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6 Urea 䈀氀漀漀搀 唀爀攀愀 一椀琀爀漀最攀渀 and Uric Acid

6 Urea 䈀氀漀漀搀 唀爀攀愀 一椀琀爀漀最攀渀 and Uric Acid

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proteins and amino acids. This takes place in the liver. First, ammonia is

formed, and then it is eventually converted into urea. The kidneys are the primary route for excretion of urea, and account for over 90% of urea excretion.

Minor loss of urea takes place through the gastrointestinal tract and skin.

Urea is freely filtered at the glomerulus and is subsequently not reabsorbed

or secreted at the tubules. However, measurement of urea levels is inferior

when assessing renal function (as compared to creatinine levels) because

serum or plasma concentration of urea may be increased in the following

situations:













Dehydration.

Hypoperfusion of the kidneys.

High-protein diet.

Protein catabolism.

Steroid administration.



Under a similar situation, serum creatinine is not elevated (normal range:

0.5À1.2 mg/dL). However, measuring the urea level along with creatinine is

of clinical relevance. The urea level in blood is usually measured as blood

urea nitrogen (BUN), with a normal level between 6 and 20 mg/dL. The following criteria are usually used to interpret the BUN/creatinine ratio:









The BUN/creatinine ratio for normal individuals is usually from 12:1 to

20:1. For example, if BUN is 15 mg/dL and creatinine is 1.1 mg/dL, then

BUN/creatinine ratio is 13.6.

A BUN/creatinine ratio below 10:1 may indicate intrinsic renal disease. A

BUN/creatinine ratio above 20:1 may be indicative of hypoperfusion of

the kidney, including pre-renal failure.



Acute kidney injury can be the result of pre-renal, renal, and post-renal

causes. In critically ill patients with renal hypoperfusion but intact tubular

function (pre-renal azotemia), BUN concentration may increase out of proportion to serum creatinine concentration; the BUN/creatinine ratio may

exceed 20:1. However, critically ill patients are also prone to accelerated protein catabolism, which can also increase the BUN/creatinine ratio without

pre-renal azotemia [8]. The BUN/creatinine ratio is not a precise test because

the ratio can be altered under many conditions other than kidney diseases.

The increase of serum creatinine is a better indicator of declining renal

function.

In humans, purines break down into xanthine and hypoxanthine, and then

xanthine oxidase transforms these compounds into uric acid (which is

excreted in the urine). The normal uric acid level in serum is 2.6 to 6.0 in

females and 3.5 mg/dL to 7.2 mg/dL in males. Eating purine-rich foods such

as liver, anchovies, mackerel, dried beans, and peas, as well as drinking



11.7 Protein in Urine and Proteinuria



alcohol, can elevate serum uric acid levels. Some drugs, such as diuretics, can

also increase uric acid levels in serum or plasma (uric acid is an antioxidant).

However, an increased uric acid level in the blood can be associated with

gout and can cause the formation of renal stones. However, the serum level

of uric acid may also be elevated due to decreased renal function as observed

in patients with renal failure. LeschÀNyhan syndrome is a rare genetic disease associated with high serum uric acid due to deficiency of the hypoxanthineÀguanine phosphoribosyl transferase enzyme.



11.7 PROTEIN IN URINE AND PROTEINURIA

Molecules less than 15 kDa pass freely into urine through glomerular filtration whereas a selected few proteins with molecular weights between 16 and

69 kDa can also be filtered by the kidney. The molecular weight of albumin,

the major protein found in serum, is 67 kDa, and, as expected, a very small

amount of albumin is also found in the urine of normal individuals.

Glomerular filtration of a protein depends on several factors, including the

molecular weight of the protein, its concentration in serum, its charge, and

its hydrostatic pressure. Although 90% of these proteins are reabsorbed

(smaller proteins are effectively absorbed by the renal tubule), the following

proteins can pass through the glomerular filtration process:















Albumin.

Alpha-1 acid glycoprotein (orosomucoid).

Alpha-1-microglobulin.

Beta-2-microglobulin.

Gamma trace protein.

Retinol binding protein.



