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9 Alcohol- and Drug-Induced Liver Disease

9 Alcohol- and Drug-Induced Liver Disease

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10.11 Liver Disease in Neonates and Children



dehydration (morning sickness). The cause of this condition is still controversial, but it may be related to hormonal changes during pregnancy, most

likely an elevated concentration of human chorionic gonadotropin. This condition may also be accompanied by mild jaundice and a mild elevation of

liver enzymes.

Intrahepatic cholestasis of pregnancy is a liver-specific disorder characterized

by maternal pruritus (itching) observed (usually) in the third trimester. The

etiology of this disease is not fully elucidated, but may occur due to cholestatic effects of reproductive hormones such as estrogen. The mechanism by

which this condition leads to fetal complication is not understood. Severe

pruritus may or may not be accompanied by jaundice. This condition may

resolve after pregnancy, but can reappear during subsequent pregnancies [9].

Acute fatty liver of pregnancy is a rare but potentially life-threatening condition that usually occurs in the third trimester with a mean gestational age of

35À36 weeks (the range is 28À40 weeks) or may also be observed in the

early postpartum period. Although exact etiology is not known, this disease

may be linked to an abnormality in fetal fatty acid metabolism. However,

diagnosis is challenging because this condition can appear similar to conditions encountered in preeclampsia, viral hepatitis, or cholestasis of pregnancy. Supportive care and expeditious delivery are required to minimize

adverse maternal and fetal outcomes [10]. Fulminant hepatic failure in late

pregnancy is also a very serious condition that can be potentially fatal.

HELLP syndrome (H, hemolysis; EL, elevated liver enzyme; LP, low platelet

count) is a serious complication of pregnancy that occurs most commonly in

patients with severe preeclampsia or eclampsia. Unconjugated hyperbilirubinemia without encephalopathy may also be observed in HELLP syndrome.

HELLP syndrome usually develops around 37 weeks of gestation or following delivery.



10.11 LIVER DISEASE IN NEONATES AND

CHILDREN

Physiological jaundice is observed in neonates due to decreased activity of

UDP-glucuronosyltransferase enzyme leading to unconjugated hyperbilirubinemia. It affects approximately 65% of newborns in the first week of life

[11]. Breast milk may have inhibitors to this enzyme, causing unconjugated

hyperbilirubinemia (also referred as breast milk jaundice). Physiological

jaundice can be treated with phototherapy, but if it persists for more than

two weeks after birth, a possible pathological cause of such jaundice must be

investigated. Neonatal hepatitis can occur due to infection with cytomegaly

virus (CMV), rubella, or toxoplasma. Biliary atresia can also cause jaundice



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in infants. Metabolic disorders such as tyrosinemia and galactosemia can

also cause jaundice. Progressive familial intrahepatic cholestasis (PFIC) refers

to a group of familial cholestatic conditions caused by defective biliary epithelial transporters. The clinical features usually appear first in childhood

with progressive cholestasis and hepatic failure. A patient may eventually

need a liver transplant. These heterogenous groups of conditions are inherited in autosomal recessive fashion. Alagille syndrome is a genetic disorder

affecting the liver, heart, kidney, and other organs, and problems associated

with this disorder first appear in infancy or early childhood. The disorder is

inherited in an autosomal dominant manner with an estimated prevalence

of 1 in every 100,000 live births. Facial dysmorphism, cardiac abnormalities,

and cholestasis are common features of this disorder.



10.12 MACRO LIVER ENZYMES

On rare occasions, isolated and unexplained elevated levels of liver enzymes

such as AST are observed which are due to AST binding with serum IgG. This

bound enzyme is referred as macro AST. Binding of ALT with IgG has also been

reported. Another enzyme that can bind to IgG is creatinine kinase (CK), giving

rise to macro CK. This phenomenon of macro enzymes is seen more frequently

in the elderly population, but macro AST may also be seen in children. There is

also an association between macro enzymes and autoimmune diseases. Macro

AST may also be detected in patients with chronic hepatitis or malignancy.

Laboratory detection of macro enzyme can be done by gel filtration chromatography, ultracentrifugation, or polyethylene glycol precipitation.



