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‫خالص الشكر والتقدير الى‬
‫الدكتورة‬
‫د‪ -‬ميادة‬
‫على ما تقدمه لنا من معلومات‬
‫وعلى موافقتها لرفع المذكرة حتى يستفيد منها الجميع‬
‫مع تحيات‬
‫طالب الدبلومه‬
‫جامعة المنيا‬
‫‪2010‬‬
CLINICAL BIOCHEMISTRY
(PART I)
Maiiada Hassan Nazmy
Lecturer of Biochemistry
Faculty of Pharmacy
Minia University
1
CLINICAL BIOCHEMISTRY
Clinical biochemistry is the meeting point of several disciplines of which analytical
chemistry, medical biochemistry, immunology, molecular biology and clinical
medicine are among the most important. This course is designed to give an integrated
picture of the mechanisms underlying major human diseases and the current
approaches to their investigation.
EDUCATIONAL GOALS
1) To provide students with core knowledge and skills in the theory and practice
of clinical biochemistry
2) To understand the impact of clinical biochemistry results on the diagnosis and
management of common medical conditions.
3) To utilize history, physical examination and laboratory tests of a patient to
generate a differential diagnosis.
4) To interpret the significance of the data obtained and advising on whether
further investigations are needed.
5) To analyze various disease patterns to reach a final diagnosis.
6) To provide students with experience of working in a research/clinical
biochemistry laboratory environment through the discussing of real case
studies besides undertaking of a limited research project.
COURSE CONTENTS
Introduction ………………………………………………………………………………………………………....
2
Core Biochemistry ………………………………………………………………………………………………. 5

Chapter I: Urinalysis ………………………………………………………………………………….

Chapter II: Complete blood count ……………………………………………………………..

Chapter III: Liver function tests ………………………………………………………………...

Chapter VI: Kidney function tests ……………………………………………………………..
2
INTRODUCTION
Clinical biochemistry involves measuring the amount of certain chemicals in body
fluids in comparison to specific reference ranges which are sets of values used by a
health professional to interpret a set of medical test results. Biochemical testing is
usually performed in groups of individual tests, called panels which provide a broad
data base demonstrating multi-systemic involvement (i.e. Liver function tests). This
requires collection of samples to determine its character as a whole or to identify
levels of its component cells, chemicals, gases, or other constituents. Many different
specimens can be used for biochemical testing including whole blood, serum, plasma,
urine, feces, synovial fluid, cerebrospinal fluid and effusions. Proper sample
collection and handling help ensure that the results are valid. This course will focus
on blood and urine-based biochemical tests.
Urine Specimens
The clinical information obtained from a urine
specimen is influenced by the collection method,
timing and handling.
Types of Collection
Figure (1): Urine collective equipments
Laboratory urine specimens are classified by the type of collection conducted or by
the collection procedure used to obtain the specimen.
Random Specimen This is the specimen most commonly sent to the laboratory for
analysis, primarily because it is the easiest to obtain and is readily available. They can
sometimes give an inaccurate view of a patient's health if the specimen is too diluted
and analyte values are artificially lowered.
First Morning Specimen This is the specimen of choice for urinalysis and
microscopic analysis, since the urine is generally more concentrated (due to the length
of time the urine is allowed to remain in the bladder) and, therefore, contains
relatively higher levels of cellular elements and analytes such as protein, if present.
3
Midstream Clean Catch Specimen This is the preferred type of specimen for culture
and sensitivity testing because of the reduced incidence of cellular and microbial
contamination. Patients are required to first cleanse the urethral area then void the first
portion of the urine stream into the toilet then collected into a clean container
Timed Collection Specimen Among the most commonly performed tests requiring
timed specimens are those measuring creatinine, urine urea nitrogen, glucose, sodium,
potassium, or analytes such as catecholamines and 17-hydroxysteroids that are
affected by diurnal variations. A timed specimen is collected to measure the
concentration of these substances in urine over a specified length of time, usually 8 or
24 hours. In this collection method, the bladder is emptied prior to beginning the
timed collection. Then, for the duration of the designated time period, all urine is
collected and pooled into a collection container, with the final collection taking place
at the very end of that period.
Blood Specimens
There are three types of blood specimens commonly used in
the clinical chemistry laboratory. These are whole blood,
serum and plasma. The whole blood comprises of plasma,
serum, white blood cells and red blood cells. The type of the
test determines which specimen should be used.
These are the main differences between serum and plasma:
Figure (2): Blood samples
1. Serum is the supernatant fluid when coagulated blood has been centrifuged. The
blood is allowed to clot at room temperature for 15 to 30 minutes then centrifuged.
Plasma, on the other hand, is the supernatant fluid obtained when anti-coagulated
blood has been centrifuged. The blood is mixed with an appropriate amount of
anticoagulant like heparin, oxalate or ethylenediaminetetraacetic acid (EDTA). This
preparation should be mixed immediately and thoroughly to avoid clotting.
4
Serum is still the most preferred specimen in clinical chemistry as the anticoagulant
interference is eliminated. Serum is clearer than plasma because of fewer proteins.
Fibrinogen- a protein- is present in plasma and not found in serum. Proteins are
sometimes considered as interfering substances in some tests as they react with the
reagent and thereby yield inaccurate results.
CLINICAL NOTES
Hemolysis can interfere with lab results due to several processes:

Leakage of analytes from lysed erythrocytes may cause a false increase
in the amount of analyte measured in serum if the analyte is normally
present in a greater amount inside the RBC than in plasma. This can
occur when measuring the levels of potassium, creatine kinase (CK), and
alanine amino transferase (ALT).

If the analyte is normally present in greater amounts in plasma than in
the erythrocytes, the analyte will be diluted by the lysing of the RBCs,
causing a false decrease.

Sodium and chloride can both be increased.
Color interference (tinting the serum pink or red) can cause false
increases when using a spectrophotometer. Hemoglobin, bilirubin and
protein are a few of the analytes affected by hemolysis.

Sometimes erythrocyte constituents can react with analytes, causing a
false decrease. This can occur when testing for carbon dioxide, thyroxin
and insulin.

Hemolysis can cause increased turbidity when using the refractometer to
determine blood protein levels.

Hemolysis is enhanced by lipemia, which increases erythrocyte fragility.
Lipids present in a specimen scatter light and can cause either an
increase or decrease in values, depending upon the analytes being
evaluated. Because electrolytes are in the aqueous phase of blood, lipids
may dilute their concentration.
5
CHAPTER I: UNINALYSIS
What is urine?
Urine is a liquid product of the body that is secreted by the kidneys. It is a clear,
transparent fluid which normally has an amber color. The average amount of urine
excreted is about 1,200 cubic centimetres per 24 hours. About 95% of the volume of
normal urine is due to water. The other 5% consists of solutes which may be the
results of normal biochemical activity within the cells or due to chemicals that
originated outside of the body, such as pharmaceutical drugs. Cellular metabolism
generates numerous waste compounds, many rich in nitrogen, that require elimination
from the bloodstream. This waste is eventually expelled from the body in a process
known as micturition, the primary method for excreting water-soluble chemicals from
the body. These chemicals can be detected and analyzed by urinalysis.
Functions of urine:
Urine is produced by the kidney to:

Maintain constant plasma osmotic concentration.

Regulate pH, electrolyte and fluid balances.

Excrete solid waste products (mostly urea and sodium chloride).
Urinalysis
Urinalysis is the physical, chemical, and microscopic examination of urine. It involves
a number of tests to detect and measure various compounds that pass through the
urine.
Purpose
Routine urinalyses are performed for several reasons:

General health screening to detect renal and metabolic diseases

Diagnosis of diseases or disorders of the kidneys or urinary tract

Monitoring of patients with diabetes
6
Normal results:
Normal values or normal ranges may vary considerably, depending on type of
specimen collection, the age of the specimen and the method of storage or
preservation. Normal values used in many laboratories are given in the following
table:
Table (1): Normal results for a typical urinalysis
Color Straw - Dark yellow
Occult blood
Negative
Appearance
Clear - Hazy
Leukocyte Esterase
Specific Gravity
1.010-1.025
Nitrite
Negative
pH
4.5-7.8
Urobilinogen
0.1-1.0 EU/dL
Protein
Negative
Bacteria
Negative
Glucose
Negative
RBCs
Ketones
Negative
WBCs
Bilirubin
Negative
Casts
Negative
0-5/hpf
0-5/hpf
0-5/lpf
EU = Ehrlich Units (ca. 1 mg), hpf = High Power Field (400x), lpf = Low Power Field (100X)
Procedure of urinalysis:
Routine Urinalysis is composed of the following examinations:
1) Physical tests for abnormal characters.
2) Chemical tests for abnormal chemical constituents.
3) Microscopic exam for abnormal insoluble constituents.
I- Physical Exam
A. Color: normal color ranges from pale yellow to amber depending on
concentration. Yellow color comes from urochrome pigment.
B. Appearance: normal appearance is clear but becomes turbid on standing.
C. Odour: characteristic aromatic
D. Specific gravity: normal value from 1.010-1.025
E. Volume: normal value from 500-2000 ml/24hrs
F. pH: normally slightly acidic
7
A- Color:
Sample
Pathological
Non-pathological
Orange
Bilirubin
Rhubarb or Carrots
Dark yellow
Bilirubin or urobilin
Concentrated or Carrots
Green
Oxidized Bilirubin or pseudomonas
Vitamin B Complex or Clorets
Red or pink
RBCs, Heamoglobin,
Beets
Brown or
Biliary Pigments
Rhubarb
Diabetes mellitus or Diabetes
Large Fluid intake
Black
Pale yellow
insipidus
B- Appearance:
Sample
Pathological
Non-pathological
Cloudy
WBCs, Bacteria
Amorphous Urate Pink (acid pH)
Epithelial cells
Amorphous Phosphates White (alk pH)
Smoky
RBCs
Milky
Fats
Radiographic media
C- Odour:
Sample
Pathological
Non-pathological
Ammonia
Urinary tract infection
Old Urine
Sweet
Diabetes mellitus
Starvation, Dieting, vomiting, Diarrhea
Mousy
Phenyl ketonuria
Maple syrup
Maple syrup disease
Distinctive
Garlic, Onions
8
D- Specific Gravity:
Sample
Pathological
Non-pathological
Low
Diabetes insipidus, Glomuronephritis
Tubular damage
High
Diabetes mellitus, Hepatic Disease
Radiographic dye, Dehydration
Vomiting, Diarrhea
E- Volume
Sample
Amount
Pathological
Non-pathological
Polyuria
> 2000 ml/24 hr
Diabetus mellitus
Large fluid intake
Diabetes insipidus
Diuretics
oligouria
Anuria
< 500 ml/ 24 hr Renal Tubular Dysfunction
None
Dehydration
End stage Kidney disease
Shoch
Obstruction
Vomiting
Edema
Diarrhea
Acute renal failure
Shock
Obstruction, Heart failure
E- pH:
Sample
Acidic
Alkaline
Pathological
Diabetes
After meals, bacterial infections
chronic renal failure
9
Non-pathological
II- Chemical Exam

The
common
chemical
testing
of
urine
utilizes
commercial disposable test strips.

They test for Glucose, Bilirubin, Ketone, Specific
Gravity, Blood, pH, Protein, Urobilinogen, Nitrite, and
Leukocyte Esterase.

The result of this testing is regarded as semiquantitative

A fresh urine specimen is collected in a clean, dry
container. A Multistix strip is briefly immersed in the
urine specimen, covering all reagent areas.

The edge of the Multistix strip is run against the rim of
the urine container to remove excess urine. The strip is
held in a horizontal position.

The reactions are read visually or automatically with a Clinitek reflection
photometer. If the strip is evaluated visually, the strip test
areas are compared to those on the Multistix color chart
at the specified times. The results are recorded, and the
strip is discarded.
Figure (3): Urinalysis strips
Metodologies & Interpretation
1) Glucose:
•
In general the presence of glucose indicates that the filtered load of glucose
exceeds the maximal tubular reabsorptive capacity for glucose. In diabetes
mellitus, urine testing for glucose is often substituted for blood glucose
monitoring.
•
False positive: Strong oxidizing reagents.
•
False negative: Ascorbic acid, Aspirin.
10
2) Bilirubin:
•
Bilirubin in the urine indicates the presence of liver disease or biliary
obstruction. Very low amounts of bilirubin can be detected in the urine, even
when serum levels are below the clinical detection of jaundice.
•
False positive: metabolites of drugs: Phenazopyridin
•
False negative: Ascorbic acid, light sensitive.
3) Ketones:
•
Ketone bodies can be detected in diabetes mellitus, insulin deficiency or
starvation, prolonged vomiting, dehydration fever, it can be present in large
amounts in the urine before any elevation in plasma levels.
•
False positive: levodopa
•
False negative: Ascorbic acid, Ketone bodies are volatile
4) Blood:
•
The presence of large numbers of RBCs in the urine sediment establishes the
diagnosis of hematuria. It can be detected in renal disease, trauma, renal
stones, infection, heamolytic anemia.
•
False positive: Bacterial enzymes
•
False negative: ascorbic acid, high specific gravity (proteinuria)
5) Protein:
•
Heavy proteinuria usually represents renal abnormality (glomerular or tubular
damage).
•
False positive: Highly alkaline pH
•
False negative: High salt concentration
6) Urobilinogen:
•
Urine urobilinogen is increased in any condition that causes an increase in
production or retention of bilirubin. It is increased in heamolytic anemia and
liver disease, but negative in obstructive juandice.
•
False positive: Indol porphobilinogen.
•
False negative: easily oxidized to urobilin
11
7) Nitrite:
•
Nitrite indicates urinary tract infection (i.e. E. coli pseudomonas,….. etc)
•
Bacteriuria caused by some Gram negative bacteria which produce the nitrate
reductase enzyme that convert of nitrate (derived from the diet) to nitrite.
•
False positive: contaminated sample
•
False negative: antibiotic therapy
8) Leukocytes:
•
A positive leukocyte esterase test provides indirect evidence for the presence
of inflammation or urinary tract infection.
•
False positive: Vaginal discharge
•
False negative: Ascorbic acid, increased Specific gravity
III- Microscopic Exam

Note that in many laboratories it is a standard practice to exclude the
microscopic exam if all chemical testing yields negative or normal results.

