma for synovial fluid production. Equilibrium between new formation and removal of synovial fluid is maintained by drainage through the intracapsular veins and lymphatic vessels; however, the mechanism for volume control is not understood
Pelvic Muscle Mass
positive correlation between pelvic muscle mass and the prevalence of hip dysplasia
- The muscle mass of dysplastic dog breeds was less than that of nondysplastic breeds, with Greyhounds having large thigh muscles
What hormone may be associated with increased hip laxity?
Relaxin
- It is elevated in last trimester of pregnancy and also in the milk of lactating bitches
- Last been assoc with increased peripheral joint laxity in humans
- Higher levels found in Labs than Beagles
Estrogen levels in the physiologic range, however, have not been shown to cause changes in hip joint laxity or dysplasia
Non-neuter male G.Ret half as likely to develop clinical signs of HD by 4.4yo
- combined effects of early neutering and an associated increased body condition score
- Neutering after 12mo seems to have a preventive effect on clinical signs
Weight and Growth
- rapidly growing pups had a higher incidence of canine hip dysplasia at maturity than those with slower weight gain
- Body weight has proved to be an influential environmental factor through several studies > plays an instrumental role in the manifestation of the disease phenotype in dogs having genetic susceptibility
- (life span study in Lab) benefit of restricted feeding in the onset of hip osteoarthritis. At 2 years of age, one restricted-fed dog expressed hip osteoarthritis compared with six dogs in the control-fed group
How does weight effect the development of HD?
- Heaviest male and female GSD puppues at 60d old had highest incidence of HD at maturity
- Overweight dogs develop radiographic OA 6 years earlier than lean counterparts
- Overweight dogs require medication 3 years earlier
- Lean dogs have a higher life expectancy by 1.8yr
Data from a life span study in Labrador Retrievers showed the profound benefit of keeping osteoarthritis-susceptible dogs lean for life. Osteoarthritis of hip dysplasia was delayed in onset and reduced in severity in lean dogs
What nutritional factors may play a role in HD?
- High dietary Ca and excessive VitD (delayed endochondral ossification ans skeletal remodeling)
- High density anion gap diet (increased osmolality in synovial fluid and increased volume)
No dietary deficiencies have been shown to “cause” hip dysplasia, but dietary excesses have been found to contribute
Environmental Factors
complex trait (also known as a quantitative or polygenic trait)
genetic and an environmental basis to explain the observed variation in expressed phenotype
- gender-matched cohorts of Labrador Retriever littermates, food restriction (i.e., an environmental influence) to maintain a lean body mass was shown to have a profound effect on delaying the onset and lowering the severity of hip dysplasia
- injectable polysulfated glycosaminoglycan (Adequate longitudinal trials imposing these strategies in cohorts of puppies matched for osteoarthritis susceptibility have not been carried out)
How have injectable polysulphated glycosaminglycans been shown to effect development of HD?
Give to puppies from dysplastic parents as twice weekly injections from 6wk to 8mo reduced subluxation scores and reduced histopath evidence of arthritis at 8mo
Proposed Pathogenesis of Hip Dysplasia
- mechanoreceptors exist within the joint capsule and within other fibrous constraints of the joint
- joint is constantly transmitting information to the brain and surrounding tissue related to its position, movement, and loading.
- pathogenic mechanism to explain how increased synovial fluid volume might lead to destructive joint forces
- ideally synovial fluid volume is fixed and minimal > low intracapsular pressure (P) limits possible translation when joint tends to subluxate during the swing phase.
- normal feedback loop triggered by capsular stretching> lower synovial fluid volume, pressure differentials would occur earlier in the subluxation > capsule invaginate > stretching it and mechanorecepters.
- mechanorecepter activation> periarticular muscles recruited protective roles> position the femoral head closer to the acetabulum > larger loads/ weight bearing results in little abrupt reduction hip.
- With increasing synovial fluid volume> protective mechanisms are triggered later during the subluxation of swing phase (i.e., it takes greater subluxation of the femoral head to trigger stretching of the capsular mechanoreceptors).
