Paediatric Reference Ranges

Question 1

What are factors affecting Reference intervals for Children and Babies?

Answer 1

• Body Size
  
  • Creatinine – marker of renal function and proportional to muscle mass. Males have higher reference ranges due to their muscle mass. Smaller individuals have lower reference ranges
• Gender – effect on number of steroid hormones
  
  • Boys vs Girls Testosterone
• Pubertal development
  
  • Testosterone and Tanner Stage
• Growth
  
  • Alkaline Phosphatase – indicative of velocity of growth
  • IGF-1 – marker of growth

Question 2

What is required for deriving reference intervals for CLSI?

Answer 2

Defined that there should 120 individuals in each definable category for example 120 males, 120 females.

Question 3

What are some issues with CLSI in defining the reference intervals?

Answer 3

• Ethics can be problematic in paediatrics
• Finding sufficient numbers of ‘healthy’ subjects for each age bin, gender or other determinant can be a challenge
• Sample volumes required vs available/possible can be limiting. Can make neonates anaemic with volume of blood taken

Need alternatives that are statistically and clinically valid

Question 4

What is used to define reference interval or statistically normal range?

Answer 4

• The Reference Interval is a 95% confidence interval i.e. the Mean ±2 Standard Deviations.
• That is to say, 95% of ‘healthy’ people have values that fall inside this range. It follows that 2.5% have values above the upper limit and 2.5% have values below the lower limit
• D-Lactate is an example of when the reference range is not particularly helpful as clinical correlation is not clear
• Creatinine has a low index of individuality and the reference range may not be helpful
  *

Question 5

How does index of individuality affect the reference interval?

Answer 5

• Reference intervals are not very useful for managing individual patients if a test has an Index of Individuality of <0.6. (The IOI is the ratio of Intraindividual CVi to group CVg).
• Index of Individually of >1 is ideal as this means the population reference range is generalisable and applicable to patients

Question 6

What are the benefits associated with age partioning?

Answer 6

• Partitioning of reference intervals into separate subclasses according to age, gender, ethnicity or ‘other’ is advisable when a clinical foundation or a logical physiological basis.
• Partitioning is a valuable tool for enhancing the diagnostic power of reference intervals.

Question 7

How is is Creatinine affected in Paediatric AKI?

Answer 7

• Acute Kidney Injury (AKI) affects ~1 in 5 adults admitted to hospital in an emergency: studies suggest about a third are preventable.
• Likely that much of this true in paediatric patients although more children are likely to be already in sub-speciality care (oncology or cardiac)
• First step to developing a uniform system for interventions is to establish and agree a method for identifying children with AKI

Question 8

How does Creatinine measured in Neonates?

Answer 8

• Babies under 1 month, possibly 6 months, should be excluded from algorithm and eGFR.
• Physiologically, there is a change in the early hours of life so therefore if the delta check was used for neonates in AKI then it would be incorrectly triggered

Question 9

What are some serial changes in Creatinine from birth?

Answer 9

• Creatinine levels are high at birth and fall within the first month of life.
• Levels (and the rate of drop) are variable and dependant on gestational age and birth and birth weight.
• There is a surge and fall in neonates in the first days of life.

Question 10

What are anabolic changes in Testosterone functions?

Answer 10

• Bone formation
• Erythropoiesis
• Muscle bulk
• Prostate growth
• Growth promoting effects on somatic tissues

Question 11

What are androgenic of testerone functions?

Answer 11

• Effects to male reproductive tract and secondary male characteristic
• Ejaculation
• Libido
• Erections
• Prenatal Differentiation

Question 12

What are causes of primary hypogonadism?

Answer 12

• Aging – loss of Leydig cells
• Chemotherapy/radiation
• Cryptorchidism
• Chromosome abnormalities (such as Klinefelter syndrome)
• HIV/AIDS
• Mitotic Dystrophy
• Orchitis (for example mumps)
• Testicular loss from trauma, tumor

Question 13

What are causes of Secondary Hypogonadism?

Answer 13

• Aging
• COPD
• Diabetes
• Haemochromatosis
• HIV/AIDS
• Hypogonadotropic Hypogonadism
• Kallman’s Syndrome
• Medication-induced such as anti-oestrogens for treatment of prostate cancer
• Obesity
• Pituitary mass lesion
• Prolactinoma
• Psychological stress
• Uraemia/Chronic renal failure

Question 14

What are causes of combined hypogonadism?

Answer 14

• Aging
• Cirrhosis
• Sickle cell disease

Question 15

What are testosterone age-related reference intervals?

Answer 15

• Levels in very first months of life are high and then fall
  
  • As children get older, testorone tends to rise

Question 16

What is tanner stages?

Answer 16

• Tanner stage is a scale of physical development in children, adolescents and adults
• The scale defines physical measurements of development based on external primary and secondary sex characteristics, such as the size of the breasts, genitalia, testicular volume and development of pubic and axillary hair
• First identified James Tanner,
• Although there is a strong age-relationship, individuals pass through the Tanner Stages at different ages
• In any given population of 13 yo boys, ALL five Tanner Stages are represented

Question 17

How do we establish age-related reference intervals not using CLSI approach?

Answer 17

• Collect patient data - remember the importance of standardised preanalytics
• Identify and remove outliers
• Define the underlying distribution of the remaining data points, stratified if necessary by age and sex
• Model the effects of variables such as age and sex

Question 18

What is Skewness?

Answer 18

• A symmetrical distribution has a skewness of zero; an asymmetrical distribution with a long tail to the right (higher values) has a positive skew; an asymmetrical distribution with a long tail to the left (lower values) has a negative skew
• A Gaussian distribution has a kurtosis of 0; a flatter distribution has a negative kurtosis; a distribution more peaked than a Gaussian distribution has a positive kurtosis

Question 19

What is Insulin-like Growth Factor type 1 (IGF-1)?

Answer 19

• Insulin-like growth factor - 1 (IGF-1) levels are an indirect measure of the average amount of growth hormone (GH) being produced by the body
• IGF-1 and GH are vital for normal bone and tissue growth and development
• GH is produced by the pituitary whereas IGF-1 is produced by the liver, primarily in response to GH stimulation, and some IGF-1 is also produced by skeletal muscles
• It mediates many of the actions of GH and so stimulates the growth of bones and other tissues and promotes the production of lean muscle mass

Question 20

What are causes of deficiencies in Insulin Growth Factor?

Answer 20

• Deficiencies may be caused
  
  • Hypopituitarism or the presence of a pituitary tumour that damages GH-producing cells
  • Functional deficiencies in IGF-1 may also occur where there is GH Insensitivity (GHI). GHI may be primary (genetic) or secondary to conditions such as malnutrition and chronic diseases

Question 21

What are the consequences of growth disorders?

Answer 21

• Deficiencies early in life can result in a child with a shorter than normal stature
• Excess GH and IGF-1 can cause abnormal growth of the skeleton and other signs and symptoms characteristic of gigantism and acromegaly