Microscopic exam include formed cellular elements, casts, bacteria, yeast,
parasites and crystals in centrifuged urine sediment.
Procedure
•
Centrifuge 5.0 mL of mixed, freshly voided or catheterized urine in a conical
centrifuge tube for 5 minutes at high speed.
•
Remove 4.9 mL (or 90% of whatever volume was centriguged) of the
supernatant fluid, leaving a 10-fold concentration of the urine sediment.
•
Re-suspend the sediment by gently mixing with a vortex mixer.
•
Place a drop of stained or unstained suspension in a 1 mm deep chamber;
allow the chamber to stand for 2 minutes, so that most elements will settle to
the bottom of the chamber.
•
Place the chamber on the microscope stage.
12
•
LPF (Low Power Fields): at 100X magnification for casts. Classify and count
the number of casts and report as a least-to-most range (eg. 5-10) for each
type.
•
HPF (High Power Field): at 400X magnification for other elements, i.e.,
WBCs, RBCs, Epithelial cells, yeast, bacteria, Trichomonas vaginalis, Sperm
cells, mucous filaments and crystals.
•
Again, classify and report each element by a least-to-most range per Yeast,
bacteria, mucous filaments and crystals are usually graded using the '+'
notation (1+ = least significant amount, 4+ = most significant amount).
•
Occasionally, the fields are packed with cellular elements or casts, so that it is
impractical to count their numbers; in this case use the notation 'TNTC' (Too
Numerous To Count).
Description of Microscopic Elements
1) Casts:
•
Hyaline casts: They are formed in the absence of cells
in the renal tubular lumen. They have a smooth texture
and a refractive index very close to that of the
surrounding fluid. Greater numbers of hyaline casts
may be seen associated with proteinuria of renal (eg.,
glomerular disease) or extra-renal (eg., overflow
Figure (4): Hyaline casts
proteinuria as in myeloma) origin.
•
Cellular casts: most commonly result when disease
processes such as ischemia, infarction or nephrotoxicity
cause degeneration and necrosis of tubular epithelial
cells.
Figure (5): Cellular casts
13
•
Waxy casts: have a smooth consistency but are more
refractive and therefore easier to see compared to hyaline
casts. They commonly have squared off ends, as if brittle
and easily broken. Waxy casts are found especially in
chronic renal diseases, and are associated with chronic
renal failure; they occur in diabetic nephropathy,
malignant hypertension and glomerulonephritis.
Figure (6): Waxy casts
2) Cells…
•
Red blood cells (RBCs): up to 5/HPF are commonly
accepted as normal. Increased RBC in urine is termed
hematuria,
which
can
be
due
to
hemorrhage,
inflammation, necrosis, trauma or neoplasia somewhere
along the urinary tract (or urogenital tract in voided
specimens).
Figure (7): Red blood cells
•
White Blood Cells (WBCs): up to 5/HPF are commonly
accepted as normal.
Greater numbers (pyuria)
generally indicate the presence of an inflammatory
process somewhere along the course of the urinary tract
(or urogenital tract in voided specimens). Pyuria often
is caused by urinary tract infections, and often
significant
bacteria
can
be
seen
on
sediment
Figure (8): White blood cells
preparations, indicating a need for bacterial culture.
•
Squamous epithelial cells are the largest cells seen in
normal urine specimens. They are thin, flat cells,
usually with an angular or irregular outline and a small
round nucleus. Squamous cells are common in lower
numbers in voided specimens and generally represent
contamination from the genital tract. Their main
significance is as an indicator of such contamination.
14
Figure (9): Squamous epithelial cells
3) Crystals…
•
Calcium Oxalate crystals typically are seen as
colorless squares whose corners are connected by
intersecting lines (resembling an envelope). They
can occur in urine of any pH. The crystals vary in
size from quite large to very small. Renal calculi
and ethylene glycol intoxication are causes for
urinary calcium oxalate formation.
Figure (10): Cacium Oxalate crystals
•
Triple phosphate (Struvite, Magnesium Ammonium
Phosphate) crystals usually appear as colorless,
prism-like "coffin lids". Urinary tract infection with
urease producing bacteria (eg. Proteus vulgaris) can
promote struvite crystalluria (and urolithiasis) by
raising urine pH and increasing free ammonia.
Figure (11): Triple Phosphate crystals
•
Cystine crystals: are seen as flat colorless hexagonal
plates. They often aggregate in layers, and their
formation is favoured in acidic urine. Cystine
crystalluria or urolithiasis is an indication of
cystinuria, which is an inborn error of metabolism
involving defective renal tubular reabsorption of
certain amino acids including cystine.
Figure (12): Cystine crystals
4) Parasites:
•
Trichomonas vaginalis is a sexually-transmitted
urogenital parasite of men and women. The
organism varies in size between 1-2 times the
diameter of WBC. The organism is readily identified
by its rapid erratic "jerky" movement.
Figure (13): Trichomonas vaginalis
15
CASE STUDY
CASE NO. (1):
A 28 year old man visits his physician complaining of an intense, sharp pain in his
back and side. In a conversation with his physician, the patient confesses to eating a
diet high in animal proteins such as meat, cheese, and fish. Results of a complete
urinalysis are shown below.
Physical Exam:
Color: Reddish yellow
Appearance: Cloudy
Volume: 400 ml/ 24 hr
Sp. Gr: 2.026
pH: 9
Chemical Exam:
Glucose: NIL
Ketones: NIL
Bilirubin: NIL
Urobilinogen: NIL
Proteins: +++
Blood: negative
Nitrite: +
Leukocyte Esterase: +
Microscopic Exam:
1-Casts:
Hyaline: ++
Waxy: +++
2-Cells:
RBCs: 20-50/ HPF
WBCs : 10/ HPF
3-Crystals:
Calcium oxalate: +++
Triple phosphate: NIL
4-Parasites: Trichomonas vaginalis
Cellular: negative
Epithelial: NIL
Cysteine: NIL
QUESTIONS:
•
What abnormalities do you observe?
•
What is the most probable diagnosis for this patient?
•
Are there a relation between the presence of nitrite and leukocyte esterase?
•
How can you explain the negative blood test inspite of presence of RBCs?
•
How can you explain the presence of blood? Is it related to the main
diagnosis?
16
CASE NO. (2):
A 50 year old female visits her primary care provider complaining of steady pain in
her right upper abdomen, nausea, vomiting, fever, and chills. The doctor notices that
there is a yellow tinge to the patient's skin and in the sclera of her eyes.
Physical Exam:
Color: Orange
Appearance: Hazy
Volume: 4000 ml/ 24 hr
Sp. Gr: 2.026
pH: 5
Odor: Sweet
Chemical Exam:
Glucose: +++
Ketones: +++
Bilirubin: +++
Urobilinogen: NIL
Proteins: NIL
Blood: NIL
Nitrite: NIL
Leukocyte Esterase: NIL
Microscopic Exam:
1-Casts:
Hyaline: NIL
2-Cells:
RBCs: 4/ HPF
3-Crystals:
Calcium oxalate: NIL
4-Parasites: NIL
Waxy:
NIL
WBCs : 5/ HPF
Triple phosphate: NIL
Cellular: NIL
Epithelial: +
Cysteine: NIL
QUESTIONS:
•
What abnormalities do you see?
•
What can you expect about her medical history?
•
What may be the cause of yellow tinge in her eyes and skin?
•
What is the most probable diagnosis of this case?
17
CASE NO. (3):
A 41 year old woman who is approximately 30 weeks pregnant reports to her Dr. with
several ailments. She complains of frequent headaches, and edema (swelling) of her
feet and hands. Her blood pressure was found to be elevated (150/90). She informs
her physician that she takes extra amounts of pre-natal vitamins due to her age. A
random specimen yields the following urinalysis results:
Physical Exam:
Color: yellow
Appearance: Hazy
Volume: 1000 ml/ 24 hr
Sp. Gr: 1.075
pH: 6.5
Odor: normal
Chemical Exam:
Glucose: negative
Ketones: negative
Bilirubin: negative
Urobilinogen: negative
Proteins: +
Blood: negative
Nitrite: negative
Leukocyte Esterase: negative
Microscopic Exam:
1-Casts:
Hyaline: NIL
2-Cells:
RBCs: 20-50 /HPF
3-Crystals:
Calcium oxalate: NIL
4-Parasites: NIL
Waxy:
NIL
WBCs : 2- 5/ HPF
Triple phosphate: NIL
Cellular: NIL
Epithelial: +
Cysteine: NIL
QUESTIONS:
1- What would account for the negative blood on the chemical test and the 20-50
RBC/hpf seen microscopically?
a. lysis of RBCs
b. hypertension (high blood pressure)
c. ascorbic acid interference
d. high specific gravity
18
2- What could account for the 10-20 squamous epithelial cells?
a. improper collection
b. renal tubular damage
c. upper UTI
d. glomerular dysfunction
3- What condition do the chemical and microscopic results point towards?
a. nephrotic syndrome
b. acute glomerulonephritis
c. pre-eclampsia
d. Hepatic disease
4- What information about the patient supports this diagnosis? (review patient history)
a. patient's age
b. hypertension
c. ~ 30 weeks pregnant
d. all of the above
19
CASE NO. (4):
A 7 year old kid named Tommy is seen by his physician. His mother brought him
concerned about edema around his eyes. Tommy has previously been diagnosed with
Type I Diabetes Mellitus. His mother also notices he has been urinating less often
than usual. The following urinalysis results were obtained:
Physical Exam:
Color: yellow
Appearance: Hazy
Volume: 1000 ml/ 24 hr
Sp. Gr: 2.025
pH: 6
Odor: acetone
Chemical Exam:
Glucose: +++
Ketones: +++
Bilirubin: negative
Urobilinogen: negative
Proteins: +
Blood: negative
Nitrite: negative
Leukocyte Esterase: negative
Microscopic Exam:
1-Casts:
Hyaline: +++
2-Cells:
RBCs: 0-2 /HPF
3-Crystals:
Calcium oxalate: NIL
4-Parasites: NIL
Waxy:
NIL
WBCs : 2- 5/ HPF
Triple phosphate: NIL
Cellular: +++
Epithelial: +
Cysteine: NIL
QUESTIONS:
•
What would you conclude about this case?
•
What is the significance of the increased glucose and ketone results?
•
What type of protein do you expect contributes most to the proteinuria?
•
What else could be seen microscopically confirm your diagnosis?
•
What causes the edema?
20
CASE NO. (5)
A 40 year old woman experiencing fatigue, headaches, unintentional weight loss and
high blood pressure is ordered to give a urine sample by her doctor. In addition, she
is experiencing excessive urination and polydipsia (excessive thirst). Her urinalysis
results are as follows:
Physical Exam:
Color: amber
Appearance: Clear
Volume: 1000 ml/ 24 hr
Sp. Gr: 2.025
pH: 6.5
Odor: sweet
Chemical Exam:
Glucose: 200 mg/dl
Ketones: negative
Bilirubin: negative
Urobilinogen: negative
Proteins: negative
Blood: negative
Nitrite: negative
Leukocyte Esterase: negative
Microscopic Exam:
1-Casts:
Hyaline: NIL
2-Cells:
RBCs: 0-2 /HPF
3-Crystals:
Calcium oxalate: NIL
4-Parasites: NIL
Waxy:
NIL
WBCs : 2- 5/ HPF
Triple phosphate: NIL
Cellular: NIL
Epithelial: +
Cysteine: NIL
QUESTIONS:
1- What is the most probable diagnosis for this patient?
a. glomerulonephritis
b. diabetes insipidus
c. chronic pyelonephritis
d. diabetes mellitus
2- The most helpful information needed to answer Question 1 was:
a. the increased specific gravity and the increased glucose levels
b. the negative leukocytes, nitrite and blood
c. the excessive urination coupled with the excessive thirst and weight loss
d. both A and C are correct
21
3- What can the patient do to treat her condition?
a. Get a prescription for acyclovir
b. Change her diet
c. Ask her doctor for pyridium
d. get a kidney transplant
CASE NO. (6)
The patient in case (5) fails to follow her doctor’s orders to change her diet. After 5
years have passed, she returns to the doctor with malaise (fatique), puffy eyelids, and
abdominal pain. She is experiencing gradual loss of eyesight and parallel white lines
on the beds of her fingernails. Follow up urinalysis results are as follows:
Physical Exam:
Color: Pink
Appearance: Hazy with foamy
appearance When shaken
Volume: 1000 ml/ 24 hr
Sp. Gr: 2.025
pH: 6.5
Odor: sweet
Chemical Exam:
Glucose: 250 mg/dl
Ketones: negative
Bilirubin: negative
Urobilinogen: negative
Proteins: +++
Blood: ++
Nitrite: negative
Leukocyte Esterase: ++
Microscopic Exam:
1-Casts:
Hyaline: +++
2-Cells:
RBCs: 10-15 /HPF
3-Crystals:
Calcium oxalate: NIL
4-Parasites: NIL
Waxy:
NIL
Cellular: ++
WBCs : 10-15/ HPF
Epithelial: +
Triple phosphate: NIL
22
Cysteine: NIL
QUESTIONS:
1-What is this patient’s present diagnosis?
a. the patient now has a urinary tract infection
b. the patient’s initial condition has progressed to nephrotic syndrome
c. she is probably pregnant
d. systemic lupus erythrematosis
2-What protein is present in this patient’s urine?
a. hemoglobin
b. albumin
c. Bence Jones light chains
d. C Reactive Protein
4- If this patient continues to go untreated, what is the probable prognosis?
a. progression into chronic renal failure
b. development of renal cancer
c. cirrhosis
d. Multiple myeloma
5- What is most likely the cause of the squamous epithelial cells?
23
CHAPTER II: COMPLETE BLOOD COUNT
What is blood?
Blood is a specialized bodily fluid (specialized form of connective tissue) that delivers
necessary substances to all body cells (e.g. nutrients and oxygen) and transports waste
products away from the body.
Blood facts

Human blood is red which owes its colour to hemoglobin, a
metalloprotein compound containing iron in the form of
heme, to which oxygen binds.

Adult humans have approximately (5.7 litres) of blood which
constitutes about 8% of an adult's body weight.

Its mean temperature is 38º degrees.

It has a pH of 7.35-7.45, making it slightly basic.