CASE REPORT

A 27-year-old female was admitted to the gastroenterology

department of the hospital because of isolated elevated AST for

more than 1.5 years. Physical examination revealed a healthy

woman with no apparent abnormality. Her abdomen was normal without hepatomegaly, tenderness, or abnormal peristalsis.

Her AST was elevated to 740 U/L, but ALT (23 U/L), LFH

(424 U/L), alkaline phosphatase (49 U/L), and GGT (17 U/L)



were within normal limits. No hemolysis was detected and the

presence of macro AST was suspected by the gastroenterologist. Precipitation of serum with polyethylene glycol followed by

measurement of the supernatant where no AST was

detectable suggested the presence of macro AST. The clinician

decided that her isolated elevated AST was due to macro

AST [12].



10.13 LABORATORY MEASUREMENT OF BILIRUBIN

AND OTHER TESTS

For determination of bilirubin, it is important to protect the specimen from

light because conjugated and unconjugated bilirubin is photooxidized. If the



Key Points



specimen is stored in the refrigerator, bilirubin is stable up to 3 days, and if

stored at 270 C in the dark, the specimen may be stable up to 3 months.

For measuring conjugated bilirubin (direct bilirubin), serum or plasma is

acidified with hydrochloric acid and then mixed with diazotized sulfanilic

acid to produce azobilirubin. Then the reaction is stopped with ascorbic acid

and the solution is made alkaline; azobilirubin produces a more intense blue

color, which is measured colorimetrically. This is called direct bilirubin,

which is the concentration of conjugated bilirubin in serum or plasma. For

determination of total bilirubin, caffeine is added to serum or plasma in

order for less reactive unconjugated bilirubin to react with diazotized sulfanilic acid. The solution after incubation is made alkaline for colorimetric measurement. This is referred to as “total bilirubin” and subtracting total

bilirubin from direct bilirubin provides the value of unconjugated bilirubin

(“indirect bilirubin”). This method is referred to as the Jendrassik and Grof

method. It is usually assumed that direct bilirubin measures mostly conjugated bilirubin species, mono and di-conjugated bilirubin, as well as delta

bilirubin (bilirubin tightly bound to albumin), while the total bilirubin

method measures both conjugated and unconjugated bilirubin.

In neonates, heel puncture is painful and distressing. Therefore, bilirubin can

be monitored with a transcutaneous bilirubin analyzer such as BiliChek,

which is a handheld fiberoptic device that measures three wavelengths by

spectral reflectance to measure bilirubin, melanin, and hemoglobin. This

method accounts for differences in skin pigment.

Liver biopsy is often done to establish a diagnosis of cirrhosis. Liver biopsy is

a procedure not without risks. There is significant interest in development of

tests that allow clinicians to avoid performing a liver biopsy. One such test

measures levels of procollagen type (III) peptide (PIIINP) in blood. Levels

are increased in cirrhosis. However, levels can also be increased in inflammation and necrosis.



KEY POINTS









Hypoalbuminemia is commonly found in chronic liver disease. In addition to

albumin, all clotting factors, with the exception of Factor VIII, are produced in the

liver. In significant liver disease, such as fulminant hepatic failure, urea levels may

also be low. The liver releases glucose into the circulation by glycogenolysis and

gluconeogenesis. In significant liver disease hypoglycemia may be apparent due

to depletion of the glycogen supply.

The liver is the site for bilirubin metabolism. Heme, derived from the breakdown of

hemoglobin, is converted to biliverdin and finally into bilirubin, which is waterinsoluble unconjugated bilirubin. Unconjugated bilirubin can also bind with serum

proteins, most commonly albumin. Unconjugated bilirubin is also taken up by the



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liver, and, with the help of UDP (uridine-50 diphosphate)glucuronyl transferase, is

converted to conjugated bilirubin (bilirubin conjugated with glucuronide). This

conjugation takes place in the smooth endoplasmic reticulum of the hepatocyte.

