CLINICAL

CHEMISTRY IN
GERIATRICS
population over 65 has increased considerably in many
other countries
increasing numbers of elderly patients admitted to hospital
for
- assessment
- treatment
many suffering from more than one disease.
specimens from elderly reported without any special
attention to possible problems in interpretation

results previously considered abnormal in elderly
patients, do not necessarily signify abnormality in the
aged if appropriate reference values are use

Special problems in investigation and management of
illness in elderly

` Different
-patterns of disease
-presentation of disease
-reference ranges
` Decline in normal functions with age

Patterns of Disease

many conditions are more common in the elderly than
in younger adults
-thyroid disease
-Paget's disease of bone
-include diabetes mellitus

Presentation of diseases
in elderly may be different from that normally seen in
younger people
- presenting with confusion, due to
reduction in cebral blood flow, rather than
chest pain in myocardial infarction

-presenting with ischaemic ulceration,
rather than polyuria and thirst in diabetes
mellitus
Reference ranges

values for healthy adults in the 18-65 age range may
not be applicable to the elderly

function of some organs decline with age
(e.g. glomerular fiItration rate)

laboratories should construct age-related reference
ranges for age-dependent ana1ytes

Plasma constituents showing age-dependent changes in
concentration

cholesterol increases progressively during adult life

Glucose increases (glucose tolerance decreases
with age)

urate increases

total protein/albumin decreases (slight decrease probably
due to decreased protein intake)


q ALP + Ca +PO4 osteomalacia







Hypomagnesaemia (may be as low as 0.1 mmol/l)
Causes
dietary deficiency
or increased intestinal or urinary loss
convulsions not corrected by Ca administration
may occur with Ca
( Mg impairing release of PTH)
Plasma sodium

Hypernatraemia
Na due to predominant water loss
e.g. insensible loss due
- pneumonia
- diarrhea
- phototherapy for jaundice
(convulsions caused by changes in cerebral
hydration)

Hyponatraemia

Na due to
prolonged maternal infusion of oxytocin to
induce labour (has antidiuretic action similar
to ADH)
infusion on water in excess of sodium
Neonatal Hyperbilirubinaemia
Two types
- unconjugated
- conjugated
Unconjugated hyperbilirubinaemia
bilirubin > 34 umol/l in 90% of normal babies
others up to 200 umol/l without pathological
cause
> 200umol/l, persistent after first week of life
pathological

Plasma Unconjugated bilirubin ^ (>340
umol/l)
albumin capacity to bind bilirubin exceeded
bilirubin crosses bld-brain barrier
is deposited in brain
kernicterus => brain damage (esp. basal ganglia)

Critical level (340umol/l) depends on
- plasma albumin conc.
- presence of drugs (e.g. sulphanamides)
- acid base disturbances
Physiological Unconjugated
hyperbilirubinaemia

` very common, causes include
not fully developed conjugating enzymes
interference with hepatic transport by drugs from
mother
reabsorption of bili. => no flora to convert to
urobilinogen

Pathological causes
increased haemolysis (ABO Rhesus)
abnormalities in RBC ( G6PD deficiency, hereditary
spherocytosis)
defective hepatic uptake or conjugation
(inherited disorders,e.g. Gilberts or Crigler Najjar
syndrome)
prematurity

Jaundice during first 24 hrs more likely to be pathological
Urine bili. negative unless there is glomerular damage
& protenuria

Management

Bili.< 340 umol/l phototherapy => UV light
(bilirubin destroyed by light)
> 340 umol/l exchange transfusion

Complication
- hyperkalaemia
- hypocalcaemia
- metabolic acidosis

Conjugated Hyperbilirubinaemia

Causes
intrahepatic cholestasis in cystic fibrosis
biliary obstruction (extrabiliary tumours)
abnormalities of biliary tree (extra or intra-hepatic
canals)


Noenatal hepatitis
presents clinically usually after first wk of life
Causes
intrauterine infection with cytomegalovirus, & rubella
metabolic causes e.g. a1 antitrypsin deficiency or
galactosaemia

LFT
cholestatic pattern, with large rise ALP activity
Lipoprotein X detectable in plasma
ALT & AST also raised

Acid Base disturbances

commonest =>Respiratory Distress Syndrome (RDS)
occurs in infants < 38 wks of gestation
due to deficiency of surfactant in the alveoli
presents with pulmonary collapse & secondary lung
infection
- + pO2 & pCO causes resp. acidosis
- + bld flow due to hypotension causes tissue hypoxia
& lactic acidosis (met. acidosis)
acidosis may be severe pH < 7.0