Whole blood is about 4.5 - 5.5 times as viscous as water, thus
more resistant to flow than water. This viscosity is vital to
the function of blood because if blood flows too easily or
with too much resistance, it can strain the heart and lead to
severe cardiovascular problems.

Blood in the arteries is a brighter red than blood in the veins
because of the higher levels of oxygen found in the arteries.

An artificial substitute for human blood has not been found.
Functions of blood
Blood has three main functions: transport, protection and regulation
I- Transport:

Gases, namely oxygen (O2) and carbon dioxide (CO2), between the lungs and
other body compartments

Nutrients from the digestive tract and storage sites to the rest of the body

Waste products to be detoxified or removed by the liver and kidneys
24

Hormones from the glands in which they are produced to their target cells
II- Protection:

Leukocytes, or white blood cells, destroy invading microorganisms and cancer
cells

Antibodies and other proteins destroy pathogenic substances

Platelet factors initiate blood clotting and help minimize blood loss
III- Regulation:

pH by interacting with acids and bases

Water balance by transferring water to and from tissues

Body temperature by transferring heat to the skin
Composition of blood
Blood is classified as a connective tissue and consists of two main components:
A- Plasma, which is a clear extracellular fluid.
B- Formed elements, are enclosed in a plasma membrane and have a definite
structure and shape. All formed elements are cells except for the platelets, which
tiny fragments of bone marrow cells. They include:
1- Erythrocytes, also known as red blood cells (RBCs)
2- Leukocytes, also known as white blood cells (WBCs)
3- Platelets
Figure (14): Blood Composition
25
The formed elements can be separated from plasma
by centrifuge, where a blood sample is spun for a
few minutes in a tube to separate its components
according to their densities. RBCs are denser than
plasma, and so become packed into the bottom of
the tube to make up 45% of total volume. This
volume is known as the haematocrit. WBCs and
platelets form a narrow cream-coloured coat known
as the buffy coat immediately above the RBCs.
Finally, the plasma makes up the top of the tube,
which is a pale yellow colour constitutes about 55%
of the total volume.
Figure (15): Separation of blood components
Blood plasma
Blood plasma is a mixture of proteins, enzymes, nutrients, wastes, hormones and
gases. The specific composition and function of its components are as follows:
A- Proteins
These are the most abundant substance in plasma by weight. They play a part in a
variety of roles including clotting, defence and transport. Collectively, they serve
several functions:

They are an important reserve supply of amino acids for cell nutrition. Cells
called macrophages in the liver, gut, spleen, lungs and lymphatic tissue can
break down plasma proteins to release their amino acids. These amino acids
are used by other cells to synthesise new products.

Plasma proteins also serve as carriers for other molecules. Many types of
small molecules bind to specific plasma proteins and are transported from the
organs that absorb these proteins to other tissues for utilisation.

These proteins help to keep the blood slightly basic at a stable pH by
functioning as weak bases themselves to bind excess H+ ions thus removing
excess H+ from the blood which keeps it slightly basic.
26

The plasma proteins play an important role in blood coagulation, which is part
of the body's response to injury to the blood vessels and helps protect against
the loss of blood and invasion by foreign microorganisms and viruses.

Plasma proteins govern the distribution of water between the blood and tissue
fluid by producing what is known as a colloid osmotic pressure.
There are three major categories of plasma proteins, and each individual type of
proteins has its own specific properties and functions in addition to their overall
collective role:
1. Albumins: which are the smallest and most abundant plasma proteins. When
plasma albumin content is decreased, it can result in a loss of fluid from the
blood and a gain of fluid in the interstitial space (space within the tissue), which
may occur in nutritional, liver and kidney disease. Albumin also acts as a carrier
for many substances such as drugs, hormones and fatty acids.
2. Globulins: They can be subdivided into three classes from smallest to largest
in molecular weight into alpha, beta and gamma globulins. The globulins
include high density lipoproteins (HDL), an alpha-1 globulin, and low density
lipoproteins (LDL), a beta-1 globulin. HDL functions in lipid transport carrying
fats to cells for use in energy metabolism, membrane reconstruction and
hormone function. HDLs also appear to prevent cholesterol from invading and
settling in the walls of arteries. LDL carries cholesterol and fats to tissues for
use in manufacturing steroid hormones and building cell membranes, but it also
favours the deposition of cholesterol in arterial walls. HDL and LDL therefore
play important parts in the regulation of cholesterol and hence have a large
impact on cardiovascular disease.
3. Fibrinogen: which is a soluble precursor of a sticky protein called fibrin,
which forms the framework of blood clot. Fibrin plays a key role in coagulation
of blood.
27
B- Amino acids
These are formed from the break down of tissue proteins or from the digestion of
digested proteins.
C- Nitrogenous waste
These are toxic end products usually cleared from the bloodstream and are excreted
by the kidneys at a rate that balances their production.
D- Nutrients
Those absorbed by the digestive tract are transported in the blood plasma. These
include glucose, amino acids, fats, cholesterol, phospholipids, vitamins and minerals.
E- Gases
Some oxygen and carbon dioxide are transported by plasma. Plasma also contains a
substantial amount of dissolved nitrogen.
F- Electrolytes
The most abundant of these are sodium ions, which account for the blood's osmolarity
than any other solute.
Formed Elements:
1- Red blood cells (RBCs), also known as erythrocytes:

An erythrocyte is a disc-shaped cell with a thick rim
and a thin sunken centre. The plasma membrane of a
mature RBC has glycoproteins and glycolipids that
determine a person's blood type. On its inner surface
are two proteins called spectrin and actin that give the
membrane resilience and durability. This allows the
Figure (16): Photographic photo for RBCs
RBCs to stretch, bend and fold as they squeeze through
small blood vessels, and to spring back to their original shape as they pass through
larger vessels. The resulting biconcave shape of the cell has a greater ratio of
surface area to volume, enabling O2 and CO2 to diffuse quickly to and from Hb.
28

RBCs are incapable of aerobic respiration, preventing them from consuming the
oxygen they transport because they lose nearly all their inner cellular components
during maturation. The inner cellular components lost include their mitochondria,
which normally provide energy to a cell, and their nucleus, which contains the
genetic material of the cell and enable it to repair itself. The lack of a nucleus
means that RBCs are unable to repair themselves.

The cytoplasm of a RBC consists mainly of a 33% solution of haemoglobin (Hb),
which gives RBCs their red colour. Haemoglobin carries most of the oxygen and
some of the carbon dioxide transported by the blood.

Circulating erythrocytes live for about 120 days. As a RBC ages, its membrane
becomes increasingly fragile. Many RBCs die in the spleen, where they become
trapped in narrow channels, broken up and destroyed. Haemolysis refers to the
rupture of RBCs, where haemoglobin is released leaving empty plasma
membranes which are easily digested by cells known as macrophages in the liver
and spleen. The Hb is then further broken down into its different components and
either recycled in the body for further use or disposed of.
2- White blood cells (WBCs), also known as leukocytes:
They can be divided into granulocytes and agranulocytes.
The former have cytoplasms that contain organelles that
appear as coloured granules through light microscopy,
hence their name. Granulocytes consist of neutrophils,
eosinophils and basophils.
In contrast, agranulocytes do
not contain granules. They consist of lymphocytes and
Figure (17): Photographic photo for WBCs
monocytes.
 Granulocytes:
1. Neutrophils: These contain very fine cytoplasmic granules that can be seen
under a light microscope. Neutrophils are also called polymorphonuclear
(PMN) because they have a variety of nuclear shapes. They play roles in the
destruction of bacteria and the release of chemicals that kill or inhibit the
growth of bacteria.
29
2. Eosinophils: These have large granules and a prominent nucleus that is
divided into two lobes. They function in the destruction of allergens and
inflammatory chemicals, and release enzymes that disable parasites.
3. Basophils: They have a pale nucleus that is usually hidden by granules. They
secrete histamine which increases tissue blood flow via dilating the blood
vessels, and also secrete heparin which is an anticoagulant that promotes
mobility of other WBCs by preventing clotting.
 Agranulocytes:
1. Lymphocytes: These are usually classified as small, medium or large.
Medium and large lymphocytes are generally seen mainly in fibrous
connective tissue and only occasionally in the circulation bloodstream.
Lymphocytes function in destroying cancer cells, cells infected by viruses,
and foreign invading cells. In addition, they present antigens to activate
other cells of the immune system. They also coordinate the actions of other
immune cells, secrete antibodies and serve in immune memory.
2. Monocytes: They are the largest of the formed elements. Their cytoplasm
tends to be abundant and relatively clear. They function in differentiating
into macrophages, which are large phagocytic cells, and digest pathogens,
dead neutrophils, and the debris of dead cells. Like lymphocytes, they also
present antigens to activate other immune cells.
Figure (18): Classification of white blood cells
30
3- Platelets

Platelets are small fragments of bone marrow cells
and are therefore not really classified as cells
themselves. Platelets are involved in important
haemostatic mechanisms during bleeding, vascular
spasms, platelet plug formation and blood clotting
(coagulation).
Figure (19): Photographic photo for platelets

Platelets have the following functions:
1. Secrete vasoconstrictors which constrict blood vessels, causing vascular
spasms in broken blood vessels
2. Form temporary platelet plugs to stop bleeding
3. Secrete procoagulants (clotting factors) to promote blood clotting
4. Dissolve blood clots when they are no longer needed
5. Digest and destroy bacteria
6. Secrete chemicals that attract neutrophils and monocytes to sites of
inflammation
7. Secrete growth factors to maintain the linings of blood vessels
Figure (20): A collective diagram for the composition of whole blood
31
Complete Blood Count (CBC) Test
Definition:
A complete blood count (CBC) is a series of tests used to evaluate the composition
and concentration of the cellular components of blood.
Purpose:
The CBC provides valuable information about the blood and to some extent the bone
marrow, which is the blood-forming tissue. The CBC is used for the following
purposes:

As a preoperative test to ensure both adequate oxygen carrying capacity and
hemostasis

To identify persons who may have an infection

To diagnose anemia

To identify acute and chronic illness, bleeding tendencies, and white blood
cell disorders such as leukemia

To monitor treatment for anemia and other blood diseases

To determine the effects of chemotherapy and radiation therapy on blood
cell production
Procedure:

Blood is taken in a test tube containing an anticoagulant (EDTA, sometimes
citrate) to stop it from clotting, and transported to a laboratory.

In the past, counting the cells in a patient's blood was performed manually,
by viewing a slide prepared with a sample of the patient's blood under a
microscope (a blood film, or peripheral smear).

Nowadays, this process is generally automated by use of an automated
analyser, with only specific samples being examined manually.
32
What it measures?

Red blood cells (RBCs) Count: It includes RBCs indices.

White blood cells (WBCs) Count: It includes the differential analysis of the
different types of WBCs.

Platelet Count.

The total amount of hemoglobin in the blood
It also measures:

Hematocrite value: which is the percentage of blood by volume that is
occupied by the red cells (i.e., the packed red cell volume (PCV). Automated
cell counters calculate the hematocrit by multiplying the RBC count by the
mean red cell volume.

Red blood cell indices, which are calculations derived from the red blood
cell count, hemoglobin, and hematocrit that aid in the diagnosis and
classification of anemia.
o MCV (mean corpuscular volume): which is the average size of the
red blood cells expressed in femtoliters. MCV is calculated by
dividing the hematocrit (as percent) by the RBC count in millions per
microliter of blood, then multiplying by 10.
o MCH (mean corpuscular hemoglobin): which is the average amount
of hemoglobin inside an RBC expressed in picograms. The MCH is
calculated by dividing the hemoglobin concentration in grams per
deciliter by the RBC count in millions per microliter, then
multiplying by 10.
o MCHC (mean corpuscular hemoglobin concentration): which is the
average concentration of hemoglobin in the RBCs expressed in
percent. It is calculated by dividing the hemoglobin in grams per
deciliter by the hematocrit, then multiplying by 100.
33

WBC Differential count: which assess, diagnose, or rule out infectious and
inflammatory diseases, leukemia, lymphoma, and bone-marrow disorders. A
WBC count test measures two things:
o The total number of WBCs (leukocytes) and the differential count.
o The differential count measures the percentages of each type of
leukocyte present. White blood cells are composed of granulocytes
(neutrophils, eosinophils, and basophils) and non-granulocytes
(lymphocytes and monocytes).
Normal Values:
34
Interpretation of CBC Test:
* Common Expressions:
Type of Cell
Increase
Decrease
RBCs
erythrocytosis or
anemia or erythroblastopenia
polycythemia
WBCs
leukocytosis
leukopenia
lymphocytes
lymphocytosis
lymphocytopenia
granulocytes
granulocytosis
granulocytopenia or
agranulocytosis
neutrophils
neutrophilia
neutropenia
eosinophils
eosinophilia
eosinopenia
Platelets
thrombocytosis
thrombocytopenia
All cell lines
---
pancytopenia
RBCs:
Low RBCs
High RBCs

Blood loss, Hemorrhage

Low oxygen tension in the blood

Anemia (various types)

Congenital heart disease

Bone
(for

Pulmonary fibrosis
example, from radiation, toxin,

Dehydration (such as from severe
marrow
failure
fibrosis, tumor)
diarrhea)

Hemolysis(RBC destruction)

Leukemia

Multiple myeloma

Malnutrition
deficiencies

Renal (kidney) disease with high
erythropoietin production
(nutritional
of
iron,
folate,
vitamin B12, or vitamin B6)
35
WBCs:
Low WBCs

High WBCs
(for

Infectious diseases
example, due to infection, tumor

Inflammatory
Bone
marrow
failure
or fibrosis)
disease
(such
as
rheumatoid arthritis or allergy)

Presence of cytotoxic substance

Leukemia

Autoimmune/collagen-vascular

Severe emotional or physical stress
diseases

Tissue damage (SUCH AS burns)
(such
as
lupus
erythematosus)

Disease of the liver or spleen

Radiation exposure
Platelets:
Low Platelets
High Platelets

AIDS.

Aplastic anemia,

Viral infections.

Leukemia,

lymphoma,

Lymphoma, or
erythematosus.