Conjugated bilirubin is water-soluble and is excreted in bile. It is measured in the

clinical laboratory as direct bilirubin. Subtracting total bilirubin from the direct

bilirubin value provides the concentration of unconjugated bilirubin (also referred to

as indirect bilirubin). In the intestine, bacterial enzymes hydrolyze conjugated

bilirubin and release free bilirubin, which is reduced to urobilinogen. Urobilinogen

bound to albumin is excreted in the urine. Some urobilinogen is converted to

stercobilinogen in the intestine and is excreted in stool. Thus, in normal urine,

urobilinogen is only present, and in normal stool, stercobilinogen is present. In

obstructive (cholestatic) jaundice, conjugated bilirubin regurgitates into blood and,

as it is water-soluble, passes into the urine. This is called choluria or the “presence

of bile in urine.” In obstructive jaundice, less conjugated bilirubin is taken up by the

intestine and, as a result, a smaller amount of stercobilinogen is found in the stool

(pale stool). Normal individuals have mostly unconjugated bilirubin in their blood,

urobilinogen in their urine, and stercobilinogen in their stool.

Breakdown of hepatocytes results in the release of aminotransferases (also referred

to as transaminases) such as ALT and AST into the blood. ALT is a cytosol

enzyme and more specific for liver disease. AST is primarily a mitochondrial

enzyme that is also found in the heart, muscle, kidney, and brain.

Alkaline phosphatase (ALP) is found in liver, bone, intestine, and placenta. ALP is

located in the canalicular and sinusoidal membrane of the liver. Production of

alkaline phosphatase is increased during cholestasis (intrahepatic or extrahepatic),

resulting in elevated activity of ALP in serum; however, it is important to

determine if the source of ALP is the liver or other organs. If alkaline phosphatase

is raised, and the question is whether the source of this enzyme is from the liver or

not, measurement of GGT or 50 -nucleotidase levels can be used to determine if the

source of ALP is liver or not because both GGT and 50 -nucleotidase are solely

produced by the biliary epithelium. Gamma glutamyl transferase (or gammaglutamyl transpeptidase, GGT) is a microsomal enzyme.

In acute liver disease without cholestasis, levels of ALT and AST are significantly

elevated and ALP is raised but usually less than three times normal. Therefore, ALT

and AST levels exceeding 500 U/L are a common finding in acute liver disease.

In acute cholestasis, ALT and AST are raised but levels are not very high. ALP is

usually more than three times normal with a parallel increase in GGT levels.

In acute liver disease, total protein and albumin levels are unaltered.

PT is the best test to assess the extent of liver dysfunction.

In chronic liver disease, albumin levels are low, but total protein may be elevated.

Elevated ALP with normal bilirubin, ALT, and AST may be seen in patients with

hepatic metastasis or bone metastasis. Patients with hepatic metastasis may also

have elevated GGT.



Key Points













































Elevated ALP in children is most likely related to osteoblastic activity in their

growing bones.

Isolated elevated ALP in the elderly is a characteristic feature of Paget’s disease.

Very high isolated ALP levels can be seen in primary biliary cirrhosis.

Normal liver function tests (except elevated GGT) are a characteristic of excessive

alcohol intake. Certain drugs (e.g. warfarin, anti-convulsants) may also produce

similar observation.

Gilbert’s syndrome is the most common familial hyperbilirubinemia and affects

2À7% of the population; this disease is transmitted as autosomal dominant. The

cause of Gilbert’s syndrome is mutation of the UGT1A1 gene that codes the

uridine diphosphate glucuronosyltransferase (UDP-glucuronosyltransferase)

enzyme essential for glucuronidation of bilirubin (conjugated bilirubin) for

excretion. In addition, there is evidence for reduced hepatic uptake of

unconjugated bilirubin. As a result, serum bilirubin is elevated due to increased

concentration of unconjugated bilirubin.

CriglerÀNajjar syndrome is a rare autosomal recessive condition caused by

complete absence of UDP-glucuronosyltransferase enzyme in Type I, or severe

deficiency of this enzyme in Type II.

DubinÀJohnson (autosomal recessive) and Rotor’s syndrome (possibly autosomal

dominant) are due to impaired excretion of conjugated bilirubin from the

hepatocytes. Both conditions result in conjugated hyperbilirubinemia.

Hepatitis B virus is a DNA virus but hepatitis A, C, D, and E are all RNA viruses.

Hepatitis A and E are transmitted by the fecalÀoral route. Hepatitis B, C, and D

are transmitted parenterally, vertically, and during sex.