Normally, total urinary protein is ,150 mg/24 h and consists of mostly albumin and TammÀHorsfall protein (secreted from the ascending limb of the

Loop of Henlé). The extent of proteinuria can be assessed by quantifying the

amount of proteinuria as well as by expressing it as the protein-to-creatinine

ratio. A normal ratio is as follows:







Adults: , 0.2

Children 6 months to 2 years ,0.5; and older than 2 years ,0.25.



Proteinuria with minor injury (typically only albumin is lost in the urine)

can be due to vigorous physical exercise, congestive heart failure, pregnancy,

certain drug therapies, high fever, and alcohol abuse. Proteinuria can be classified into glomerular, tubular, and combined proteinurias. Glomerular proteinuria can be sub-classified as selective (albumin and transferrin in urine)



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and non-selective (all proteins are present). In glomerular proteinuria, albumin is always the major protein.

In mild glomerular proteinuria, total protein concentration is usually within

1,500 mg/24 h of urine, but with moderate glomerular proteinuria, the total

protein level can be 1,500À3,000 mg/24 h. In the case of non-selective proteinuria, total protein in urine often exceeds 3,000 mg/24 h.

Total protein/creatinine ratio is also useful in grading proteinuria:









Low-grade proteinuria: 0.2À1.0

Moderate proteinuria: 1.0À5.0

Non-selective proteinuria: . 5.0.



The major difference between glomerular and tubular proteinuria is the difference between the molecular weight ranges of protein found in urine. In

glomerular proteinuria, albumin is the major component found in urine,

while in tubular proteinuria, albumin is a minor component; proteins with

smaller molecular weight, such as alpha-1 microglobulin and beta-2 microglobulin, are the major proteins found in urine. In mixed-type proteinuria,

both albumin and low-molecular-weight proteins such as alpha-1 microglobulin and beta-2 microglobulin are present [9].



11.8 OTHER RENAL DISEASES

Acute and chronic renal failure, acute nephritis, and nephrotic syndrome represent commonly observed renal diseases. Drug-induced renal injury also

represents a frequent clinical entity. The most common drugs encountered in

renal failure include vancomycin, aminoglycosides, amphotericin B, cyclosporine, and radiographic contrast agents. Various renal diseases are summarized in Table 11.2.



CASE REPORT

A 48-year-old woman with a diagnosis of hypertension for

2 years and hyperlipidemia for 10 months showed a steadily

increased creatinine level from 0.7 mg/dL to 1.8 mg/dL over a

period of 8 months. Her medications included hydrochlorothiazide (12.5 mg/day) for hypertension and fenofibrate (200 mg/

day) for reducing cholesterol. Because of the increasing creatinine related to fenofibrate therapy, the drug was



discontinued and her creatinine level returned to normal in a

few months [10]. The precise mechanism by which fenofibrate therapy results in increased levels of creatinine (which

is reversible upon discontinuation of therapy) is not fully

understood. However, it has been speculated that fenofibrate

therapy may impair GFR in certain patients.



11.9 Laboratory Measurements of Creatinine and Related Tests



Table 11.2 Various Renal Disorders

Disease



Comments



Acute renal failure (ARF)



ARF is the sudden deterioration of renal function that can be broadly divided

into pre-renal, renal, and post-renal subtypes. The pre-renal subtype is

associated with hypoperfusion of the kidneys. Renal causes include

glomerulonephritis and interstitial nephritis. Post-renal causes are related to

obstructive uropathy.

Tubulointerstitium is damaged due to various agents such as drugs,

infections, and immunological injuries.

Necrosis of renal tubules may be related to hypoperfusion and hypoxia.

Patient undergoes three phases: oliguric phase, polyuric phase, and, finally,

phase of recovery.

Defined as chronic and progressive loss of renal function. Based on the GFR

it is divided into 5 stages (stage 5 with the lowest GFR, see Table 11.1).

Defined as proteinuria ( . 3 g/day), hypoalbuminemia, hypercholesterolemia,

and edema. Most common cause of nephritic syndrome in adults is

membranous glomerulonephritis, and common cause of nephrotic syndrome

in children is minimal lesion.