Bone marrow fibrosis
Patients taking certain drugs,

Heparin treatment

most
notably
and
quinine
lupus
and
quinidine.
Heamoglobin:
Low Hemoglobin

Anemia (various types)

Blood loss (hemorrhage)

Hypoxia
36
Hematocrit Value:
Low Hematocrit
High Hematocrit

Anemia (various types)

Dehydration

Blood loss (hemorrhage)

Burns

Bone
(for

Diarrhea
example, due to radiation, toxin,

Polycythemia vera
fibrosis, tumor)

Low

marrow
failure
oxygen
tension
(smoking,
Hemolysis (RBC destruction)
congenital heart disease, living at
related to transfusion reaction
high altitudes)

Leukemia

Malnutrition
or
specific
nutritional deficiency

Multiple myeloma

Rheumatoid arthritis
Pathology
General medical disorders
* Disorders of volume
o Injury can cause blood loss through bleeding.[27] A healthy adult can lose
almost 20% of blood volume (1 L) before the first symptom, restlessness, begins, and
40% of volume (2 L) before shock sets in. Thrombocytes are important for blood
coagulation and the formation of blood clots, which can stop bleeding. Trauma to the
internal organs or bones can cause internal bleeding, which can sometimes be severe.
o Dehydration can reduce the blood volume by reducing the water content of
the blood. This would rarely result in shock (apart from the very severe cases) but
may result in orthostatic hypotension and fainting.
* Disorders of circulation
o Shock is the ineffective perfusion of tissues, and can be caused by a variety of
conditions including blood loss, infection, poor cardiac output.
o Atherosclerosis reduces the flow of blood through arteries, because atheroma
lines arteries and narrows them. Atheroma tends to increase with age, and its
37
progression can be compounded by many causes including smoking, high blood
pressure, excess circulating lipids (hyperlipidemia), and diabetes mellitus.
o Coagulation can form a thrombosis, which can obstruct vessels.
o Problems with blood composition, the pumping action of the heart, or
narrowing of blood vessels can have many consequences including hypoxia (lack of
oxygen) of the tissues supplied. The term ischemia refers to tissue that is inadequately
perfused with blood, and infarction refers to tissue death (necrosis), which can occur
when the blood supply has been blocked (or is very inadequate).
Hematological disorders
* Anemia
o Insufficient red cell mass (anemia) can be the result of bleeding, blood
disorders like thalassemia, or nutritional deficiencies; and may require blood
transfusion. Several countries have blood banks to fill the demand for transfusable
blood. A person receiving a blood transfusion must have a blood type compatible with
that of the donor.
o Sickle-cell anemia
* Disorders of cell proliferation
o Leukemia is a group of cancers of the blood-forming tissues.
o Non-cancerous overproduction of red cells (polycythemia vera) or platelets
(essential thrombocytosis) may be premalignant.
o Myelodysplastic syndromes involve ineffective production of one or more
cell lines.
* Disorders of coagulation
o Hemophilia is a genetic illness that causes dysfunction in one of the blood's
clotting mechanisms. This can allow otherwise inconsequential wounds to be lifethreatening, but more commonly results in hemarthrosis, or bleeding into joint spaces,
which can be crippling.
o Ineffective or insufficient platelets can also result in coagulopathy (bleeding
disorders).
38
o Hypercoagulable state (thrombophilia) results from defects in regulation of
platelet or clotting factor function, and can cause thrombosis.
* Infectious disorders of blood
o Blood is an important vector of infection. HIV, the virus, which causes AIDS,
is transmitted through contact with blood, semen or other body secretions of an
infected person. Hepatitis B and C are transmitted primarily through blood contact.
Owing to blood-borne infections, bloodstained objects are treated as a biohazard.
o Bacterial infection of the blood is bacteremia or sepsis. Viral Infection is
viremia. Malaria and trypanosomiasis are blood-borne parasitic infections.
Carbon monoxide poisoning
Substances other than oxygen can bind to hemoglobin; in some cases this can cause
irreversible damage to the body. Carbon monoxide, for example, is extremely
dangerous when carried to the blood via the lungs by inhalation, because carbon
monoxide irreversibly binds to hemoglobin to form carboxyhemoglobin, so that less
hemoglobin is free to bind oxygen, and fewer oxygen molecules can be transported
throughout the blood. This can cause suffocation insidiously. A fire burning in an
enclosed room with poor ventilation presents a very dangerous hazard, since it can
create a build-up of carbon monoxide in the air. Some carbon monoxide binds to
hemoglobin when smoking tobacco.[citation needed]
ANEMIA

It is a condition that is characterized by low RBC count, hemoglobin, and
hematocrit. The mechanisms by which anemia occurs will alter the RBC
indices in a predictable manner. Therefore, the RBC indices permit the
physician to narrow down the possible causes of an anemia. The category into
which a person's anemia is placed is in part based upon the red blood cell
indices provided.
39
 Most common types of anemias include:
a. Macrocytic anemia (high MCV) can be caused by vitamin B12 and
folic acid deficiencies.
b. Microcytic anemia (low MCV) can be due to Lack of iron in the diet,
thalassemia (a type of hereditary anemia), and chronic illness.
c. Normocytic anemia (normal MCV) can be caused by kidney and liver
disease, bone marrow disorders, leukemia, excessive bleeding, or
hemolysis of the red blood cells. Normocytic anemias are usually also
normochromic and share the same causes.
d. Hypochromic anemia (low MCHC) may be due to Iron deficiency and
thalassemia.
e. Sickle cell anemia may result from Abnormal hemoglobins, which can
change the shape of red blood cells as well as cause them to hemolyze,
or rupture.
BLOOD CULTURE…

A blood culture is a test to determine if microorganisms such as bacteria,
mycobacteria, or fungus are present in the blood. A sample of blood is put in a
special laboratory preparation and is incubated in a controlled environment for
1 to 7 days. Blood culture is performed when an infection of the blood
(bacteremia or septicemia) is suspected because of symptoms such as fever,
chills, or low blood pressure. Bacteremia sometimes comes and goes, so a
series of three blood cultures may be performed before a negative result is
confirmed.
BLOOD TYPE:

Your blood type is established before you are born, by specific genes inherited
from your parents. You receive one gene from your mother and one from your
father; these two combine to establish your blood type. These two genes
determine your blood type by causing proteins called agglutinogens to exist on
the surface of all of your red blood cells. In addition, other genes make
proteins called agglutinins that circulate in your blood plasma. Agglutinins are
40
responsible for ensuring that only the blood cells of your blood type exist in
your body.

There are three alleles or versions of the blood type gene: A, B, and O. Since
everybody has two copies of these genes, there are six possible combinations;
AA, BB, OO, AB, AO, and BO. In genetic terms, these combinations are
called genotypes, and they describe the genes you got from your parents.

The agglutinogen produced by the O allele has no special enzymatic activities.
However, the agglutinogens produced by the A and B alleles do have
enzymatic activities, which are different from each other.
Figure (21): The ABO Blood System
41
Figure (22): Blood transfusions
CASE STUDY
CASE NO. (1):
8 years old girl came with her mother to the physician complaining from general
fatigue, her mother says she does not eat enough, her skin seems pale. Her CBC
shows the following:
TEST
RESULT
UNIT
REFERENCE RANGE
Heamoglobin
9.4
g/dl
(C: 11-14 , M: 13-18 , F: 12-16)
RBCs
4.53
m/ul
(M: 4.5-6.5 , F :3.8-5.8)
Hematocrite
33.3
%
(M: 40-54 , F: 37-47)
MCV
73.5
fl
(76-95)
MCH
25.2
pg
(27-32)
MCHC
34.2
g/dl
(30-36)
Platelet count
98
thous/ul
(150-400)
WBCs
4.9
thous/ul
(A: 4-11 , C: 5-15)
Differential:
 Neutrophils
 Lymphocytes
 Monocytes
 Eosinophils
 Basophils
 Staff
64
22
8
4
0
2
%
%
%
%
%
%
(40-75)
(20-45)
(2-8)
(1-6)
(0-1)
(0-6)
QUESTIONS:

What is the most probable diagnosis?

What could be the cause of this condition?

What do you advice the mother to do?
42
CASE NO. (2):
52 years old man complaining from severe inability to perform any excessive
exercise. The physician notices a yellow discoloration in his eyes and skin. His CBC
shows the following:
TEST
RESULT
UNIT
REFERENCE RANGE
Heamoglobin
7.8
g/dl
(C: 11-14 , M: 13-18 , F: 12-16)
RBCs
5.11
m/ul
(M: 4.5-6.5 , F :3.8-5.8)
Hematocrite
27.7
%
(M: 40-54 , F: 37-47)
MCV
54
fl
(76-95)
MCH
15.3
pg
(27-32)
MCHC
28.3
g/dl
(30-36)
Platelet count
227
thous/ul
(150-400)
WBCs
4.7
thous/ul
(A: 4-11 , C: 5-15)
Differential:
 Neutrophils
 Lymphocytes
 Monocytes
 Eosinophils
 Basophils
 Staff
43.8
51.2
5
0
0
0
%
%
%
%
%
%
(40-75)
(20-45)
(2-8)
(1-6)
(0-1)
(0-6)
QUESTIONS:

What is the most probable diagnosis?

What could be the cause of this condition?

What do you expect the physician may do?
43
CASE NO. (3):
48 years old woman was admitted to hospital after a sudden severe pain not
responding to any medications, and severe constipation, the physician suspects it may
be Lymphoma, and he decides to give her radiotherapy immediately?
TEST
RESULT
UNIT
REFERENCE RANGE
Heamoglobin
10.8
g/dl
(C: 11-14 , M: 13-18 , F: 12-16)
RBCs
3.1
m/ul
(M: 4.5-6.5 , F :3.8-5.8)
Hematocrite
31.5
%
(M: 40-54 , F: 37-47)
MCV
87.2
fl
(76-95)
MCH
29
pg
(27-32)
MCHC
33.2
g/dl
(30-36)
Platelet count
216
thous/ul
(150-400)
WBCs
6.4
thous/ul
(A: 4-11 , C: 5-15)
Differential:
 Neutrophils
 Lymphocytes
 Monocytes
 Eosinophils
 Basophils
 Staff
30
59
5
5
0
1
%
%
%
%
%
%
(40-75)
(20-45)
(2-8)
(1-6)
(0-1)
(0-6)
QUESTIONS:

Do you agree with the physician’s diagnosis? Give reasons?

Is radiotherapy convenient to be given immediately in this case?
Give reasons?

If you were the physician what would be your decision?
44
CHAPTER III: LIVER FUNCTION TESTS
Anatomy of the liver

Liver is the largest and most versatile organ
in the body. It consists of two main lobes,
both of which are made up of thousands of
lobules. These lobules are connected to
small ducts that connect with larger ducts to
ultimately form the hepatic duct. The
hepatic duct transports the bile produced by
liver cells to the gallbladder and duodenum

The liver is located just below the
diaphragm
(the
muscular
membrane
separating the chest from the abdomen), in
Figure (23): Liver Anatomy
the right upper quadrant of the abdomin.

It has an abundant blood supply from two major vessels: hepatic artery and
portal vein
Liver facts

The liver has both external and internal secretions, which are formed in the
hepatic cells. Its external secretion, the bile, is collected after passing through
the bile ducts, which join two large ducts that unite to form the hepatic duct.
Bile is either carried to the gallbladder by the cystic duct or poured directly
into the duodenum by the common bile duct where it aids in digestion.

The bile helps to carry away waste products from the liver. All blood leaving
the stomach and intestines passes through the liver. Liver processes this blood
and breaks down the nutrients and drugs into forms that are easier to use for
the rest of the body.

Liver has reserve functional power and can operate effectively when most of
the hepatocytes are not working well. In addition, diseased hepatocytes can
actually regenerate and return to normal function.
45
Functions of the liver
Liver regulates most chemical levels in the blood. It is involved with almost all of the
biochemical pathways that allow growth, fight disease, supply nutrients, provide
energy, and aid reproduction. More than 500 vital functions have been identified with
the liver. Some of the more well-known functions include:

Metabolism: The liver is the organ that regulates the metabolism of fats,
carbohydrates, and protein. It does this in conjunction with the circulatory
system, the lymphatic system, and the endocrine (hormone) system. A healthy
liver is critical to proper protein, carbohydrate, and fat metabolism. It is
responsible for the production of certain proteins for blood plasma, production
of cholesterol and special proteins to help to carry fats through the body,
storing carbohydrates for energy, regulation of blood levels of amino acids,
which form the building blocks of proteins.

Detoxification: Drug detoxification is an important liver function. It is a
complex process that occurs in the endoplasmic reticulum of the hepatocyte.
Several phases are involved with this detoxification. Conversion of poisonous
ammonia to urea, which is one of the end products of protein metabolism that
is excreted in the urine. Clearing the blood of drugs and other poisonous
substances also occurs in the liver.

Bile Metabolism: Bile is made up of electrolytes, cholesterol, bile acids,
bilirubin, and globulins. It is produced and secreted by hepatocytes into
channels in the liver called bile cannaliculi, and stored in the gall bladder.
Drugs are eliminated in the bile, red blood cell are re-circulated through the
bile system, also fats are absorbed from the intestines into the bloodstream
only in the presence of bile. Fat soluble vitamins, A, D, E, and K, require bile
for proper absorption form the intestines. These vitamins are stored in the liver,
and are converted to active compounds as the liver maintains normal
physiology (homeostasis).
46

Coagulation Factors: The proteins that initiate and maintain clotting of blood
are synthesized by the liver. These proteins undergo very complex
biochemical processes to achieve this vital function. A diseased liver is unable
to synthesize these proteins, leading to a potential bleeding problem. Vitamin
K is also an essential component of these clotting mechanisms. When rat
poison (warfarin poisoning) is ingested it interferes with the ability of vitamin
K to perform this vital function. Controlling blood sugar levels and regulating
blood clotting.

Red Blood Cell System: Liver removes old or damaged red blood cells from
the circulation, and is involved with the storage of iron and the breakdown of
hemoglobin. Because of this, chronic liver disease could cause anemia.
Liver (along with the spleen), is a storage organ for blood. If there is a severe
blood loss the liver expels this blood into the bloodstream to help make up for
the loss.

Reticuloendothelial System: Specific cells, called Kupffer cells, line the
inside of the liver. These cells are part of the immune system. They eliminate
and degrade the substances that are brought into the liver by the portal vein.
Some of these substances are bacteria, toxins, nutrients, and chemicals. A
diseased liver will not filter these compounds normally, resulting in toxic
accumulations of toxins, chemicals, or bacteria. Excess accumulation of
bacteria in the bloodstream is called septicemia, and is one of the reasons that
antibiotics are commonly used in liver disease.