Hepatitis B, C, and D can cause chronic liver disease. However, with acute

infection with hepatitis A and E, most patients recover; the mortality rate with

hepatitis A is less than 1%, while with hepatitis E it is 1À2%. However, the

mortality rate increases to 10À20% in pregnant patients with hepatitis E.

Approximately 90% or more of patients with acute infection of hepatitis B

eventually clear the virus and achieve immunity. The rest are at risk of developing

chronic liver disease and possibly hepatocellular carcinoma. In contrast, 50À70%

of patients with hepatitis C infection fail to clear the virus and these patients are

at risk for chronic liver disease and possibly hepatocellular carcinoma. Hepatitis D

infection occurs either as a co-infection with hepatitis B, or as a superinfection in

a hepatitis B-infected, hepatitis B surface antigen (HBsAg)-positive patient.

However, concurrent infection of hepatitis B and hepatitis D results in a poor

outcome of hepatitis B infection in a patient.

In chronic liver disease, moderate to severe hypoalbuminemia is commonly

observed, but other liver function tests may be normal or abnormal depending on

the severity of illness. However, serum gammaglobulins may be increased along

with increased IgA levels. This feature is manifested in serum protein

electrophoresis as polyclonal hypergammaglobulinemia with beta gamma

bridging, as IgA travels at the junction of the beta and gamma bands.



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In autoimmune liver disease, anti-nuclear antibody (ANA), anti-smooth muscle

actin, anti-soluble liver antigen, and anti-liver/kidney microsomal antibodies may

be present. IgG levels may be raised.

Primary biliary cirrhosis is mostly seen in women. Anti-mitochondrial antibodies

are found in most patients. IgM levels are often raised. Pruritus preceding other

features is a characteristic finding as well as secondary hyperlipidemia.

Primary or hereditary hemochromatosis is transmitted as autosomal recessive.

Hemochromatosis is a multisystemic disease with bronze discoloration of skin

(due to melanin deposition) and diabetes mellitus. This disease is also referred to

as bronze diabetes.

Hypogonadism due to pituitary dysfunction is the most common endocrine

feature. It can cause cardiomyopathy with heart failure and cardiac arrhythmias.

Pseudo gout due to deposition of calcium pyrophosphate dihydrate (CPPD)

crystals is a common feature. Iron stores, as well as liver iron content, may also be

increased. Other causes of increased liver iron content include alcohol intake and

iron overload due to chronic transfusion.

Wilson’s disease is transmitted as an autosomal recessive disorder. Normally

copper is incorporated into apo-ceruloplasmin to form ceruloplasmin, but this

process is defective in Wilson’s disease. The unbound free copper may be

secreted in the urine (urinary copper is high) and may also be deposited in certain

tissues, including the liver, basal ganglia, and cornea. Quantification of liver

copper may be done and should be high. Other causes of increased liver copper

include chronic cholestasis. KayserÀFleischer ring is a greenish brown pigment at

the sclera corneal junction due to deposition of copper in the Descemet’s

membrane in the cornea. Wilson’s disease is an important cause of acute liver

disease in young people.

Alpha-1 antitrypsin deficiency can cause liver disease as well as panacinar

emphysema. Serum alpha-1 antitrypsin levels are low, which could be evident in

serum protein electrophoresis. Genetic variants of alpha-1 antitrypsin are

characterized by their electrophoretic mobilities as medium (M), slow (S), and very

slow (Z). Normal individuals are MM. Homozygotes are ZZ and heterozygotes are

either MZ or SZ.

The liver is the major site of drug metabolism. Drugs are converted into more

water-soluble forms through drug metabolism so that drug metabolites can be

excreted in bile or urine. Drugs that cause liver damage may do so in a dosedependent or dose-independent manner. An example of a drug causing dosedependent hepatotoxicity is acetaminophen. Interestingly, alcoholics can

experience acetaminophen toxicity from a therapeutic dose of acetaminophen.

However, acetaminophen toxicity can be treated with N-acetylcysteine that can

restore the liver glutathione supply.