Defined as oliguria, hematuria with hypertension, and edema. Acute diffuse

glomerulonephritis is the leading cause of nephritic syndrome.

A group of disorders characterized by normal anion gap metabolic acidosis

with inappropriately high urine pH ( . 5.5 in early morning urine). Type I (distal)

is associated with decreased hydrogen ion secretion at the distal tubule. Type

II is associated with increased loss of bicarbonate from the proximal tubule. In

type IV (type III is discontinued) there is hyporeninemic hypoaldosteronism.



Acute interstitial nephritis

Acute tubular necrosis (ATN)



Chronic renal failure (CRF)/Chronic

kidney disease (CKD)

Nephrotic syndrome



Nephritic syndrome

Renal tubular acidosis



11.9 LABORATORY MEASUREMENTS OF

CREATININE AND RELATED TESTS

Plasma creatinine may be measured using either chemical or enzymatic

methods. Most chemical methods utilize the Jaffe reaction. In this method

creatinine reacts with picrate ion in an alkaline medium to produce an orangeÀred complex. The Jaffe reaction is not entirely specific for creatinine.

Substances such as ascorbic acid, high glucose, cephalosporins, and ketone

bodies can interfere with this method. High bilirubin (both conjugated and

unconjugated) may falsely lower the creatinine value (negative interference)

as measured by the Jaffe reaction. Enzymatic methods are also available for

serum creatinine determination. Enzymes commonly used for creatinine

determination are creatininase (also called creatinine deaminase) and creatinine hydrolase (also called creatinine aminohydrolase). Although enzymatic

creatinine methods are subject to less interference than the Jaffe method,

interferences in enzymatic methods have nevertheless been reported. The reference method for creatinine measurement is isotope dilution mass



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spectrometry. Liu et al. reported that although enzymatic methods are less

affected than creatinine determination using the Jaffe reaction in patients

undergoing hemodialysis, the gold standard for creatinine determination is

isotope dilution mass spectrometry, which is free from interferences [11].



CASE REPORT

A healthy 3-year, 4-month-old boy was brought into the pediatric emergency department by his parents after presumed

ingestion of model car fuel (Dynamite Blue Thunder, Horizon

Hobby, Inc., Champaign, IN). This car fuel contains nitromethane and methanol, and it was estimated that the boy ingested

only 5 mL of fuel. When examined in the emergency department, the patient was found to be alert and responsive with no

abnormality in respiration. His serum electrolytes, glucose,

and venous blood gas parameters were within normal ranges.

However, serum creatinine (measured by the Jaffe reaction)

was highly elevated (926 μmol/L, or 10.2 mg/dL), indicating

acute renal failure; but the patient was not as unwell as

expected from such high serum creatinine. His urea, however,

was only slightly elevated (4.7 mmol/L, or 28.3 mg/dL). The



initial methanol level was 4.2 mmol/L. The patient continued

to do well, and three hours later his creatinine level dropped to

817 μmol/L (9.0 mg/dL) and serum methanol dropped to

2.2 mmol/L. The patient received intravenous fluid and supportive therapy. Considering that creatinine values were

falsely elevated, specimens were sent to another hospital laboratory and the specimen that showed creatinine of 926 μmol/L

(10.2 mg/dL) showed a normal creatinine level of 29 μmol/L

(0.3 mg/dL) using an enzymatic method. Other elevated creatinine levels when reanalyzed by an enzymatic method showed

normal creatinine values. The authors concluded that falsely

elevated creatinine as measured by the Jaffe reaction was due

to interference of nitromethane present in the model car

fuel [12].



Blood urea can be measured by both chemical and enzymatic methods. Most

chemical methods are based on the “Fearon Reaction,” where urea reacts

with diacetyl-forming diazine (which absorbs at 540 nm). Enzymatic methods are based on hydrolysis of ureas by the enzyme urease and these reactions generate ammonia. Ammonia can be measured using the Berthelot

method or another enzymatic method such as with glutamate dehydrogenase. Ammonia can also be measured by conductometry.

Measurement of uric acid can be done by either a chemical or enzymatic

method. A commonly used colorimetric method employs phosphotungstic

acid, which is reduced by uric acid in alkaline medium to produce a blue

color (tungsten blue) that can be measured spectrophotometrically.