Vitamins: Many vitamins are stored in the liver, and perform their functions
only when activated by the liver, and are degraded by the liver. These include
some of the B vitamins and Vitamin C, along with A, D, E, and K previously
described.
47
Diagnosis of liver diseases

The diagnosis of liver disease depends upon a complete history, complete
physical examination, and evaluation of liver function tests and further
invasive and noninvasive tests. The hepatobiliary tree represents hepatic cells
and biliary tract cells.

In liver disease there are crossovers between purely biliary disease and
hepatocellular disease. To interpret these, the physician will look at the entire
picture of the hepatocellular disease and biliary tract disease to determine
which is the primary abnormality.

The function of the liver can not be evaluated with any single test. Because of
the organ’s many functions, including synthesis of proteins, detoxification,
immune modulation and bile metabolism, a battery of tests is necessary to
form a complete picture. As always, a thorough history and physical is the
basis of further testing. A variety of serologic and biochemical tests are
available, which may be supplemented by various specialized serum,
radiologic and histologic studies.
I. History:
A. Acute or chronic symptoms (many patients with abnormal liver tests are
asymptomatic)
B. Symptoms of liver disease such as: jaundice, acholic stool, dark urine, pruritus,
abdominal pain, fever, rash, fatigue.
C. Drug and toxin exposure: acetaminophen, non-steroidal anti-inflammatory
drugs (NSAIDS), herbal remedies, mushroom poisoning, any new drug use
D. Past History: previous biliary surgery, blood transfusions
E. Family history of liver disease
F. Social history: travel, alcohol abuse, tattoos
II. Physical examination:
A. General appearance: muscle wasting, paucity of body hair (axillary, pubic),
testicular atrophy, gynecomastia
B. Skin: abnormal pigmentation, needle tracks, scarring from skin abscesses or
popping, peripheral edema
48
C. Abdomen: Liver tenderness, enlargement, firmness; ascites; splenomegaly;
prominent abdominal collateral vessels
D. Neuropsychiatric: Confusion, depression, memory loss, inappropriate or
unusual behavior
III. Liver Function Tests (LFTs):
Liver function tests (LFTs) represent a broad
range of normal functions performed by the
liver. Interpretation of these tests, especially
their pattern, will narrow the differential
diagnosis and allow more refined diagnostic
procedures. LFTs include:
1. Liver Enzymes:
a. Alanine Aminotransferase (ALT)
b. Aspartate Aminotransferase (AST)
Figure (24): Liver function tests
c. Alkaline Phosphatase (AP)
d. Gamma Glutamyltranspeptidase (GGT)
2. Albumin: besides total proteins
3. International Normalized Ratio (INR): a standardized value of prothrombin time
4. Total/Direct Bilirubin (TB/DB): These two values are measured directly in the
laboratory. The difference between the two values is termed the indirect bilirubin.
Liver enzymes:
There are two general categories of “liver enzymes”. The first group includes ALT
and AST, sometimes referred to as the SGPT and SGOT respectively. These are
enzymes that are indicators of liver cell damage. The other frequently used liver
enzymes are the ALP and gamma-glutamyltranspeptidase (GGT) that indicate
obstruction to the biliary system, either within the liver or in the larger bile channels
outside the liver.
49
Transaminases
These enzymes involved in the transfer of amino groups to ketoglutaric acid. AST and
ALT are elevated in syndromes of hepatocellular injury. Aminotransferase elevation
is often the first biochemical abnormality detected in a patient with viral, druginduced or alcoholic hepatitis. Normal range varies by laboratory but is generally (0 35 U/L).
a. Alanine Aminotransferase (ALT):
ALT is an enzyme produced within the cells of the liver. The level of ALT
abnormality is increased in conditions where cells of the liver have been inflamed or
undergone cell death. As the cells are damaged, the ALT leaks into the bloodstream
leading to a rise in the serum levels. Any form of hepatic cell damage can result in an
elevation in the ALT. The ALT level may or may not correlate with the degree of cell
death or inflammation. ALT is the most sensitive marker for liver cell damage.
b. Aspartate Aminotransferase (AST):
This enzyme also reflects damage to the hepatic cell. It is less specific for liver
disease. Although AST is not a specific for liver as the ALT, ratios between ALT and
AST are useful to physicians in assessing the etiology of liver enzyme abnormalities.
Clinical Notes
a. ALT > 1000 U/L: a limited differential diagnosis
• Acute viral hepatitis
• Drug toxicity (especially acetaminophen)
• Autoimmune hepatitis
b. AST/ALT ratio > 2: sensitive but not specific for alcoholic hepatitis. It should
be noted, however, that aminotransferases are rarely elevated greater than ten
times the upper limit of normal in alcoholic liver disease
c. ALT predominance
• Chronic viral hepatitis or Autoimmune hepatitis
• Nonalcoholic fatty liver disease (NAFLD)
• Metabolic diseases (Hemochromatosis, Wilson’s disease, Alpha-1antitrypsin deficiency)
• Medications
50
Alkaline Phosphatase (ALP):
Alkaline phosphatase is an enzyme, which is associated with the biliary tract. It is not
specific to the biliary tract. It is also found in bone and the placenta. Renal or
intestinal damage can also cause rise in the alkaline phosphatase level. If the alkaline
phosphatase is elevated, biliary tract damage and inflammation should be considered.
However, considering the above other etiologies must also be entertained. One way to
assess the etiology of the alkaline phosphatase is to perform a serologic evaluation
called isoenzymes. Another more common method to asses the etiology of the
elevated alkaline phosphatase is to determine whether the GGT is elevated or whether
other function tests are abnormal (e.g. bilirubin). Alkaline phosphatase may be
elevated
in
primary
biliary
cirrhosis,
alcoholic
hepatitis,
gallstones
in
cholecholithiasis.
Gamma Glutamyl Transpeptidase (GGT):
This enzyme is also produced by the bile ducts. However, it is not very specific to the
liver or bile ducts. It is used often times to confirm that the alkaline phosphatase is of
the hepatic etiology. Certain GGT levels, as an isolated finding, reflect rare forms of
liver disease. Medications commonly cause GGT to be elevated. Liver toxins such as
alcohol can also cause increases in the GGT.
Clinical Notes:
1. Extrahepatic cholestasis (biliary obstruction): Synthesis of AP by biliary
epithelial cells is increased, leading to serum elevation. Imaging by ultrasound, CT
or MRI will demonstrate biliary dilatation
a. Gallstones
b. Tumor (pancreas, bile duct, lymph nodes)
2. Intrahepatic cholestasis: Dysfunction of bile transport due to acute or chronic
injury
a. Primary biliary cirrhosis
b. Medications
c. alcohol
51
ALBUMIN:
Albumin: major plasma protein, synthesized exclusively by the liver. Albumin can be
decreased in any chronic illness, but in the setting of chronic liver disease, decreased
serum albumin (normal 3.5-5.5 g/dL) is indicative of severe hepatic disease and liver
synthetic dysfunction. Other causes of decreased serum albumin include nephrotic
syndrome, protein-losing enteropathy and malnutrition.
* Total protein (TP):
Total protein is a rough measure of the total protein in the blood. Measurements of
protein may reflect liver disease, nutritional state, kidney disease and others. In
general, protein consists of albumin and globulin. Albumin is formed in the liver; it
transports blood constituents. Globulin is a building block of antibodies, proteins, and
clotting factors. Globulin is made up of about 60 different important proteins. A
decreased value of total protein may indicate liver or kidney disease.
* Serum protein electrophoresis:
This is an evaluation of the types of proteins that are present with in a patient's serum.
By using an electrophoretic gel, major proteins can be separated out. This results in
four major types of proteins. These are albumin, alpha globulins, beta globulins and
gammaglobulins. This test is useful for evaluation of patients who have abnormal
liver function tests since it allows a direct quantification of multiple different serum
proteins. If the gamma globulin fraction is elevated, autoimmune hepatitis may be
present. In addition a deficiency in the alpha globulin fraction can result in the
diagnosis, or a clinical clue to alpha-1 antitrypsin deficiency.
International Normalized Ratio (INR):
A measurement of clotting factor II, prothrombin. An early and sensitive marker of
liver synthetic dysfunction
1. Acute liver injury: elevated INR implies a worse prognosis for recovery
2. Chronic liver disease: Elevation of INR, an early sign of liver synthetic
dysfunction, implies advanced disease
3. Cholestatic liver disease: INR may be elevated due to malabsorption of fatsoluble Vitamin K.
4. Extensive antibiotic use and malnutrition can lead to Vitamin K deficiency
52
Platelet count:
Platelets are fragments of cells that form the primary mechanism in blood clots.
They're also the smallest of blood cells. They derived from the bone marrow from the
larger cells known as megakaryocytes. Individuals with liver disease develop a large
spleen. As this process occurs platelets are trapped with in the sinusoids (small
pathways within the spleen) of the spleen. While the trapping of platelets is a normal
function for the spleen, in liver disease it becomes exaggerated because subsequently,
the platelet count may become diminished.
BILIRUBIN:
Bilirubin is the main bile pigment that is formed from the breakdown of heme in red
blood cells. The broken down heme travels to the liver, where it is secreted into the
bile by the liver. Serum bilirubin is considered a true test of liver function, as it
reflects the liver's ability to take up, process, and secrete bilirubin into the bile.
Bilirubin production and excretion follows a specific pathway. When the
reticuloendothelial system breaks down old red blood cells, bilirubin is one of the
waste products. This "free bilirubin", is in a lipid-soluble form that must be made
water-soluble to be excreted. The free, or unconjugated, bilirubin is carried by
albumin to the liver, where it is converted or conjugated and made water soluble.
Once it is conjugated into a water-soluble form, bilirubin can be excreted in the urine.
Because the bilirubin is chemically different after it goes through the conjugation
process in the liver, lab tests can differentiate between the unconjugated or indirect
bilirubin and conjugated or direct bilirubin (see figure 25)
Bilirubin concentrations are elevated in the blood either by increased production,
decreased conjugation, decreased secretion by the liver, or blockage of the bile ducts.
In cases of increased production, or decreased conjugation, the unconjugated or
indirect form of bilirubin will be elevated. Unconjugated hyperbilirubinemia is caused
by
accelerated
erythrocyte
hemolysis
(lheamolytic
anemia).
Conjugated
hyperbilirubinemia is caused by obstruction of the biliary ducts, as with gallstones or
hepatocellular diseases such as cirrhosis or hepatitis. Elevated serum bilirubin test
results may also be caused by the effects of many different drugs, including
antibiotics, barbiturates, steroids, or oral contraceptives. In chronic acquired liver
53
diseases, the serum bilirubin concentration is usually normal until a significant
amount of liver damage has occurred and cirrhosis is present. In acute liver disease,
the bilirubin is usually increased in relation to the severity of the acute process.
Almost all of the bilirubin produced is excreted as one of the components of bile salts.
Bilirubin is the pigment that gives bile its characteristic bright greenish yellow color.
When the bile salts reach the intestine via the common bile duct, the bilirubin is acted
on by bacteria to form chemical compounds called urobilinogens. Most of the
urobilinogen is excreted in the feces; some is reabsorbed and goes through the liver
again and a small amount is excreted in the urine. Urobilinogen gives feces their dark
color. An absence of bilirubin in the intestine, such as may occur with bile duct
obstruction, blocks the conversion of bilirubin to urobilinogen, resulting in claycolored stools.
Figure (25): Bilirubin metabolism
Step 1: Red blood cells are broken down by the reticuloendothelial system and unconjugated bilirubin in the bloodstream is
carried by albumin to the liver. This is known as "pre-hepatic," "free," "unconjugated," or"indirect bilirubin" (normal
value = 0.1 - 1.0 mg/dl)
Step 2: The liver converts or conjugates bilirubin and makes it water-soluble. This is known as "post-hepatic", "conjugated" or
"direct" bilirubin (normal value = 0.0 - 0.4 mg/dl)
Step 3: Conjugated bilirubin is excreted via bile salts to intestine. Bacteria in the intestine break down bilirubin to urobilinogen
for excretion in the feces (normal value for fecal urobilinogen = 40 - 280 mg/day)
54
Jaundice
Jaundice is the discoloration of body
tissues caused by abnormally high levels
of bilirubin. Bilirubin levels greater than
3mg/dl usually produce jaundice. Once
the jaundice is recognized clinically, it is
important to determine whether the
increased bilirubin level is prehepatic or
posthepatic jaundice.
Figure (26): Jaundice
A rise in unconjugated bilirubin indicates prehepatic or hepatic jaundice and is treated
medically, whereas a rise in conjugated bilirubin indicates posthepatic jaundice or
biliary obstruction, a condition that may require bile duct surgery or therapeutic
endoscopy.
Figure (27): Biliary Obstruction
Physiologic jaundice:
Physiologic jaundice of the newborn is a result of
the immature liver's lacking sufficient conjugating
enzymes. The newborn's inability to conjugate
bilirubin results in high circulating blood levels of
unconjugated bilirubin, which, if untreated, passes
Figure (28): Physiologic jaundice
55
through the blood-brain barrier. The bilirubin level must be monitored closely to
prevent brain damage. Bilirubin levels can be decreased by exposing newborns to
ultraviolet light.
Clinical Notes:
Total bilirubin is composed of unconjugated (indirect) bilirubin and conjugated (direct)
bilirubin
1. Unconjugated hyperbilirubinemia: diagnosed if more than 80% of an elevated total
bilirubin is indirect. Elevation results from either increased bilirubin production
outstripping the liver capacity to conjugate bilirubin, or reduced hepatic ability to
conjugate bilirubin
a. Increased bilirubin production
• Hemolytic anemias (bilirubin rarely > 4 mg/dL)
• Hematoma
• Ineffective erythropoiesis (thalassemia, pernicious anemia)
• Neonatal (physiologic) jaundice
b. Reduced or absent glucuronosyltransferase activity
• Gilbert’s syndrome: this is common in young men. Often runs in families
• Crigler-Najjar syndromes (Types I & II): rare syndromes
• Neonatal (physiologic) jaundice
2. Conjugated hyperbilirubinemia: diagnosed if more than 50% of the elevated bilirubin
is direct. Elevation results from either impaired hepatic secretion or decreased hepatic
uptake of conjugated bilirubin
a. Impaired biliary secretion
• Extrahepatic obstruction – (e.g. stones, tumors, stricture)
• Intrahepatic hepatocellular, canalicular, or ductular damage
• Dubin-Johnson syndrome (rare)
b. Decreased hepatic uptake/storage/secretion
• Rotor’s syndrome (rare)
56
OTHER DIAGNOSTIC TECHNIQUES
Abdominal ultrasound
Abdominal ultrasound is an imaging procedure
used to examine the internal organs of the
abdomen including the liver. It is a perfect
technique for visualizing the circulation of the
liver, the bile duct system, the density of the liver
tissue, the size of the liver.
Figure (29): Abdominal ultrasound
Liver Biopsy
The liver is a pyramid-shaped organ that lies
within the upper right side of the abdomen. In a
typical liver biopsy, a needle is inserted through
the rib cage or abdominal wall and into the liver
to obtain a sample for examination. The
procedure can also be performed by inserting a
needle into the jugular vein in the neck and
passing a catheter through the veins down to the
liver to obtain the sample.
Figure (30): Liver Biopsy
Approach to a patient with abnormal liver profile
1. History and Physical examination: Exposures to infectious agents, alcohol use,
medications toxicity, complementary remedies, known history of liver disease, family
history, etc.
2. Differentiate hepatocellular pattern from cholestatic/infiltrative profile
a. If AST/ALT elevation is the predominant abnormality: hepatocellular injury
b. If alkaline phosphatase, bilirubin elevation is the predominant abnormality:
cholestasis/infiltrative-cross sectional image needed to assess dilatation of
biliary system: if non-dilated, intrahepatic cholestasis. If dilated: biliary
obstruction
c. Further testing as needed to narrow diagnosis.
57
CASE STUDY
CASE NO. (1):
The following laboratory test results were obtained in a patient with severe jaundice,
right upper quadrant abdominal pain, fever and chills. What is the most likely cause of
jaundice in this patient???
Serum ALP
Serum Chol.
AST
5’ Nucleotidase
4 times normal
Increased
Normal or slightly increased
Increased
Total bilirubin
25 mg/dl
Conj. bilirubin
Prothronbin time
19 mg/dl
Prolonged but improves with vit. K injection
CASE NO. (2):
The following laboratory test results were found in a patient with mild weight loss and
nausea and vomiting, who later developed jaundice and an enlarged liver
(hepatomegaly). What disease process is most likely in this patient???
Total bilirubin
20 mg/dl
Conj. Bilirubin
ALP
10 mg/dl
Mildly elevated
AST
Markedly elevated
ALT
Albumin
Gamma Globulin
Moderately elevated
Decreased
Increased
58
HEPATITIS
Definition
Hepatitis is an inflammation of the liver characterized by the presence of
inflammatory cells in the tissue of the organ. The condition can be self-limiting
(healing on its own) or can progress to fibrosis (scarring) and cirrhosis. Hepatitis may
occur with limited or no symptoms, but often leads to jaundice, anorexia (poor
appetite) and malaise. Hepatitis is acute when it lasts less than six months and chronic
when it persists longer. A group of viruses known as the hepatitis viruses cause most
cases of hepatitis worldwide, but it can also be due to toxins (notably alcohol, certain
medications and plants), other infections and autoimmune diseases.
Causes
Acute hepatitis