HELLP syndrome is accompanied by hemolysis, elevated liver enzymes, and low

platelet count, and is a serious complication of pregnancy that occurs most

commonly in patients with severe preeclampsia or eclampsia. Unconjugated



References







hyperbilirubinemia without encephalopathy may also be observed in HELLP

syndrome. HELLP syndrome usually develops around 37 weeks of gestation or

following delivery.

On rare occasions, isolated and unexplained elevated levels of liver enzymes such

as AST are observed. This is due to binding of AST with serum IgG. This bound

enzyme is referred to as macro AST. Binding of ALT with IgG has also been

reported. Another enzyme that may bind to IgG is creatinine kinase (CK), giving

rise to macro CK. This phenomenon of macro enzymes is seen more frequently in

the elderly population, but macro AST may also be seen in children. There is an

association between macro enzyme and autoimmune diseases. Macro AST may

also be detected in patients with chronic hepatitis or malignancy.



REFERENCES

[1] Tynjala J, Kangastupa P, Laatikainen T, Aalto M, et al. Effect of age and gender on the relationship

between alcohol consumption and serum GGT: time to recalibrate goals for normal ranges.

Alcohol Alcohol 2012;47:558À62.

[2] Lee WC, Kuo LC, Cheng YC, Chen CW, et al. Combination of white blood cell count with liver

enzymes in the diagnosis of blunt liver laceration. Am J Emerg Med 2010;28:1024À9.

[3] Ritchie AH, Willscroft DM. Elevated liver enzymes as a predictor of liver injury in

stable blunt abdominal trauma patients: case report and systematic review of the literature.

Can J Rural Med 2006;11:283À7.

[4] Schwertner HA, Vitek L. Gilbert syndrome UGT1A1*28 allele and cardiovascular disease

risk: possible protective effects and therapeutic applications of bilirubin. Atherosclerosis

2008;198:1À11.

[5] Passuello V, Puhl AG, Wirth S, Steiner E, et al. Pregnancy outcome in maternal CriglerNajjar syndrome Type II: a case report and systematic review of literature. Fetal Diagn Ther

2009;26:121À6.

[6] Winger J, Mchelfelder A. Diagnostic approach to the patients with jaundice. Prim Care Clin

Office Pract 2011;38:469À82.

[7] DeBarkey SF, Stinson FS, Grant BF, Dufour MC. Surveillance report #41. Liver cirrhosis mortality in the United States 1970À1993. National Institute of Alcohol Abuse and Alcoholism,

1996.

[8] Prescott LF. Paracetamol, alcohol and the liver. Br J Clin Pharmacol 2000;49:291À301.

[9] Greenes V, Willamson C. Intrahepatic cholestasis of pregnancy. World J Gastroenterol

2009;15:2049À66.

[10] Ko HH, Yoshida E. Acute fatty liver of pregnancy. Can J Gastroenterol 2006;20:25À30.

[11] Jangaard KA, Curtis H, Goldbloom RB. Estimation of bilirubin using BiliChek, a transcutaneous bilirubin measurement device: effect of gestational age and use of phototherapy.

Paediatr Child Health 2006;11:79À83.

[12] Szmuness W, Stevens CE, Harley EJ, Zang EA, et al. Hepatitis B vaccine in medical staff of

hemodialysis units: efficacy and subtype cross-protection. N Engl J Med 1982;307

(24):1481.



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CHAPTER 11



Renal Function Tests



11.1 BASIC FUNCTIONS OF KIDNEYS

Kidneys are a paired organ system located in the retroperitoneal space. They

weigh approximately 150 g each. Renal blood supply represents roughly 25%

of cardiac output. The functional unit of the kidney is the nephron, and the

components of each nephron include the glomerulus, proximal tubule, loop

of Henlé, distal tubule, and the collecting duct. Kidneys have three very

important physiological roles:













Excretory Function: Removal of undesirable end products of metabolism,

excess inorganic ions ingested in the diet, and drugs and toxins from the

body through urine formation.

Regulatory Function: Maintaining proper acidÀbase balance and

homeostasis.

Endocrine Function: The kidney can be regarded as an endocrine organ

that produces certain hormones and is also responsible for activation of

several hormones.