Management
positive pressure ventilation
monitor PO
2
, & PCO
2


Lecithin: Sphingomyelin ratio used to predict
likelihood of developing RDS

Failure To Thrive
Many causes
- malnutrition
- vitamin deficiency diseases
- cystic fibrosis
- other errors of metabolism

Malnutrition
kwashiorkor & marasmus => protein deficiency

Determine albumin
> 36 g/l normal
< 30 g/l abnormal
< 25g/l associated with increasing degrees of oedema
and conc. of some essential AA (valine, Leucine,
isoleucine )
Immunoglobulins
IgG fall at birth
high plasma IgM at birth (umbilical cord bld)
or within first 4wks.
- intrauterine infection or neonatal infection e.g. syphilis,
rubella, toxoplasmosis or cytomegalovirus
Plasma Ig level also measured to exclude deficiency states


Rickets Of The Premature

Nutritional rickets
- Ca & PO4 +
- ALP^
rickets of the premature =>low birth wt infants
evident between 4
th
& 12
th
wk
decalcification of bones predisposes to pathological
factures
respiration impaired by soft bones of ribs

Causes
` maternal vit. D deficiency during pregnancy or in
infant after birth
` drugs like frusemide ^ urinary Ca loss renal tubular
disorders of PO4 absorption
Ca
2+
N or ^ => cannot be deposited in bone without
PO4

Mgt
Vit. D, Ca
2+
,PO
4-
supplementation. Monitor with
ALP

Neonatal hypothyroidism

TSH rises rapidly at birth 15x adult
(responding to stress at birth)
reachs peak within 1
st
hr
falls (rapidly at first) during the next wk
screen after one wk (TSH)

Prenatal diagnosis or prenatal screening
is testing for diseases or conditions in a fetus or
embryo before it is born

aim is to detect birth defects such as
neural tube defects, Down syndrome,
chromosome abnormalities, & genetic diseases
- and other conditions, Tay Sachs disease, sickle cell
anemia, thalassemia, cystic fibrosis

Screening can also be used for prenatal sex
discernment.
Common testing procedures include,

- amniocentesis,
- ultrasonography including nuchal
translucency ultrasound,
- serum marker testing, or genetic
screening
Amniotic Fluid

forms protective cushion for fetus in fluid
filled sac in utero

is formed from both amniotic membrane & secretions
from fetal cells (gastrointestinal, respiratory, umbilical
cord, & in late pregnancy fetal urine)

there is also feto-maternal exchange of water
between amniotic fluid & maternal fluids


removal of amniotic fluid , called amniocentesis

usually performed to determine
isoimmunization, fetal maturity in high risk
pregnancies or for genetic screening
Isoimmunization
results from bld group incompatability
between mother & fetus
Rh or other bld group IgG antibodies
destroying infants RBCs
haemolysis detected by presence of bilirubin

normal fetus- bilirubin picks at 23-25weeks
gestation => diappears by end of 36
th
wk
haemolysis evaluation usually carried out at 28 wks
amniocentesis indicated if maternal antibody titers
shows increasing pattern
done every month prior to 26 wks, then every 2 wks
there after

Fetal Maturity
Lecithin/ Sphingomylin (L/S) Ratio

Respiratory Distress Syndrome caused by deficiency
of pulmonary surfactant at birth

Pulmonary surfactant => a phospholipid protein
complex that coats alveoli preventing collapse of air
spaces on expiration
synthesized by type II pneumocytes lining alveoli
Major surfaceactive constituents of surfactant
- Lecithin ( dipalmitoyl phoshatidyl choline )
- Phosphatidal glycerol (PG)
both are phospholipids secreted by fetal lungs
their levels aid determination of fetal lung maturity

Sphingomyelin
another phospholipid
remains constant throughout embryonic development
used as internal std since
corrects for difference in volume


Normal development

up to 26wks sphingomyelin > lecithin
- L/S ratio < 1.0
- lecithin concentration slowly increases until 35
th
wk
- after 35
th
lecithin surges
- results in L/S of 2.0 or more
- Phosphatidal glycerol (PG) normally appears around
36 37 wks of gestation
indicates first biochemical stage of lung maturity
Bubble Stability or Shake Test

bubble stability primarily due to presence surfactant
in sufficient concentration.
shake amniotic fluid with 95 % ethanol for 15 sec
observe bubble stability at air- liquid interface after
sample has remained undisturbed for 15 min

` ethanol inhibits bubble formation by other constituents of
amniotic fluid ( bile salts, proteins etc.)except those by
active phospholipid surfactants
` Positive => continuum of bubbles around the
circumference of liquid surface at end of 15 min