- severe laxity> protective mechanisms fail to be recruited before foot strike> lead to catastrophic hip reduction at foot strike
What are some common DDx for HD? (6)
Panosteitis
OCD
HOD
CCLR
LS stenosis
Neoplasia
What are common findings on the gait exam
- Wide or narrow based stance
- Hips or spinal sway
- Stiff, short-strided
- shifting weight to thoracic limbs by extending stifle and tarsocrural joints
- Bunny-hopping
Signalment and History
- large and giant breeds, such as GSD, Rottweilers, Labrador, Golden Retrievers
- clinical signs can be divided into two forms. In the juvenile or severe form, dogs are typically presented between 5 and 12 months of age
(result of extreme joint laxity, pain dt stretch lig/capsule + microfracture) - capsular strain and inflammation induced by joint laxity cause periarticular fibrosis. This phase of the disease is often associated with reduction or even elimination of clinical signs
- chronic form of canine hip dysplasia has highly variable onset (dt OA)
Hip-Extended Radiography
VD rads: dorsal recumbency, pelvic limbs pulled into extension with femora parallel and slightly pronated (internally rotated), patella superimposed over the trochlear groove
- reported to be an insensitive diagnostic tool, having poor precision and poor predictive accuracy for the diagnosis
- windup of the joint capsule > masking observable joint laxity ,factor contributing to the high rate of false-negative diagnoses
Hip dysplasia dx:
- Hip joint laxity, subjectively or objectively interpreted as subluxation
- radiographic presence of osteoarthritis (4)
radiographic signs of osteoarthritis lags behind the early in vivo structural changes associated with osteoarthritis. Early changes typical of osteoarthritis can, however, be found on arthroscopy
- Orthopedic Foundation for Animals (OFA) decided to limit the earliest age of hip screening in the United States to dogs 2 years of age
- hip-extended screening Australian systems, specify dogs 1 year of age or older
- evaluating hips at 1 year of age versus 2 years of age is associated with a minimum error in diagnosis of 30%
Radiographic Evidence of Osteoarthritis (4)
Femoral periarticular osteophyte formation
Subchondral sclerosis of the craniodorsal aspect of the acetabulum
Osteophytes on the cranial or caudal acetabular margin
Joint remodeling from chronic wear
Newer radiographic changes associated with osteoarthritis
Femoral periarticular osteophyte formation
- caudolateral curvilinear osteophyte (CCO) (“Morgans line)
- circumferential femoral head osteophyte (CFHO)
- “puppy line” - gone by 18m, dont confuse with CCO (shorter, more subtle)
A; CFHO B; CCO C; puppy line
predict later development of well-accepted radiographic signs of OA
What are some of the main downfalls of the OFA, FCI and Kennel club?
- Voluntary film submission forming a large prescreening bias
- Not required to be evaluated later in life
Selection bias makes it impossible to arrive at accurate disease prevalence figures or to assess the rate of improvement
data suggest that dogs carrying the genes (susceptibility) for canine hip dysplasia, falsely diagnosed as “normal,” are routinely returned to the gene pool for breeding purposes based on OFA scores
Orthopedic Foundation for Animals
What views are required for PennHIP?
VD extended (for comparison)
Compression (shows congruency and true depth of hip joint)
Distraction (quantification of the relative degree of femoral head displacement)
Dorsolateral Subluxation
The anesthetized animal is placed in a kneeling, sternal recumbency, with femora adducted and stifle joints flexed
- forced to subluxate in a dorsolateral direction, and the degree of subluxation is quantified by assessment of the percentage of femoral head coverage (increase risk OA if % of femoral head coverage ≥ 56)
- strong correlation between distraction index and dorsolateral subluxation score
- No longitudinal studies linking DLS score to the development of radiographic OA been performed (i.e no life span study like for DI)
- study DLS vs DI: 23% of dogs predicted to be unsusceptible to OA by the DLS had radiographic evidence of OA > Such dogs would be false-negative diagnoses.
- resolved lateralization force in the DLS test. The cartilage contact tangent becomes more vertical with progressive lateralization of the femoral head. This results in a decrease in the resolved lateralization force, meaning that femoral head displacement in the DLS test is strongly influenced by remodeling of the craniodorsal rim of the acetabulum
- hip is more extended and more adducted than the position of maximum laxity (estimated reduction of ~30% compared with neutral positioning)
- no clinical or diagnostic advantages over PennHIP.
Flückiger Subluxation Index
- Flückiger et al.
- quantifies hip joint laxity radiographically by using a dorsally directed force that causes dorsolateral displacement of the femoral heads
- dog in dorsal recumbency
- hip position is approximately the same as DLS
- subluxation index: using circle gauges laid over the structures of the femoral head and acetabulum.
- No follow-up studies beyond 1 year of age have been published
Computed Tomography and Magnetic Resonance Imaging
MRI was used to demonstrate a relationship between joint laxity, as measured by distraction index in 7- to 9-week-old puppies, and the synovial fluid volume index; however, a poor association was seen between hip joint laxity at 7 to 9 weeks compared with laxity measured later in life,
- At 16 weeks of age, a combination of radiographic distraction index with the CT-determined center-edge angle was found to be most strongly associated with later development of hip osteoarthritis at 2 years of age (BUT evidence of OA at 2 years of age is not a definitive gold standard for hip dysplasia)
Heritability and Selection Pressure
heritability reflects the degree phenotype predicts the genotype
- Mass selection: choosing breeding stock based on the individual dog’s hip joint phenotype (not consider relatives)
- highly heritable traits (≥0.5), mass selection is an acceptable approach for choosing replacement breeders, but, as heritability decreases (≤0.35), it becomes increasingly important to consider the phenotypes of relatives (like EBV)
- environmental and nongenetic factors contribute to the variation observed, further obscuring the underlying genotype giving rise to that phenotype
- lower heritability > observed phenotype should be recognized as a poor predictor of genetic value
- mass selection, if linked to a highly heritable phenotype, such as the PennHIP distraction index, holds the greatest promise to reduce the frequency and severity of osteoarthritis
- heritibility = ratio of additive genetic variation (VG) to overall phenotypic variation (VP genetic and nongenetic)) of a given trait (h2 = VG/VP)
selection pressure
- amount of selection pressure applied to genetically improve a trait is determined by the magnitude of the selection differential.