However, this method is subject to interferences, including interference from

endogenous compounds such as high glucose and ascorbic acid (vitamin C).

The enzymatic method based on uricase is more specific.



11.10 URINE DIPSTICK ANALYSIS

Urinalysis is a good screening tool for diagnosis of urological conditions

such as urinary tract infection, as well as sub-clinical kidney disease. Urine



Key Points



dipstick analysis is usually the first test performed during urinalysis, followed

by microscopic examination. Urine dipsticks are inexpensive paper or plastic

devices with various segments (reaction pads) capable of color change if a

particular substance of interest is present; such change in color can be compared to a color chart provided by the manufacturer for interpretation of

results. Usually test strips can detect the presence of glucose, bilirubin,

ketones, blood, protein, urobilinogen, nitrite, and leukocytes in the urine.

Specific gravity of urine and pH can also be roughly estimated using a dipstick. Normal specific gravity of urine is between 1.002 and 1.035, and pH is

between 4.5 and 8.0. On a typical Western diet, urine pH is around 6.0 [13].

The urine dipstick is very sensitive to the presence of red blood cells and free

hemoglobin. Negative or trace protein in urine is normal, but a value of 11

should be investigated further. Typically glucose does not appear in urine

unless plasma glucose is over 180 mg/dL to 200 mg/dL. A positive nitrite test

is indicative of bacteria in urine, and a urine culture is recommended. In

addition, a positive test for leukocyte esterase indicates the presence of neutrophils (neutrophils produce leukocyte esterase) due to infection or inflammation. However, both false positive and false negative test results may be

encountered with urine dipstick analysis. Major interferences include:

















A protein reaction pad of urine dipstick detects albumin in urine but

cannot detect BenceÀJones proteins. If urine is alkaline, a false positive

protein test result may occur.

A hemoglobin test pad can show a false positive result if myoglobin is

present.

A ketone reaction pad based on sodium nitroprusside can detect only

acetoacetic acid and is weakly sensitive to acetone, but cannot detect

beta-hydroxybutyric acid.

The presence of ascorbic acid (vitamin C) in urine can cause a false

negative dipstick test with glucose and hemoglobin. Such interference

may occur after taking vitamin C supplements or even fruit juice enriched

with vitamin C [14]. Most glucose test strips use a glucose oxidase-based

method where ascorbic acid can cause falsely lower values (negative

interference). However, in a glucometer that uses glucose dehydrogenase,

ascorbic acid can cause a false positive result (see Chapter 7).



KEY POINTS









The kidney has three important functions: excretory, regulatory, and endocrine

functions.

The kidney produces two important hormones: erythropoietin and renin.

Erythropoietin is produced in response to renal hypoxia and acts on the bone

marrow to stimulate erythropoiesis. Renin is produced by the juxtaglomerular



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apparatus. Renin converts angiotensinogen released by the liver into angiotensin I,

which is then converted into angiotensin II in the lungs by angiotensin-converting

enzyme (ACE). Angiotensin II is a vasoconstrictor and also stimulates release of

aldosterone from the adrenal cortex.

The kidney also produces an active form of vitamin D (1,25-dihydroxyvitamin D or

1,25-dihydroxycholecalciferol). A serum vitamin D level over 30 ng/mL is

considered adequate.

The basement membrane of capillaries serves as a barrier to passage of large

proteins into the glomerular filtrate. Molecules with a weight of more than 15

kilodaltons (kDa) are not found in the glomerular filtrate. The loop of Henlé is the

site where urine is concentrated.

GFR can be estimated with the formula: GFR 5 (Ua 3 V)/Pa. Ua is the

concentration of a solute in urine, V is the volume of urine in mL/minute, and Pa is

the concentration of the same solute in plasma.

Serum creatinine levels are affected by gender, age, weight, lean body mass, and

dietary protein intake (mol/L). Cystatin C is a low-molecular-weight protein

(13.3 kDa) that can be used for calculating GFR. In contrast to creatinine, plasma

concentrations of cystatin C are unaffected by sex, diet, or muscle mass.

