Urine Screening of Metabolic Disorders

Overflow vs Renal DisordersOverflow

Overproduction of a normal or abnormal substance to the point that the tubules are not able to prevent it from escaping into the urine.

• Increased levels in blood & urine

• Inherited defect • Acquired defect

Renal Faulty tubular

reabsorption mechanism Increased levels seen in

urine only

Value of Urinalysis

Value of Urinalysis

Phenylketonuria (PKU) “Mousy odor urine” 1/10,000 - 20,000 births Autosomal recessive trait Absence of phenylalanine

hydroxylase Urinalysis

Follow-up procedure in doubtful Dx cases

Screening test for proper dietary control in previously Dx cases

Monitoring the dietary intake of pregnant women known to lack phenylalanine hydroxylase

Phenylketonuria Diagnostic Tests

Microbial inhibition test (Guthrie)

Uses Bacillus subtilis (+) Phenylalanine

counteracts the action of β-2-thienylalanine,an inhibitor of B. subtilis (present in the media) growth is observed

Urinalysis1. Place 1 mL of urine in a

tube.2. Slowly add 5 qtts.of

10% ferric chloride.3. Observe colorpermanent blue green color

(+)

Tyrosyluria urine may contain excess tyrosine or its

degradation products, p-hydroxyphenylpyruvic acid and p-hydroxyphenyllactic acid.

Transitory tyrosinemia in premature infants

Acquired severe liver diseases

Enzyme deficiency

Type I - no fumarylacetoacetate hydrolase (FAH)

Type II – no tyrosine aminotransferase

Type III - p-hydroxyphenylpyruvic acid dioxygenase

Tested with nitroso-naphthol test and MS/MS

Autosomal Recessive

Clinical Presentations & Lab Dx

Tyrosine metabolized further to melanin, thyroxine, epinephrine, protein and tyrosine sulfate

Deficiency albinism Increased in urine urine darkening (after

exposure to air) Proliferation of melanocytes

malignant melanoma Tumors secrete 5,6- dihydroxyindole

melanogen melanin Melanin may react with Na nitroferricyanide

(acetone rgt. Strip) may producer ed color Ferric chloride tube test, a gray or black

precipitate forms in the presence

Melanuria

(“Alkali lover”) One of the 6 IEM described by Garrod

(1902) No Homogentisic acid oxidase HA

accumulation Brown or black-stained cloth or reddish-

stained disposable diapers May progress to arthritis, liver and

cardiac disorders Ferric chloride test deep blue color Clinitest yellow ppt. Addition of alkali in urine urine

darkening AgNO3 test, paper and TLC

Alkaptonuria

Amino Acid Disorders (Branched-Chain Amino Acid Disorders)

• Having a methyl group that branches from the main aliphatic C chain

Inherited as autosomal recessive trait

Failure to inherit gene for enzyme capable of oxidative decarboxylation of α-ketoisovaleric, α-ketoisocaproic, α-keto-β-methylvaleric

Exhibit failure to thrive w/in 1 wk

Maple Syrup odor is due to rapid accumulation of keto-acids

2,4-dinitrophenylhydrazine urine screening test

Maple Syrup Urine Disease

Sx: Early severe illness, vomiting, metabolic acidosis, hypoglycemia, ketonuria and increased serum NH3

Commonly: Isovaleric acidemia Propionic acidemia Methylmalonic acidemia

Isovaleric acidemia sweaty feet urine due to accumulation of isovaleryl glycine w/o isovaleryl CoA

Organic Acidemias

Indicanuria Due to obstruction, abnormal bacteria present,

malabsorption syndromes, Hartnup disease “Blue diaper syndrome”

5-hydroxyindoleacetic acid (5-HIAA) Carcinoid tumors involving argentaffin excess amounts

of serotonin increased urinary 5-HIAA levels Addition of nitrous acid and 1-nitroso-2-naphthrol purple

to black urine >25 mg/24h indicates tumor

Amino Acid Disorders (Tryptophan Disorders)

Cystine Disorders (Sulfur-like odor urine)

Cystinuria Inability of renal tubules

to reabsorb cystine Only amino acid found

during analysis of calculi Has two modes of

inheritance Poor reabsorption of all

four amino acids—cystine, lysine, arginine, and ornithine

cystine and lysine are not reabsorbed

Tested by cyanide-nitroprusside test red-purple color

Cystinosis Genuine IEM, can be

nepropathic/non-nepropathic Subdivided as infantile

and late-onset cystinosis

Defect in lysosomal membranes

Leads to crystalline deposits in cornea, bone marrow, lymph nodes, and internal organs

Fanconi syndrome Renal transplants and cystine-

depleting meds – extend lives from renal failure

Nonnephropathic – benign but may cause ocular disorders

Infantile nephropathic cystinosis Lab dx: poluria, generalized

aminoaciduria, (+) Clinitest for reducing substances, lack of urinary concentration

Cystinosis (cont’d)

Defect in metabolism of methionine Leads to failure to thrive, cataracts and mental

retardation, thromboembolic problems, and death (+) with cyanide-nitroprusside test Silver nitroprusside test – confirms presence Thromboembolism is related with:

Endothelial cell damage Smooth muscle cell proliferation Lipid peroxidation Upregulation of prothrombotic factors (XII and V) Downregulation of antithrombotic factors or endothelial-

derived nitric oxide

Homocystinuria

Porphyrin – heme intermediate Free erythrocyte protoporphyrin CDC

screening test for Pb poisoning Pophyrias commonly due to lead

poisoning, excessive alcohol intake, iron deficiency, chronic liver disease and renal disease

Rarity: Inherited porphyrias > Acquired

Related with vampirism

Porphyrin Disorders

Laboratory Diagnosis Ehrlich reaction - can be

used only for the detection of ALA and porphobilinogen

Watson-Schwartz reaction - differentiation between the presence of urobilinogen and porphobilinogen

Hoesch Test Fluorescence tests – does

not distinugish porphyrins

Mucopolysaccharide Disorders Mucopolysaccharides aka glycosaminoglycans

Incomplete breakdown of polysacchride portion in lysosomes of CT

Usually found in urine as dermatan, keratan and heparan sulfates.

Hurler syndrome – skeletal structure and mental retardation; cornea

Hunter syndrome – rarely seen in females, Sanfilippo syndrome – only mental retardation

Bone marrow transplants and gene replacement therapy U/A: Acid-Albumin, Cetyltrimethylammonium bromide

(CTAB) turbdity tests and metachromatic staining spot tests

Mucopolysaccharidosis

Purine and CHO Disorders Lesch-Nyhan Disease

Inherited, sex-linked recessive Without enzyme hypoxanthine guanine

phosphoribosyltransferase Sx: severe motor defects, mental retardation, tendency

towards self destruction, gout and renal calculi. Uric acid like orange sand in diapers

Melituria Pentosuria Galactosuria – failure to thrive, liver disorders, cataracts and

severe mental retardation Deficiency in GALT, galactokinase, UDP-galactose-4-epimerase

Lactosuria Fructosuria