Kidneys are responsible for urine formation and secretion of undesired end

products of metabolism from the body, including urea formed from protein

catabolism and uric acid produced from nucleic acid metabolism. The glomerulus is the site of filtration. The basement membrane of the 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. Approximately two-thirds of the filtrate volume is

reabsorbed in the proximal tubule. Ninety percent of hydrogen ion secretion

by the kidney takes place at the proximal tubule. Further reabsorption of

water and solutes takes place in the more distal parts of the nephron.

Typically the volume of the glomerular filtrate in one day ranges from

150À200 liters. This volume is reduced to 1À2 liters of urine per day. The

loop of Henlé is the site where urine is concentrated. At the distal tubule,

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

DOI: http://dx.doi.org/10.1016/B978-0-12-407821-5.00011-5

© 2014 Elsevier Inc. All rights reserved.



CONTENTS

11.1 Basic Functions

of Kidneys ................ 197

11.2 Glomerular

Filtration Rate.......... 199

11.3 Creatinine

Clearances ............... 199

11.4 Chronic Kidney

Disease ..................... 201

11.5 Cystatin C...... 202

11.6 Urea (Blood Urea

Nitrogen) and Uric

Acid........................... 203

11.7 Protein in Urine

and Proteinuria........ 205

11.8 Other Renal

Diseases ................... 206

11.9 Laboratory

Measurements of

Creatinine and Related

Tests ......................... 207

11.10 Urine Dipstick

Analysis.................... 208

Key Points ................ 209

References ............... 211



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sodium and chloride are reabsorbed while potassium and hydrogen ions are

excreted. Proper function of the distal tubule is essential in maintaining

plasma acidÀbase and electrolyte homeostasis. The collecting duct is the site

of further water reabsorption, which occurs under the influence of antidiuretic hormone (ADH).

The kidneys also produce two 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 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. This is

defined as the “renin-angiotensin-aldosterone” system. Aldosterone, a mineralocorticoid, acts on the distal tubules and collecting ducts of the nephron

and causes retention of water and sodium as well as excretion of potassium

and hydrogen ions.

The kidneys are responsible for producing the active form of vitamin D, a

fat-soluble vitamin essential for absorption of calcium. Vitamin D deficiency

can cause osteomalacia in adults and rickets in children. Human skin is capable of synthesizing an inactive form of vitamin D (cholecalciferol, vitamin

D3) from 7-dehydrocholesterol in the presence of sunlight (solar ultraviolet

radiation: 290À315 nm; reaches earth between 10 AM and 3 PM). This is

why vitamin D is also called the “sunshine vitamin.” Very few foods naturally contain vitamin D and as a result many foods are fortified with an inactive form of vitamin D. The inactive form of vitamin D obtained either from

skin exposure to the sun or food is first converted into 25-hydroxyvitamin D

(25-hydroxycholecalciferol) in the liver by the action of enzyme vitamin

D-25 hydroxylase. Finally, the kidneys (proximal tubular epithelial cells)

convert this form of vitamin D into the active form, which is called 1,25dihydroxyvitamin D (1,25-dihydroxycholecalciferol) by the action of the

enzyme 25-hydroxylcholecalciferol-1α-hydroxylase. The biologically active

form of vitamin D is 1,25-dihydroxycholecalciferol, which plays an important role in absorption of calcium from the gastrointestinal tract. The enzyme

25-hydroxylcholecalciferol-1α-hydroxylase is stimulated by parathyroid hormone (PTH) and inhibited by high blood levels of calcium and phosphate.

Although 1,25-dihydroxyvitamin D is the bioactive form of vitamin D, the

best laboratory parameter to monitor vitamin D status of a patient is to measure 25-hydroxyvitamin D. A serum 25-hydroxyvitamin D level of 30 ng/mL

or greater is considered an adequate level [1]. Prostaglandins are synthesized

by the action of cyclooxygenase enzyme acting on arachidonic acid. This

enzyme is present in many organs, including kidneys. The kidney is also a

site of degradation of hormones such as insulin and aldosterone.