Both creatinine clearance and cystatin C clearance may be used to evaluate

glomerular filtration rate, but cystatin C may be slightly superior to creatinine.

The CockroftÀGault formula is widely used for calculating GFR.

The CockroftÀGault formula: Creatinine Clearance 5 ((140 2 Age in years) 3

(Weight in kg))/(Serum Creatinine in μmol/L) 3 (1.23 if male or 1.04 if female).

However, in the U.S., creatinine concentration is expressed in mg/dL, and this

formula can be modified into: Creatinine Clearance 5 ((140 2 Age in years) 3

(Weight in kg))/(72 3 (Serum Creatinine in mg/dL)) 3 (0.85 if female).

The CockroftÀGault formula was modified to the MDRD formula by Modification

of Diet in Renal Disease Study Group as follows: Estimated GFR (mL/min/

1.73 m2) 5 186 3 (plasma creatinine in mg/dL)-1.154 3 Age-0.203 3 F.

In chronic renal disease, creatinine clearance is usually less than 60 mL/min/

1.73 m2, but a value below 15 mL/min is indicative of end-stage renal disease.

Fractional excretion of sodium over 3% may indicate acute tubular necrosis, but

less than 1% may indicate hypoperfusion of the kidney.

The BUN/creatinine ratio for normal individuals is usually from 12:1 to 20:1. A

BUN/creatinine ratio below 10:1 may indicate intrinsic renal disease. A BUN/

creatinine ratio above 20:1 may be because of hypoperfusion of the kidney,

including pre-renal failure.

Normally, total urinary protein is ,150 mg/24 h and consists of mostly albumin and

TammÀHorsfall protein (secreted from the ascending limb of the Loop of Henlé).

Proteinuria can be classified into glomerular proteinuria, tubular proteinuria, and

combined proteinuria. Glomerular proteinuria can be sub-classified as: selective



References





































(albumin and transferrin in urine) and non-selective (all proteins are present). In

glomerular proteinuria the major protein present is always albumin.

In tubular proteinuria, albumin is a minor component, but proteins with smaller

molecular weight such as alpha-1 microglobulin and beta-2 microglobulin are the

major proteins found in the urine. In mixed-type proteinuria both albumin and

low-molecular-weight proteins such as alpha-1 microglobulin and beta-2

microglobulin are present.

Plasma creatinine can be measured using chemical or enzymatic methods. Most

chemical methods utilize the Jaffe reaction. In this method creatinine reacts with

picrate ion in an alkaline medium to produce an orangeÀred complex.

The Jaffe reaction is not entirely specific for creatinine. Substances such as

ascorbic acid, high glucose, cephalosporins, and ketone bodies can interfere with

this method. High bilirubin (both conjugated and unconjugated) can falsely lower

the creatinine value (negative interference) measured by using the Jaffe reaction.

Usually test strips can detect the presence of glucose, bilirubin, ketones, blood,

protein, urobilinogen, nitrite, and leukocytes in the urine. The specific gravity of

urine and pH can also be roughly estimated using a dipstick.

Typically glucose does not appear in urine unless plasma glucose is over 180 mg/

dL to 200 mg/dL. A positive nitrite test is indicative of bacteria in urine and urine

culture is recommended. In addition, a positive test for leukocyte esterase

indicates the presence of neutrophils (neutrophils produce leukocyte esterase) due

to infection or inflammation.

A protein reaction pad of urine dipstick detects albumin in urine but cannot detect

BenceÀJones proteins. If urine is alkaline, a false positive protein test result may

occur.

A hemoglobin test pad can show a false positive result if myoglobin is present.

A ketone reaction pad based on sodium nitroprusside can detect only acetoacetic

acid and is weakly sensitive to acetone, but cannot detect beta-hydroxybutyric

acid.

The presence of ascorbic acid (vitamin C) in urine can cause a false negative

dipstick test with glucose and hemoglobin. Such interference may occur after

taking a vitamin C supplement or even fruit juice enriched with vitamin C. Most

glucose test strips use glucose oxidase-based methods where ascorbic acid can

cause falsely lower values (negative interference).