Creatinine

later in gestation fetal urine contributes to amniotic fluid
amniotic fluid creatinine level is related to, fetal muscle
mass, renal function & maternal creatinine levels
creatinine increases as fetus matures

creatinine of 170mol predictive of mature fetus only if
maternal creatinine does not exceed 80 mol

used only to assess fetal size & gestational age but not
lung maturity

INBORN ERRORS OF METABOLISM
(Congenital Metabolic Or Inherited Metabolic Diseases)

` large class of genetic diseases involving disorders of
metabolism
` majority due to defects of single genes that code for
enzymes that facilitate conversion of various substances
(substrates) into others (products)
` problems arise due to accumulation of substances which
are toxic or interfere with normal function
` or to the effects of reduced ability to synthesize essential
compounds.

Glycogen Storage Disease (GSD,)
Glycogenosis And Dextrinosis)

defects in the processing of glycogen synthesis or
breakdown within muscles, liver, and other cell types

eleven distinct diseases
Glycogen Storage Disease Type I
(Von Gierke's disease)

named after Edgar von Gierke, the German doctor who
discovered it
the most common of the glycogen storage diseases
results from deficiency of the enzyme glucose-6-
phosphatase
deficiency impairs the ability of the liver to produce free
glucose from glycogen and from gluconeogenesis

` Reduced glycogen breakdown results in
increased glycogen storage in liver and
kidneys, causing enlargement of both

` Both function normally in childhood but
susceptible to variety of problems in adult
years
Clinical manifestations result, directly or
indirectly, from
1. inability to maintain an adequate blood glucose level
during the post-absorptive hours of each day
2. organ changes due to glycogen accumulation
3. excessive lactic acid generation
4. damage to tissue from hyperuricemia

Hypoglycemia
is the central clinical problem
one that is most damaging
one that most often prompts the initial diagnosis

maternal glucose transferred across the placenta prevents
hypoglycemia in a fetus with GSD I
But the liver is enlarged with glycogen at birth
inability to generate and release glucose results in
hypoglycemia and
occasionally in lactic acidosis presenting as a primary
respiratory problem in the newborn period


Hepatomegaly and liver problems
` impairment of glycogenolysis causes the characteristic
enlargement of the liver due to accumulation of glycogen
` glycogen also accumulates in kidneys and small intestine
` hepatomegaly, is usually without splenomegaly
- begins to develop in fetal life
- usually noticeable in the first few months of life.
- By the time the child is standing and walking, the
hepatomegaly may be severe enough to cause the
abdomen to protrude
- the liver edge is often at or below the level of the
umbilicus.
other liver functions are usually spared, and liver
enzymes and bilirubin are usually normal
Lactic acidosis
impaired gluconeogenesis results in elevations of lactic
acid (4-10 mmol) even when the child is well
Growth failure
without treatment, common
due to
- low insulin levels
- persistent acidosis
- chronic elevation of catabolic hormones
- calorie insufficiency
- and/or malabsorption

Presentation and Diagnosis

several problems may lead to the diagnosis (usually by
two years of age)
- seizures or other manifestations of severe fasting
hypoglycemia
- hepatomegaly with abdominal protuberance
- hyperventilation and apparent respiratory distress due to
metabolic acidosis
- episodes of vomiting due to metabolic acidosis, often
precipitated by minor illness and accompanied by
hypoglycemia.
` hypoglycemia often occurs within six hours
` a bld specimen obtained at the time of hypoglycemia
typically reveals
- a mild metabolic acidosis
- high free fatty acids and beta-hydroxybutyrate, very low
insulin levels
- and high levels of glucagon, cortisol, and growth
hormone
administration of intramuscular or intravenous glucagon
(0.25 to 1 mg, depending on age) or epinephrine produces
little rise of blood sugar
Diagnosis
definitively confirmed by

- liver biopsy with electron microscopy
- assay of glucose-6-phosphatase activity in the tissue
- and/or specific gene testing
Treatment

primary goal
- prevention of hypoglycemia and the secondary metabolic
derangements by
= frequent feedings of foods high in glucose or starch
(readily digested to glucose)

Prognosis, Long Term Complications

` without adequate metabolic treatment, pts with GDS die
in infancy or childhood of hypoglycemia and acidosis

` hepatic complications serious in some pts
` adenomas of the liver can develop in the second decade
or later
(with a small chance of later malignant transformation to
hepatoma or hepatic carcinomas )