Infectious viral hepatitis such as hepatitis A, B, C, D and E.

Other viral diseases such as: mononucleosis and cytomegalovirus.

Severe bacterial infections.

Amoebic infections.

Medicines (i.e. paracetamol poisoning and halothane (an anaesthetic).

Toxins: alcohol and fungal toxins.
Chronic hepatitis

Contagious viral hepatitis such as hepatitis B, C and D.

Medicines.

Toxins such as alcohol.

Autoimmune hepatitis. This is a disease in which a number of liver cells are
destroyed by the patient's own immune system. Autoimmune hepatitis can also
sometimes occur as acute hepatitis. The cause is unknown.

Inborn metabolic disorders, such as Wilson's disease (disorder of the body's
copper metabolism) and haemochromatosis (disorder of the body's iron
metabolism).
59
Hepatitis A virus

Hepatitis A (formerly known as infectious
hepatitis) is an acute infectious disease of the
liver caused by the hepatitis A virus (HAV).

It is a Picornavirus, it is non-enveloped and
contains a single-stranded RNA packaged in a
protein shell. There is only one serotype of the
virus, but multiple genotypes exist.

It is most commonly transmitted by the fecal-oral route via contaminated food
or drinking water. The incubation period is between two and six weeks and the
average incubation period is 28 days.

Hepatitis A is not progressive, does not have a chronic stage and does not
cause permanent liver damage. Following infection, the immune system
makes antibodies against HAV that confer immunity against future infection.

The disease can be prevented by vaccination, and hepatitis A vaccine has been
proven effective in controlling outbreaks worldwide.
Signs and symptoms
Early symptoms of hepatitis A infection can be mistaken for influenza, but some
patients, especially children, exhibit no symptoms at all. Symptoms typically appear 2
to 6 weeks, (the incubation period), after the initial infection. Symptoms can return
over the following 6–9 months and include:

Sharp pains in the right-upper quadrant of the abdomen

Fatigue, Fever, Appetite loss and Weight loss

Abdominal pain, Nausea, Diarrhea, Itching and Depression

Jaundice, a yellowing of the skin or whites of the eyes

Bile is removed from blood stream and excreted in urine, giving it a dark
amber colour

Feces tend to be light in colour due to lack of bilirubin in bile.
60
Diagnosis

Specific diagnosis is made by the detection of HAV-specific IgM antibodies in
the blood. IgM antibody is only present in the blood following an acute
hepatitis A infection. It is detectable from one to two weeks after the initial
infection and persists for up to 14 weeks.

While the presence of IgG antibody in the blood means that the acute stage of
the illness is past and the person is immuned to further infection. IgG antibody
to HAV is also found in the blood following vaccination.

During the acute stage of the infection, alanine transferase enzyme (ALT) is
highly elevated in blood which reflects the hepatocellular damage caused by
the virus.

Hepatitis A virus is present in the blood, (viremia), and feces of infected
people up to two weeks before clinical illness develops.
Figure ():Serum IgG, IgM and ALT following Hepatitis A virus infection
Treatment
There is no specific treatment for hepatitis A. patients are advised to rest, avoid fatty
foods and alcohol (these may be poorly tolerated for some additional months during
the recovery phase and cause minor relapses), eat a well-balanced diet, and stay
hydrated.
61
Hepatitis B virus

Hepatitis B is an infectious illness caused by
hepatitis
B
virus
(HBV).
It
is
an
hepadnavirus—hepa from hepatotrophic and
dna because it is a DNA virus- and it has a
circular genome composed of partially
double-stranded DNA.

Although replication takes place in the liver, the virus spreads to the blood
where virus-specific proteins and their corresponding antibodies are found in
infected people.

Unlike hepatitis A, hepatitis B does not generally spread through water and
food. Instead, it is transmitted through body fluids; prevention is thus the
avoidance of such transmission: blood transfusions, re-use of contaminated
needles and syringes, and vertical transmission during child birth. Infants may
be vaccinated at birth
Signs and symptoms

Acute infection with hepatitis B virus is associated with acute viral hepatitis –
an illness that begins with general ill-health, loss of appetite, nausea, vomiting,
body aches, mild fever, dark urine, and then progresses to development of
jaundice. It has been noted that itchy skin has been an indication as a possible
symptom of all hepatitis virus types. The illness lasts for a few weeks and then
gradually improves in most affected people. A few patients may have more
severe liver disease (fulminant hepatic failure), and may die as a result of it.
The infection may be entirely asymptomatic and may go unrecognized.

Chronic infection with hepatitis B virus may be either asymptomatic or may
be associated with a chronic inflammation of the liver (chronic hepatitis),
leading to cirrhosis over a period of several years. This type of infection
dramatically increases the incidence of hepatocellular carcinoma (liver cancer).
Chronic carriers are encouraged to avoid consuming alcohol as it increases
their risk for cirrhosis and liver cancer
62
Structure

The hepatitis B virion, is a complex,
spherical, double shelled particle with a
diameter of 42 nm.

The thick outer viral envelope or membrane
contains host-derived lipids and surface
proteins, known collectively as HBsAg.

Within the membrane sphere is a thick icosahedral nucleocapsid inner core
composed of protein (HBcAg). When viewed through an electron microscope
the inner core may appear pentagonal or hexagonal, depending on the relative
position of the sample.

The nucleocapsid contains a viral genome of circular, partially double
stranded DNA and endogenous DNA polymerase.
Serotypes and genotypes
The virus is divided into four major serotypes (adr, adw, ayr, ayw) based on antigenic
epitopes presented on its envelope proteins, and into eight genotypes (A-H) according
to overall nucleotide sequence variation of the genome. The genotypes have a distinct
geographical distribution and are used in tracing the evolution and transmission of the
virus. Differences between genotypes affect the disease severity, course and
likelihood of complications, and response to treatment and possibly vaccination..
Africa has five genotypes (A-E). Of these the predominant genotypes are B and D in
Egypt.
Diagnosis

Assays for detection of hepatitis B virus infection involve serum or blood tests
that detect either viral antigens (proteins produced by the virus) or antibodies
produced by the host. Interpretation of these assays is complex.

The hepatitis B surface antigen (HBsAg) is most frequently used to screen for
the presence of infection. It is the first detectable viral antigen to appear during
63
infection. However, early in an infection, this antigen may not be present and
it may be undetectable later in the infection as it is being cleared by the host.

The infectious virion contains an inner "core particle" enclosing viral genome.
The icosahedral core particle is made of 180 or 240 copies of core protein,
alternatively known as hepatitis B core antigen, or HBcAg. During this
'window' in which the host remains infected but is successfully clearing the
virus, IgM antibodies to the hepatitis B core antigen (anti-HBc IgM) may be
the only serological evidence of disease.

Shortly after the appearance of the HBsAg, another antigen named as the
hepatitis B e antigen (HBeAg) will appear. Traditionally, the presence of
HBeAg in a host's serum is associated with much higher rates of viral
replication and enhanced infectivity; however, variants of the hepatitis B virus
do not produce the 'e' antigen, so this rule does not always hold true. During
the natural course of an infection, the HBeAg may be cleared, and antibodies
to the 'e' antigen (anti-HBe) will arise immediately afterwards. This
conversion is usually associated with a dramatic decline in viral replication.
Figure (): Hepatitis B viral antigens and antibodies detectable in the blood following acute infection.
64

If the host is able to clear the infection, eventually the HBsAg will become
undetectable and will be followed by IgG antibodies to the hepatitis B surface
antigen and core antigen, (anti-HBs and anti HBc IgG).[7] The time between
the removal of the HBsAg and the appearance of anti-HBs is called the
window period. A person negative for HBsAg but positive for anti-HBs has
either cleared an infection or has been vaccinated previously.

Individuals who remain HBsAg positive for at least six months are considered
to be hepatitis B carriers. Carriers of the virus may have chronic hepatitis B,
which would be reflected by elevated serum alanine aminotransferase levels
and inflammation of the liver, as revealed by biopsy. Carriers who have
seroconverted to HBeAg negative status, particularly those who acquired the
infection as adults, have very little viral multiplication and hence may be at
little risk of long-term complications or of transmitting infection to others.

PCR tests have been developed to detect and measure the amount of HBV
DNA, called the viral load, in clinical specimens. These tests are used to
assess a person's infection status and to monitor treatment. Individuals with
high viral loads, characteristically have ground glass hepatocytes on biopsy.
.Figure (): Hepatitis B viral antigens and antibodies detectable in the blood of a chronically infected person.
Prevention
Following vaccination, hepatitis B surface antigen may be detected in serum for
several days; this is known as vaccine antigenaemia. The vaccine is administered in
65
either two-, three-, or four-dose schedules into infants and adults, which provides
protection for 85–90% of individuals.
Treatment
Acute hepatitis B infection does not usually require treatment because most adults
clear the infection spontaneously. Early antiviral treatment may only be required in
fewer than 1% of patients, whose infection takes a very aggressive course (fulminant
hepatitis) or who are immunocompromised. On the other hand, treatment of chronic
infection may be necessary to reduce the risk of cirrhosis and liver cancer.
Chronically infected
individuals
with
persistently
elevated
serum
alanine
aminotransferase (ALT) and HBV DNA levels are candidates for therapy. Although
none of the available drugs can clear the infection, they can stop the virus from
replicating, thus minimizing liver damage. The treatment reduces viral replication in
the liver, thereby reducing the viral load (the amount of virus particles as measured in
the blood). The use of interferon, which requires injections daily or thrice weekly, has
been supplanted by long-acting PEGylated interferon, which is injected only once
weekly. However, some individuals are much more likely to respond than others and
this might be because of the genotype of the infecting virus or the patient's heredity.
Prognosis
Hepatitis B virus infection may either be acute (self-limiting) or chronic (longstanding). Persons with self-limiting infection clear the infection spontaneously within
weeks to months. Children are less likely than adults to clear the infection. More than
95% of people who become infected as adults or older children will stage a full
recovery and develop protective immunity to the virus. However, this drops to 30%
for younger children, and only 5% of newborns that acquire the infection from their
mother at birth will clear the infection.
Reactivation
Hepatitis B virus DNA persists in the body after infection and in some people the
disease recurs. Although rare, reactivation is seen most often in people with impaired
immunity. HBV
goes
through
cycles of
replication and non-replication.
Approximately 50% of patients experience acute reactivation. Male patients with
66
baseline ALT of 200 UL/L are three times more likely to develop a reactivation than
patients with lower levels.
Hepatitis C Virus

Hepatitis C is an infectious disease affecting the liver,
caused by the hepatitis C virus (HCV). The virus was
first identified in the 1970s as "non-A non-B hepatitis"
then proven conclusively in 1989. The Hepatitis C virus
is a small (50 nm in size), enveloped, single-stranded,
positive sense RNA virus. There are six major
genotypes of the hepatitis C virus.

The hepatitis C virus is transmitted by blood-to-blood contact. In developed
countries, it is estimated that 90% of persons with chronic HCV infection were
infected through transfusion of unscreened blood or blood products or via
injecting drug use or sexual exposure. In developing countries, the primary
sources of HCV infection are unsterilized injection equipment and infusion of
inadequately screened blood and blood products. The virus may be sexually
transmitted, although this is rare.