- selection differential = amount by which the average parental hip score differs from the overall population average (Avgparents − Avgpopulation).
- heritability + selection pressure determine the rate of expected genetic change (ΔG) in the ensuing generation.
- ΔG is the difference in average of the offspring minus the mean of the parents:
- genetic improvement = heritability (h2) of the hip score x selection differential (determined by the parents)
- campred to subjective OFA hip score, Higher estimates of heritability have been found for (PennHIP) distraction index (>0.46 to 0.83)
DI the only hip scoring metric having high correlation with OA
Correlation of distraction index with arthroscopic findings in
juvenile dogs with hip dysplasia
Ulfelder 2019
Retrospective case series.
Animals: Twenty dogs (36 hip joints).
dogs undergoing unilateral or bilateral DPO
(2011–2016) were reviewed.
less than 12 months of age, no or minimal signs of OA identified on radiographs
A Vezzoni-modified Badertscher distension device
Distraction index ranged from 0.4 to 1.0
- grade 2 lesions at the insertion of the ligament
of the femoral head were present in 44% - 47% of hips had grade 2 lesions on the acetabular labrum
- 22% (8/36) of hips had grade 0 cartilage wear in all regions of the hip
- Pathological changes that were not seen on rads were seen in up to 69% of hips > these dogs may not be the best candidates for a DPO
This study did not include clinical or radiographic follow-up; therefore, we were unable to correlate long-term outcome after DPO with either preoperative DI or arthroscopically identified intra-articular wear grades
There was a low positive correlation between synovitis and DI. No other differences in DI were identified.
Clinical significance: Arthroscopic evaluation of the coxofemoral joint prior to DPO can allow detection of joint pathology that might not be appreciated by using
traditional radiographic screening criteria
our results provide evidence that DI is not an accurate method for predicting the magnitude of joint pathology detected by hip arthroscopy in juvenile dogs with HD
time point in the progression of HD at which irreversible, pathological joint changes have occurred such that surgical intervention with pelvic osteotomy surgery would no longer provide significant benefit to the dog has not been clearly defined.
The study reported here provides
evidence that the results of arthroscopic assessment of coxofemoral joint cartilage and support structure (DAR, ligament of insertion of the femoral head, and labrum) wear do not correlate with the degree of coxofemoral joint laxity as measured by the DI. The lack of a correlation between DI and our
arthroscopic findings is likely related to the relatively static nature of the DI
Studies have provided evidence that up to 100%16,17 of dogs that have undergone triple pelvic osteotomies can have progression of radiographically identified OA.
Our cartilage wear findings support previously reported find ings,
providing evidence that cartilage changes around the
fovea could be one of the earliest degenerative changes in dogs with HD.
Evolution of Radiographic Parameters of Canine
Passive Hip Laxity at 4, 6 and 12 months: A Study
of 306 Dogs
Taroni 2018
we show a significant variation of the DI values
between 4, 6 and 12 months of age for the studied population.
This variation implies an increase between 4 and
6 months of age and a decrease between 6 and 12 months of age. The DI is an accepted indicator of hip laxity and thus hip dysplasia, but the changes reported in our study between the different evaluations brings into question the interpretation
of the DI value at a given time. It is unclear whether the DI value at 4, 6 or 12 months of age is the best predictor of hip dysplasia and osteoarthritis development.
Our results show an average difference of 0.035 between 4 and 6 months for the total population. Even if this difference is significant, the clinical relevance can be considered null. However, the
difference between 4 and 12 months is on average 0.1 and cannot be considered a minor difference.
Joint laxity in canine hip dysplasia assessed using the hip flexed not distracted ventrodorsal view
L. Meomartino 2021
VDF can be considered a valid in-house method for the evaluation of canine hip joint laxity.
the VDF view is obtained without the help of
an operator, does not require any special devices, and the measurements
obtained using this view in our sample showed good
agreement with measurements obtained using the VDD view.
Radiographic procedures are
frequently associated with small doses of human exposure to ionizing
radiation, which accumulate over a lifetime and can result in substantial
radiation exposure. Radiographic hands-free techniques for the assessment
of hip laxity, degenerative joint changes or hip osseous structure
can be used for breeding selection or clinical case management