=> detectable by alpha-fetoprotein screening

Phenylketonuria (PKU)

autosomal recessive metabolic genetic disorder
characterized by a deficiency in the hepatic enzyme
phenylalanine hydroxylase (PAH)
due to a mutated gene for the phenylalanine hydroxylase

- PAH necessary to metabolize the amino acid
phenylalanine ('Phe') to the amino acid tyrosine
- phenylalanine accumulates & is converted to
phenylpyruvate(phenylketone),
- phenylketone detected in the urine

Clinical Presentation
` seizures, albinism (excessively fair hair and skin)
` "musty odor" to the baby's sweat and urine (due to
phenylacetate, one of the ketones produced

Treatment
` monitoring diet
` combining a low-phenylalanine diet with protein
supplements
` lowering bld phenylalanine levels to a safe range
` oral administration of tetrahydrobiopterin (or BH4), a
cofactor for the oxidation of phenylalanine
( reduces bld levels of phenylalanine in some patients)
Currently no cure
PKU detected through newborn screening 6 -14 days
after birth

Therapies Currently Under Investigation
- gene therapy
- enzyme substitution therapy with phenylalanine ammonia
lyase (PAL)
Alkaptonuria (black urine disease or alcaptonuria)

` rare inherited genetic disorder of phenylalanine and
tyrosine metabolism
` autosomal recessive due to a defect in the enzyme
homogentisate 1,2-dioxygenase
- enzyme participates in the degradation of tyrosine
- a toxic tyrosine byproduct homogentisic acid (oalkapton)
accumulates in the blood
- excreted in urine in large amounts
- excessive homogentisic acid causes damage to cartilage
( leading to osteoarthritis) and heart valves
- also precipitates as kidney stones
Signs and symptoms

Alkaptonuria often asymptomatic
sclera of the eyes may be pigmented (often only at a later
age)
skin may be darkened in sun-exposed areas and around
sweat glands
sweat may be coloured brown
urine turns brown if left exposed to open air
ear wax exposed to air turns red or black (depending on
diet) because of homogentisic acid accumulation

- kidney stones and stone formation in the prostate
common
- accumulation of homogentisic acid in tissues & joints
leads to cartilage damage
- in the spine, leads to low back pain at a young age
- cartilage damage may also occur in the hip and shoulder
- joint replacement surgery (hip and shoulder) often
necessary at a relatively young age
- valvular heart disease (aortic and mitral valves) may
occur
- in severe valve replacement may be necessary


Treatment

no treatment modality has been unequivocally
demonstrated to reduce the complications of alkaptonuria

dietary restriction of phenylalanine and tyrosine and
taking large doses of ascorbic acid (vitamin C) commonly
recommended
dietary restriction may be effective in children, but
benefits in adults have not been demonstrated
= the insecticide nitisinone, which suppresses homogentisic
acid production, is being studied


LeschNyhan syndrome (LNS),
( Nyhan's syndrome, Kelley-Seegmiller syndrome ,Juvenile
gout)

rare inherited disorder => hypoxanthine-guanine
phosphoribosyltransferase (HGPRT), deficiency
produced by mutations in the HPRT gene
X-linked recessive disease

lack of HGPRT causes a build-up of uric acid in all body
fluids => (hyperuricemia and hyperuricosuria)
leads to severe gout and kidney problems, poor muscle
control, and moderate mental retardation
(usually in the first year of life)


Signs and Symptoms
striking feature => uncontrollable self -mutilating
behaviors, (lip and finger biting & head banging )
( in 2nd year of life =>can increase during times of stress)
neurological symptoms include facial grimacing,
involuntary writhing, and repetitive movements of the
arms and legs
megaloblastic anemia may develop in some boys because
lack of HGPRT causes the body to poorly utilize vitamin
B12
males suffer delayed growth and puberty, and most
develop shrunken testicles or testicular atrophy

Diagnosis
overproduction of uric acid present at birth, but may not
be recognized by routine clinical laboratory testing
methods.
serum uric acid concentration is often normal, as the
excess purines are promptly eliminated in the urine
urate to creatinine concentration ratio in urine is elevated.
a urate to creatinine ratio above two is typically found
molecular genetic studies of the HPRT gene mutations
may confirm diagnosis
helpful for subsequent 'carrier testing' in at-risk females
such as close family relatives on the female side


Treatment

` no cure, but many patients live to adulthood
` symptoms caused by the buildup of uric acid (gout
and renal symptom) respond well to treatment with
allopurinol
` mental deficits and self-mutilating behavior do not
respond well to treatment

Prognosis
- for individuals with severe LNS => poor
- death is usually due to renal failure or complications from
hypotonia, in the first or second decade of life

less severe forms have better prognoses