Vertical transmission refers to the transmission of a communicable disease
from an infected mother to her child during the birth process. Mother-to-child
transmission of hepatitis C has been well described, but occurs relatively
infrequently. Transmission occurs only among women who are HCV RNA
positive at the time of delivery; the risk of transmission in this setting is
approximately 6 out of 100. Among women who are both HCV and HIV
positive at the time of delivery, the risk of transmitting HCV is increased to
approximately 25 out of 100. The risk of vertical transmission of HCV does
not appear to be associated with method of delivery or breastfeeding

Hepatitis C is a strictly human disease. It cannot be contracted from or given
to any other animal. Chimpanzees can be infected with the virus in the
laboratory, but do not develop the disease, which has made research more
difficult. No vaccine against hepatitis C is available.
67
Signs and symptoms
A- Acute

Acute hepatitis C refers to the first 6 months after infection with HCV.
Between 60% to 70% of people infected develop no symptoms during the
acute phase. In the minority of patients who experience acute phase symptoms,
they are generally mild and non-specific, and rarely lead to a specific
diagnosis of hepatitis C. Symptoms of acute hepatitis C infection include
decreased appetite, fatigue, abdominal pain, jaundice, itching, and flu-like
symptoms.

The hepatitis C virus is usually detectable in the blood within one to three
weeks after infection by PCR, and antibodies to the virus are generally
detectable within 3 to 15 weeks. Spontaneous viral clearance rates are highly
variable and between 10–60% of persons infected with HCV clear the virus
from their bodies during the acute phase as shown by normalization in liver
enzymes (alanine transaminase (ALT) & aspartate transaminase (AST), and
plasma HCV-RNA clearance (this is known as spontaneous viral clearance).
However, persistent infections are common and most patients develop chronic
hepatitis C, i.e., infection lasting more than 6 months.

Previous practice was to not treat acute infections to see if the person would
spontaneously clear; recent studies have shown that treatment during the acute
phase of genotype 1 infections has a greater than 90% success rate with half
the treatment time required for chronic infections.
B- Chronic

Chronic hepatitis C is defined as infection with the hepatitis C virus persisting
for more than six months. Clinically, it is often asymptomatic (without
symptoms) and it is mostly discovered accidentally (e.g. usual checkup).

The natural course of chronic hepatitis C varies considerably from one person
to another. Although almost all people infected with HCV have evidence of
68
inflammation on liver biopsy, the rate of progression of liver scarring
(fibrosis) shows significant variability among individuals. Accurate estimates
of the risk over time are difficult to establish because of the limited time that
tests for this virus have been available.

Recent data suggest that among untreated patients, roughly one-third progress
to liver cirrhosis in less than 20 years. Another third progress to cirrhosis
within 30 years. The remainder of patients appear to progress so slowly that
they are unlikely to develop cirrhosis within their lifetimes.

Factors that have been reported to influence the rate of HCV disease
progression include age (increasing age associated with more rapid
progression), gender (males have more rapid disease progression than females),
alcohol consumption (associated with an increased rate of disease progression),
HIV coinfection (associated with a markedly increased rate of disease
progression), and fatty liver (the presence of fat in liver cells has been
associated with an increased rate of disease progression).

Symptoms specifically suggestive of liver disease are typically absent until
substantial scarring of the liver has occurred. Generalized signs and symptoms
associated with chronic hepatitis C include fatigue, flu-like symptoms, joint
pains, itching, sleep disturbances, appetite changes, nausea, and depression.

Once chronic hepatitis C has progressed to cirrhosis, signs and symptoms may
appear that are generally caused by either decreased liver function or increased
pressure in the liver circulation, a condition known as portal hypertension.
Possible signs and symptoms of liver cirrhosis include ascites (accumulation
of fluid in the abdomen), bruising and bleeding tendency, varices (enlarged
veins, especially in the stomach and esophagus), jaundice, and a syndrome of
cognitive
impairment
known
as
hepatic
encephalopathy.
Hepatic
encephalopathy is due to the accumulation of ammonia and other substances
normally cleared by a healthy liver.
Diagnosis

The diagnosis of chronic phase hepatitis C is also challenging due to the
absence or lack of specificity of symptoms until advanced liver disease
develops, which may not occur until decades into the disease. The diagnosis of
69
"hepatitis C" is rarely made during the acute phase of the disease because the
majority of people infected experience no symptoms during this phase of the
disease.

Chronic hepatitis C may be suspected on the basis of the medical history
(particularly if there is any history of IV drug abuse or inhaled substance
usage such as cocaine), a history of piercings or tattoos, unexplained
symptoms, or abnormal liver enzymes or liver function tests found during
routine blood testing. Occasionally, hepatitis C is diagnosed as a result of
targeted screening such as blood donation (blood donors are screened for
numerous blood-borne diseases including hepatitis C) or contact tracing.

Hepatitis C testing begins with serological blood tests used to detect
antibodies to HCV. Anti-HCV antibodies can be detected in 80% of patients
within 15 weeks after exposure, in >90% within 5 months after exposure, and
in >97% by 6 months after exposure. Overall, HCV antibody tests have a
strong positive predictive value for exposure to the hepatitis C virus, but may
miss patients who have not yet developed antibodies (sero-conversion), or
have an insufficient level of antibodies to detect.

Rarely, people infected with HCV never develop antibodies to the virus and
therefore, never test positive using HCV antibody screening. Because of this
possibility, RNA testing should be considered when antibody testing is
negative but suspicion of hepatitis C is high (e.g. because of elevated
transaminases in someone with risk factors for hepatitis C). However, liver
function tests alone are not useful in predicting the severity of infection and
normal results do not exclude the possibility of liver disease.

Anti-HCV antibodies indicate exposure to the virus, but cannot determine if
ongoing infection is present. All persons with positive anti-HCV antibody
tests must undergo additional testing for the presence of the hepatitis C virus
itself to determine whether current infection is present. The presence of the
virus is tested for using molecular nucleic acid testing methods such as
polymerase chain reaction (PCR). All HCV nucleic acid molecular tests have
the capacity to detect not only whether the virus is present, but also to measure
the amount of virus present in the blood (the HCV viral load). The HCV viral
load is an important factor in determining the probability of response to
70
interferon-based therapy, but does not indicate disease severity nor the
likelihood of disease progression.

In people with confirmed HCV infection, genotype testing is generally
recommended. HCV genotype testing is used to determine the required length
and potential response to interferon-based therapy.
Figure (): Serologic profile of Hepatitis C infection
Prevention
Strategies such as the provision of new needles and syringes, and education about
safer drug injection procedures, greatly decrease the risk of hepatitis C spreading
between injecting drug users. No vaccine protects against contracting hepatitis C, or
helps to treat it. Vaccines are under development and some have shown encouraging
results.
Treatment
The hepatitis C virus induces chronic infection in 50%-80% of infected persons.
Approximately 50% of these do not respond to therapy. There is a very small chance
of clearing the virus spontaneously in chronic HCV carriers (0.5% to 0.74% per year).
However, the majority of patients with chronic hepatitis C will not clear it without
treatment.
71
Medications (interferon and ribavirin)

Current treatment is a combination of Pegylated interferon-alpha-2a or
Pegylated interferon-alpha-2b and the antiviral drug ribavirin for a period of
24 or 48 weeks, depending on hepatitis C virus genotype.

Treatment is generally recommended for patients with proven hepatitis C virus
infection and persistently abnormal liver function tests. Treatment during the
acute infection phase has much higher success rates (greater than 90%) with a
shorter duration of treatment.

Those with low initial viral loads respond much better to treatment than those
with higher viral loads (greater than 400,000 IU/mL).

The treatment may produce some side effects ranging from a 'flu-like'
syndrome (the most common, experienced for a few days after the weekly
injection of interferon) to severe adverse events including anemia,
cardiovascular events and psychiatric problems such as suicide or suicidal
ideation.

Responses can vary by genotype. Genotype 4 is more common in the Middle
East and Africa. Sustained response is about 65% in those with genotype 4
given 48 weeks of treatment.
Additional recommendations and alternative therapies

Current guidelines strongly recommend that hepatitis C patients be vaccinated
for hepatitis A and B if they have not yet been exposed to these viruses, as
infection with a second virus could worsen their liver disease.

Alcohol consumption accelerates HCV associated fibrosis and cirrhosis, and
makes liver cancer more likely; insulin resistance and metabolic syndrome
may similarly worsen the hepatic prognosis. There is also evidence that
smoking increases the fibrosis (scarring) rate.

Several alternative therapies aim to maintain liver functionality, rather than
treat the virus itself, thereby slowing the course of the disease to retain quality
of life (i.e. extract of Silybum).
72
Case No. (1):
A 42-year-old single white male went to his physician with complaints of fatigue,
abdominal pain and loss of appetite.
Past medical history: He had no history of hepatitis A vaccination or hepatitis B
vaccination. He reported being subjected to earlier blood transfusion
Physical examination: the whites of his eyes were yellow liver was slightly enlarged
and tender to palpation.
The serologic results were as follows:

IgM anti-HAV - negative

HBsAg - positive

IgM anti-HBc - positive

anti-HCV - negative
What is your suspected diagnosis?
Acute hepatitis A
Acute hepatitis B
Chronic Hepatitis B
Chronic Hepatitis C
Answer : (B) Acute hepatitis B
The diagnosis is acute hepatitis B because IgM anti-HBc positivity indicates that he has been recently
infected with HBV.
73
Case No. (2):
A 27-year-old woman presents to the urgent care clinic with the new onset of nausea
and jaundice. During the past 3 years, she has experienced major problems with drug
addiction. She has never received HBV vaccine. Two years ago, she had negative
antibody tests for hepatitis A, B, and C, but did not return for follow-up and
vaccinations. Her physical examination is normal except for track marks on her arms
and visible jaundice.
Laboratory studies show:

Total bilirubin of 6.8 mg/dl

Aspartate aminotransferase (AST) level of 1906 U/L

Alanine aminotransferase (ALT) level of 2086 U/L.
Serology tests for hepatitis A, B, and C viruses are ordered. The panel ordered for
hepatitis B includes hepatitis B surface antigen (HBsAg), antibody to hepatitis B
surface antigen (anti-HBs), total hepatitis B core antibody (total anti-HBc), hepatitis e
antigen (HBeAg), and antibody to hepatitis B e antigen (anti-HBe).
Which of the following serologic profiles would be most consistent with acute
HBV infection?
HBsAg (-), anti-HBs (+), Total anti-HBc (+), HBeAg (-), anti-HBe (+).
HBsAg (+), anti-HBs (-), Total anti-HBc (-), HBeAg (-), anti-HBe (+).
HBsAg (+), anti-HBs (-), Total anti-HBc (+), HBeAg (+), anti-HBe (-).
HBsAg (-), anti-HBs (+), Total anti-HBc (-), HBeAg (-), anti-HBe (-).
Correct Answer: C (HBsAg (+), anti-HBs (-), Total anti-HBc (+), HBeAg (+), anti-HBe (-)
This serologic profile is consistent with acute HBV infection, but it is also consistent with chronic
HBV infection. In the case presented here, several factors—the recent epidemiologic exposure, the
negative hepatitis B serologic test 2 years prior, and the markedly elevated hepatic aminotransferase
levels—suggest that this woman has acute HBV infection. Patients with acute HBV infection typically
have high titers of viral antigens (HBsAg and HBeAg) and absence of anti-HBs and anti-HBe. Patients
74
with chronic infection usually have a similar profile, but may have negative HBeAg with positive antiHBe. A positive total anti-HBc is present with both acute and chronic HBV infection. To differentiate
acute versus chronic infection, an IgM anti-HBc should be ordered, since this test is positive with acute
HBV infection, but not chronic HBV infection.
KIDNEY FUNCTION TESTS
Anatomy of the kidney
The kidneys are bean-shaped organs,
located near the middle of the back, just
below the rib cage in the abdominal
cavity,
in
a
space
called
the
retroperitoneum. There are two, one on
each side of the spine. The right kidney
sits just below the diaphragm and
posterior to the liver, the left below the
diaphragm and posterior to the spleen.
Resting on top of each kidney is an
adrenal gland. The asymmetry within the
abdominal cavity caused by the liver
Figure (31): Anatomy of the kidney
typically results in the right kidney
being slightly lower than the left, and left kidney being located slightly more medial
than the right. The left kidney is typically slightly larger than the right.
Functions of the kidney
The kidneys are sophisticated reprocessing machines. The kidney participates in
whole-body homeostasis, regulating acid-base balance, electrolyte concentrations,
extracellular fluid volume, and regulation of blood pressure. The kidney accomplishes
these homeostatic functions both independently and in concert with other organs,
particularly those of the endocrine system. Various endocrine hormones coordinate
these endocrine functions; these include renin, angiotensin II, aldosterone, antidiuretic
hormone, and atrial natriuretic peptide, among others. Many of the kidney's functions
are accomplished by relatively simple mechanisms of filtration, reabsorption, and
75
secretion, which take place in the nephron. Filtration, which takes place at the renal
corpuscle, is the process by which cells and large proteins are filtered from the blood
to make an ultrafiltrate that will eventually become urine. The kidney generates 180
liters of filtrate a day, while reabsorbing a large percentage, allowing for only the
generation of approximately 2 liters of urine. Reabsorption is the transport of
molecules from this ultrafiltrate and into the blood. Secretion is the reverse process, in
which molecules are transported in the opposite direction, from the blood into the
urine.
1. Excretion of wastes: The kidneys excrete a variety of waste products produced by
metabolism. These include the nitrogenous wastes urea, from protein catabolism, and
uric acid, from nucleic acid metabolism.
2. Acid-base homeostasis: Two organ systems, the kidneys and lungs, maintain acidbase homeostasis, which is the maintenance of pH around a relatively stable value.
The kidneys contribute to acid-base homeostasis by regulating bicarbonate (HCO3-)
concentration.
3. Osmolality regulation: Any significant rise or drop in plasma osmolality is
detected by the hypothalamus, which communicates directly with the posterior
pituitary gland. A rise in osmolality causes the gland to secrete antidiuretic hormone
(ADH), resulting in water reabsorption by the kidney and an increase in urine
concentration. The two factors work together to return the plasma osmolality to its
normal levels. ADH binds to principal cells in the collecting duct that translocate
aquaporins to the membrane allowing water to leave the normally impermeable
membrane and be reabsorbed into the body by the vasa recta, thus increasing the
plasma volume of the body.
4. Blood pressure regulation: Long-term regulation of blood pressure predominantly
depends upon the kidney. This primarily occurs through maintenance of the
extracellular fluid compartment, the size of which depends on the plasma sodium
concentration. Although the kidney cannot directly sense blood pressure, changes in
the delivery of sodium and chloride to the distal part of the nephron alter the kidney's
secretion of the enzyme renin. When the extracellular fluid compartment is expanded
and blood pressure is high, the delivery of these ions is increased and renin secretion
76
is decreased. Similarly, when the extracellular fluid compartment is contracted and
blood pressure is low, sodium and chloride delivery is decreased and renin secretion is
increased in response.
Renin is the first in a series of important chemical messengers that comprise the reninangiotensin system. Changes in renin ultimately alter the output of this system,
principally the hormones angiotensin II and aldosterone. Each hormone acts via
multiple mechanisms, but both increase the kidney's absorption of sodium chloride,
thereby expanding the extracellular fluid compartment and raising blood pressure.
When renin levels are elevated, the concentrations of angiotensin II and aldosterone
increase, leading to increased sodium chloride reabsorption, expansion of the
extracellular fluid compartment, and an increase in blood pressure. Conversely, when
renin levels are low, angiotensin II and aldosterone levels decrease, contracting the
extracellular fluid compartment, and decreasing blood pressure.
5. Hormone secretion: The kidneys secrete a variety of hormones, including
erythropoietin, calcitriol, and renin. Erythropoietin is released in response to hypoxia
(low levels of oxygen at tissue level) in the renal circulation. It stimulates
erythropoiesis (production of red blood cells) in the bone marrow. Calcitriol, the
activated form of vitamin D, promotes intestinal absorption of calcium and the renal
reabsorption of phosphate. Part of the renin-angiotensin-aldosterone system, renin is
an enzyme involved in the regulation of aldosterone levels.
Causes of renal diseases