REFERENCES

[1] Khan KA, Akram J, Fazal M. Hormonal cations of vitamin D and its role beyond just a vitamin: a review article. Int J Med Mol Med 2011;3:65À72.

[2] Snyder S, Pendergraph B. Detection and evaluation of chronic kidney disease. Am Fam

Physician 2005;72:1723À32.

[3] Stevens L, Coresh J, Greene T, Levey AS. Assessing kidney function: measured and estimated

glomerular filtration rate. N Eng J Med 2006;345:2473À83.



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[4] National Kidney Foundation. K/DQQI clinical practice guidelines for chronic kidney

disease: evaluation, classification and stratification. Am J Kidney Dis 2002;39(Suppl. 2):

S1À266.

[5] Rosenthal SH, Bokenkamp A, Hoffmann W. How to estimate GDR serum creatinine, serum

cystatin C or equation? Clin Biochem 2007;40:153À61.

[6] Hojs R, Bevc S, Ekhart R, Gorenjak M, et al. Serum cystatin C based equation compared to

serum creatinine based equations for estimation of glomerular filtration rate in patients

with chronic kidney disease. Clin Nephrol 2008;70:10À7.

[7] Yap L, Lamarche J, Peguero A, Courville C. Serum cystatin C verus serum creatinine in the

estimation of glomerular filtration rate in rhabdomyolysis. J Ren Care 2011;37:155À7.

[8] Rachoin JS, Dahar R, Moussallem C, Milcarek B, et al. The fallacy of the BUN: creatinine

ratio in critically ill patients. Nephrol Dial Transplant 2012;27:2248À54.

[9] Lillehoj EP, Poulik MD. Normal and abnormal aspects of proteinuria: Part I: Mechanisms,

characteristics and analyses of urinary protein. Part II: Clinical considerations. Exp Pathol

1986;29:1À28.

[10] Samara M, Abcar AC. False estimate of elevated creatinine. Perm J 2012;16:51À2.

[11] Liu WS, Chung YT, Yang CY, Lin CC, et al. Serum creatinine determined by Jaffe, enzymatic

methods and isotope dilution liquid chromatography-mass spectrometry in patients under

hemodialysis. J Clin Lab Anal 2012;26:206À14.

[12] Killorn E, Lim RK, Rieder M. Apparent elevated creatinine after ingestion of nitromethane:

interference with the Jaffe reaction. Ther Drug Monit 2011;33:1À2.

[13] Patel H. The abnormal urinalysis. Pediatr Clin N Am 2006;53:325À7.

[14] Brigden ML, Edgell D, McPherson M, Leadbeater A, et al. High incidence of significant urinary ascorbic acid concentrations in west coast population-implications for routine urinalysis. Clin Chem 1992;38:426À31.



CHAPTER 12



Inborn Errors of Metabolism



12.1 OVERVIEW OF INBORN ERRORS OF

METABOLISM

Congenital metabolic disorders are a class of genetic diseases that result from

lack of (or abnormality of) an enzyme or its cofactor that is responsible for a

clinically significant block in a metabolic pathway. As a result, abnormal

accumulation of a substrate or deficit of the product is observed. In the

majority of cases this is due to a single gene defect that encodes a particular

enzyme important in the metabolic pathway. All inborn errors of metabolism are genetically transmitted, typically in an autosomal recessive or

X-linked recessive fashion. Although individual inborn errors of metabolism

are rare genetic disorders, over 500 human diseases related to inborn errors

of metabolism have been reported. Therefore, collectively inborn errors of

metabolism affect more than one baby out of 1,000 live births [1]. Children

with inherited metabolic disorders most likely appear normal at birth

because metabolic intermediates responsible for the disorder are usually

small molecules that can be transported by the placenta and then eliminated

by the mother’s metabolism. However, symptoms usually appear due to

accumulation of metabolites days, weeks, or months after birth, and very

rarely a few years after birth. Although clinical presentation may vary, infants

with metabolic disorders typically present with lethargy, decreased feeding,

vomiting, tachypnea (related to acidosis), decreased perfusion, and seizure.