11.3 Creatinine Clearances



11.2 GLOMERULAR FILTRATION RATE

Glomerular filtration is one of the major functions of the kidney. Neutral

molecules show much higher glomerular permeability than highly negatively

charged molecules. Glomerular filtration rate (GFR) is a measure of the functional capacity of the kidney and is an important parameter to assess kidney

function. GFR can be estimated by using the formula in Equation 11.1:

GFR 5 ðUa 3 VÞ=Pa



ð11:1Þ



Here, 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.

However, this formula is often corrected to take into account body surface

area (Equation 11.2):

GFR 5 ðUa 3 VÞ=Pa 3 1:73=A



ð11:2Þ



Here, A is the body surface area in square meters. Standard body surface is

1.73 m2.

The body surface area of most adults is between 1.6 and 1.9. The formula for

calculating GFR using any analyte that is freely filtered through the glomerula

is only valid if the solute is in stable concentration in plasma and is inert

(neutral charge), freely filtered at the glomerulus. This compound must not

be secreted, reabsorbed, synthesized, or metabolized by the kidneys.

Estimation of GFR by insulin clearance is considered to be the gold standard.

However, in routine clinical practice creatinine clearance is more practical.

More recently, cystatin C was introduced as an alternative to creatinine clearance. For example, if serum creatinine is 1.0 mg/dL (0.01 mg/mL), urine creatinine is 1 mg/mL, the volume of urine is 60 mL in 1 hour, and body

surface area is 1.70. Then GFR for this patient using creatinine clearance

should be as follows (Equation 11.3):

GFR ðCreatinine ClearanceÞ 5 1:0 mg=mL 3 1 mL=min=0:01 mg=mL

3 1:73=1:70 5 101:7 mL=min=1:73 m2



ð11:3Þ



In order to calculate GFR based on creatinine clearance, a 24-h urine collection is recommended which should be from one morning void to the next

day’s morning void. This is difficult in real practice and usually GFR is estimated using a formula.



11.3 CREATININE CLEARANCES

Creatine is synthesized in the kidneys, liver, and pancreas, and then transported in blood to other organs, especially the brain and muscles, where it



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is phosphorylated to phosphocreatine. Phosphocreatine is a high-energy

compound and interconversion of phosphocreatine to creatinine is important for muscular functions. Creatinine is the waste product derived from

creatine and phosphocreatine, and creatinine production is related to the

muscle mass of an individual. Women usually excrete 1.2 g of creatinine

per day while men excrete 1.5 g/day. Dietary intake of meat also affects the

amount of creatinine produced daily. Therefore, serum creatinine levels are

affected by gender, age, weight, lean body mass, and dietary protein intake.

Creatinine is produced in the body at a constant rate and is freely filtered

and not reabsorbed, although a small amount of creatinine is secreted by

the tubules. Thus it is a convenient marker for estimation of glomerular filtration rate (GFR). Because collection of 24-h urine is difficult, estimation

of GFR can be done using values of plasma creatinine concentration and

relevant formulas. However, it is also important to take into account the

age, sex, and race of the patient when performing such calculations.

The CockroftÀGault formula is widely used for calculating GFR

(Equation 11.4):

Creatinine clearance 5



ð140 2 Age in yearsÞ 3 Weight in kg

3 1:23 if male ðor 1:04 if femaleÞ

Serum creatinine ðμmol=LÞ

ð11:4Þ



Another version of the formula that is also commonly used and which produces the same results is shown in Equation 11.5:

Creatinine clearance 5



ð140 2 Age in yearsÞ 3 Weight in kg

3 0:85 ðif femaleÞ

0:814 3 Serum creatinine ðμmol=LÞ



ð11:5Þ



If serum creatinine is given in mg/dL, as is often the case with U.S. laboratories, then this equation can be further modified so that GFR can be calculated

directly using creatinine concentration expressed in mg/dL (Equation 11.6):

Creatinine clearance 5



ð140 2 Age in yearsÞ 3 Weight in kg

3 0:85 ðif femaleÞ

72 3 Serum creatinine ðmg=dLÞ



ð11:6Þ



The conversion factor for converting serum creatinine given in mg/dL into

μmol/L is 88.4. Therefore, 88.4 3 0.814 is 71.9, which can be rounded up to

72, as used in the modified equation. Alternatively, if serum creatinine is

expressed in μmol/L, it can be multiplied by 0.011 to get the creatinine concentration in mg/dL.



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