With progression of the disease, infants may be presented to the hospital

with stupor or coma. Metabolic screening must be initiated in any infant suspected of inborn errors of metabolism; elevated plasma ammonia level,

hypoglycemia, and metabolic acidosis are indications of inborn errors of

metabolism. Therefore, presenting clinical features of inborn errors of metabolism, although variable, may include:







Failure to thrive, weight loss, delayed puberty, precocious puberty.

Recurrent vomiting, diarrhea, abdominal pain.



A. Dasgupta and A. Wahed: Clinical Chemistry, Immunology and Laboratory Quality Control

DOI: http://dx.doi.org/10.1016/B978-0-12-407821-5.00012-7

© 2014 Elsevier Inc. All rights reserved.



CONTENTS

12.1 Overview of

Inborn Errors of

Metabolism .............. 213

12.2 Amino Acid

Disorders .................. 214



12.2.1

Phenylketonuria ... 214

12.2.2 Maple Syrup

Urine Disease

(MSUD) .................. 214

12.2.3 Other Amino

Acid Disorders...... 216

12.3 Carbohydrate

Metabolism

Disorders .................. 217



12.3.1

Galactosemia ........ 217

12.3.2 Glycogen

Storage Disease.... 217

12.3.3 Fructose

Intolerance ............ 218

12.3.4 Lactose

Intolerance ............ 218

12.4 Urea Cycle

Disorders .................. 218

12.5 Organic Acid

Disorders (Organic

Aciduria)................... 219

12.6 Fatty Acid

Oxidation Disorders 220

12.7 Mitochondrial

Disorders .................. 221



213



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12.8 Peroxisomal

Disorders .................. 221







12.9 Lysosomal

Storage Disorders.... 221







12.10 Purine or

Pyrimidine Metabolic

Disorders .................. 223

12.11 Disorders of

Porphyrin

Metabolism .............. 223

12.12 Newborn

Screening and

Evaluation ................ 224















Neurologic features such as seizures and stroke.

Organomegaly such as lymphadenopathy and hepatosplenomegaly.

Dysmorphic features.

Cytopenias.

Heart failure.

Immunodeficiency.



Currently, newborn screenings are performed in many states to potentially

identify any of 40 of the most commonly encountered inborn errors of

metabolism, preferably using the new technology of tandem mass spectrometry. Common inborn errors of metabolism are listed in Table 12.1.



Key Points ................ 225

References ............... 227



12.2 AMINO ACID DISORDERS

Amino acids are an integral part of proteins and may also act as substrates

for gluconeogenesis. Out of twenty amino acids, nine of them are essential

because they cannot be synthesized by the human body. In a patient with

amino acid disorders, accumulation of amino acids in the blood is a common feature, and, as expected, increased excretion of amino acids is observed

in urine. Common amino acid disorders are phenylketonuria and maple

syrup urine disease.



12.2.1 Phenylketonuria

Phenylketonuria is due to deficiency of phenylalanine hydroxylase enzyme,

which converts phenylalanine into tyrosine. As a result, phenylalanine accumulates in the circulation and is then converted to phenylpyruvate, a phenyl

ketone that is eventually excreted in the urine. Phenylketonuria is an autosomal recessive disorder caused by a mutation in the gene that is responsible

for coding of phenylalanine hydroxylase. A sustained phenylalanine concentration greater than 20 mg/dL (1,211 µmol/L) correlates with classical symptoms of phenylketonuria such as mental retardation, impaired head

circumference growth, poor cognitive function, and lighter skin pigmentation. The disease is mild if phenylalanine concentration is in the range of

9.9À19.9 mg/dL (600À1,200 µmol/L). The phenylalanine-to-tyrosine ratio is

also used for diagnosis of phenylketonuria; this ratio is helpful in reducing

false positive rates. Treatment consists of a phenylalanine-restricted diet.



12.2.2 Maple Syrup Urine Disease (MSUD)

Maple syrup urine disease is a metabolic disorder caused by a deficiency of the

branched-chain alpha-keto acid dehydrogenase complex that results in accumulation of branched-chain amino acids including leucine, isoleucine, and

valine. The urine of such patients has an odor like maple syrup, thus the name



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