Type 1 and type 2 diabetes mellitus cause a condition called diabetic
nephropathy, which is the leading cause of kidney disease.

High blood pressure (hypertension), if not controlled, can damage the kidneys
over time.

Glomerulonephritis is the inflammation and damage of the filtration system of
the kidneys, which can cause kidney failure. Post-infectious conditions are
among the many causes of glomerulonephritis.

Polycystic kidney disease is an example of a hereditary cause of chronic
kidney disease in which both kidneys have multiple cysts.
77

Atherosclerosis: clogging and hardening of the arteries leading to the kidneys
causes a condition called ischemic nephropathy, which is another cause of
progressive kidney damage.

Obstruction of the flow of urine by stones, an enlarged prostate, strictures
(narrowings), or cancers may also cause kidney disease.

Use of analgesics such as acetaminophen (Tylenol) and ibuprofen (Motrin,
Advil) regularly over long durations of time can cause analgesic nephropathy,
another cause of kidney disease. Certain other medications can also damage
the kidneys.

Other causes of chronic kidney disease include HIV infection, sickle cell
disease, heroin abuse, amyloidosis, kidney stones, chronic kidney infections,
and certain cancers.
Chronic kidney diseases
Chronic kidney disease occurs when one suffers from gradual and usually permanent
loss of kidney function over time. This happens gradually, usually months to years.
Chronic kidney disease is divided into five stages of increasing severity (see Table 1
below). Mild kidney disease is often called renal insufficiency. With loss of kidney
function, there is an accumulation of water; waste; and toxic substances, in the body,
that are normally excreted by the kidney. Loss of kidney function also causes other
problems such as anemia, high blood pressure, acidosis (excessive acidity of body
fluids), disorders of cholesterol and fatty acids, and bone disease. Stage 5 chronic
kidney disease is also referred to as kidney failure, end-stage kidney disease, or endstage renal disease, wherein there is total or near-total loss of kidney function. There
is dangerous accumulation of water, waste, and toxic substances, and most individuals
in this stage of kidney disease need dialysis or transplantation to stay alive.
Unlike chronic kidney disease, acute kidney failure develops rapidly, over days or
weeks.

Acute kidney failure usually develops in response to a disorder that directly
affects the kidney, its blood supply, or urine flow from it.
78

Acute kidney failure is often reversible, with complete recovery of kidney
function.

Some patients are left with residual damage and can have a progressive
decline in kidney function in the future.

Others may develop irreversible kidney failure after an acute injury and
remain dialysis-dependent.
Stage
Description
GFR*
mL/min/1.73m2
1
Slight kidney damage with normal or increased
More than 90
filtration
2
Mild decrease in kidney function
60-89
3
Moderate decrease in kidney function
30-59
4
Severe decrease in kidney function
15-29
5
Kidney failure
Less than 15 (or dialysis)
Table (1): Stages of Chronic Kidney Disease
Diagnosis of renal diseases
The kidneys are remarkable in their ability to compensate for problems in their
function. That is why chronic kidney disease may progress without symptoms for a
long time until only very minimal kidney function is left. Because the kidneys
perform so many functions for the body, kidney disease can affect the body in a large
number of different ways. Symptoms vary greatly. Several different body systems
may be affected. Notably, most patients have no decrease in urine output even with
very advanced chronic kidney disease.
I. History:

Acute or chronic symptoms (many patients in the early stages of CKD usually
do not feel sick at all.

Past medical history: previous infections or concurrent diseases (DM, liver
diseases,….etc) especially in pregnant women.
79

Family history of renal disease

Social history: Drug and toxin exposure: acetaminophen and ibuprofen.
II. Physical examination:
Several signs and symptoms may suggest complications of chronic kidney disease:

Need to urinate frequently, especially at night (nocturia).

Swelling of the legs and puffiness around the eyes (fluid retention).

High blood pressure.

Fatigue and weakness (from anemia or accumulation of waste products in the
body).

Loss of appetite, nausea and vomiting.

Itching, easy bruising, and pale skin (from anemia).

Shortness of breath from fluid accumulation in the lungs.

Headaches, numbness in the feet or hands (peripheral neuropathy), disturbed
sleep, altered mental status (encephalopathy from the accumulation of waste
products or uremic poisons), and restless legs syndrome.

Chest pain due to pericarditis (inflammation around the heart).

Bleeding (due to poor blood clotting).

Bone pain and fractures.

Change in energy level or strength
The following signs and symptoms represent the possibility of a severe complication
of chronic kidney disease and warrant a visit to the nearest hospital emergency
department.

Change in level of consciousness - extreme sleepiness or difficult to awaken

Fainting

Chest pain

Difficulty breathing

Severe nausea and vomiting

Severe bleeding (from any source)

Severe weakness
80
Kidney function tests
Chronic kidney disease usually causes no symptoms in its early stages. Only lab tests
can detect any developing problems. Anyone at increased risk for chronic kidney
disease should be routinely tested for development of this disease. These tests include
urine, blood, and imaging tests (X-rays) to detect kidney disease, as well as to follow
its progress. They are often used together to develop a picture of the nature and extent
of the kidney disease.
Urine Tests
Urinalysis: Analysis of the urine affords enormous insight into the function of the
kidneys. It is often the first test conducted if kidney problems are suspected. A small,
randomly collected urine sample is examined physically for things like color, odor,
appearance, and concentration (specific gravity); chemically, for substances such a
protein, glucose, and pH (acidity/alkalinity); and microscopically for the presence of
cellular elements (RBCs, WBCs and epithelial cells), bacteria, crystals, and casts
(structures formed by the deposit of protein, cells, and other substances in the
kidneys's tubules). If results indicate a possibility of disease or impaired kidney
function, one or more of the following additional tests is usually performed to
pinpoint the cause and the level of decline in kidney function.
Twenty-four hour urine tests: This test requires collection of urine for 24
consecutive hours. The urine may be analyzed for protein and waste products (urea
nitrogen, and creatinine). The presence of protein in the urine indicates kidney
damage. The amount of creatinine and urea excreted in the urine can be used to
calculate the level of kidney function and the glomerular filtration rate (GFR).
Glomerular filtration rate (GFR): The GFR is a standard means of expressing
overall kidney function. As kidney disease progresses, GFR falls. The normal GFR is
about 100-140 mL/min in men and 85-115 mL/min in women. It decreases in most
people with age. The GFR may be calculated from the amount of waste products in
the 24-hour urine or by using special markers administered intravenously. An
estimation of the GFR (eGFR) can be calculated from the patient's routine blood tests.
81
Creatinine clearance test: This test evaluates how efficiently the kidneys clear a
substance called creatinine from the blood. Creatinine, a waste product of muscle
energy metabolism, is produced at a constant rate that is proportional to the
individual's muscle mass. Because the body does not recycle it, all creatinine filtered
by the kidneys in a given amount of time is excreted in the urine, making creatinine
clearance a very specific measurement of kidney function. The test is performed on a
timed urine specimen—a cumulative sample collected over a two to 24-hour period.
Determination of the blood creatinine level is also required to calculate the urine
clearance.
Urea clearance test: Urea is a waste product that is created by protein metabolism
and excreted in the urine. The urea clearance test requires a blood sample to measure
the amount of urea in the bloodstream and two urine specimens, collected one hour
apart, to determine the amount of urea that is filtered, or cleared, by the kidneys into
the urine.
Urine osmolality test: Urine osmolality is a measurement of the number of dissolved
particles in urine. It is a more precise measurement than specific gravity for
evaluating the ability of the kidneys to concentrate or dilute the urine. Kidneys that
are functioning normally will excrete more water into the urine as fluid intake is
increased, diluting the urine. If fluid intake is decreased, the kidneys excrete less
water and the urine becomes more concentrated. The test may be done on a urine
sample collected first thing in the morning, on multiple timed samples, or on a
cumulative sample collected over a 24-hour period. The patient will typically be
prescribed a high-protein diet for several days before the test and be asked to drink no
fluids the night before the test.
Urine protein test: Healthy kidneys filter all proteins from the bloodstream and then
reabsorb them, allowing no protein, or only slight amounts of protein, into the urine.
The persistent presence of significant amounts of protein in the urine, then, is an
important indicator of kidney disease. A positive screening test for protein (included
in a routine urinalysis ) on a random urine sample is usually followed up with a test
on a 24-hour urine sample that more precisely measures the quantity of protein.
Blood Tests
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Blood urea nitrogen test (BUN): Urea is a byproduct of protein metabolism. Formed
in the liver, this waste product is then filtered from the blood and excreted in the urine
by the kidneys. The BUN test measures the amount of nitrogen contained in the urea.
High BUN levels can indicate kidney dysfunction, but because BUN is also affected
by protein intake and liver function, the test is usually done together with a blood
creatinine, a more specific indicator of kidney function.
Creatinine test: This test measures blood levels of creatinine, a by-product of muscle
energy metabolism that, similar to urea, is filtered from the blood by the kidneys and
excreted into the urine. Production of creatinine depends on an person's muscle mass,
which usually fluctuates very little. With normal kidney function, then, the amount of
creatinine in the blood remains relatively constant and normal. For this reason, and
because creatinine is affected very little by liver function, an elevated blood creatinine
level is a more sensitive indicator of impaired kidney function than the BUN.
Estimated GFR (eGFR): The laboratory or your physician may calculate an
estimated GFR using the information from your blood work. It is important to be
aware of your estimated GFR and stage of chronic kidney disease. Your physician
uses your stage of kidney disease to recommend additional testing and suggestions on
management.
Electrolyte levels and acid-base balance: Kidney dysfunction causes imbalances in
electrolytes, especially potassium, phosphorus, and calcium. High potassium
(hyperkalemia) is a particular concern. The acid-base balance of the blood is usually
disrupted as well. Decreased production of the active form of vitamin D can cause
low levels of calcium in the blood. Inability to excrete phosphorus by failing kidneys
causes its levels in the blood to rise. Testicular or ovarian hormone levels may also be
abnormal.
Blood cell counts: Because kidney disease disrupts blood cell production and
shortens the survival of red cells, the red blood cell count and hemoglobin may be low
(anemia). Some patients may also have iron deficiency due to blood loss in their
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gastrointestinal system. Other nutritional deficiencies may also impair the production
of red cells.
Other blood tests:
Measurement of the blood levels of other elements regulated in part by the kidneys
can also be useful in evaluating kidney function. These include sodium, potassium,
chloride, bicarbonate, calcium, magnesium, phosphorus, protein, uric acid, and
glucose.
Other tests
Ultrasound: Ultrasound is often used in the diagnosis of kidney disease. An
ultrasound is a noninvasive type of imaging test. In general, kidneys are shrunken in
size in chronic kidney disease, although they may be normal or even large in size in
cases caused by adult polycystic kidney disease, diabetic nephropathy, and
amyloidosis. Ultrasound may also be used to diagnose the presence of urinary
obstruction, kidney stones and also to assess the blood flow into the kidneys.
Biopsy: A sample of the kidney tissue (biopsy) is sometimes required in cases in
which the cause of the kidney disease is unclear. Usually, a biopsy can be collected
with local anesthesia by introducing a needle through the skin into the kidney. This is
usually done as an outpatient procedure, though some institutions may require an
overnight hospital stay.
Normal Values
Normal values for many tests are determined by the patient's age and gender.
Reference values can also vary by laboratory, but are generally within the following
ranges:
Urine tests

Creatinine clearance: For a 24-hour urine collection, normal results are 90
mL/min–139 mL/min for adult males younger than 40, and 80–125 mL/min
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for adult females younger than 40. For people over 40, values decrease by 6.5
mL/min for each decade of life.

Urine osmolality: With restricted fluid intake (concentration testing),
osmolality should be greater than 800 mOsm/kg of water. With increased fluid
intake (dilution testing), osmolality should be less than 100 mOSm/kg in at
least one of the specimens collected. A 24-hour urine osmolality should
average 300–900 mOsm/kg. A random urine osmolality should average 500–
800 mOsm/kg.

Urine protein: A 24-hour urine collection should contain no more than 150 mg
of protein.

Urine sodium: A 24-hour urine sodium should be within 75–200 mmol/day.
Blood tests

Blood urea nitrogen (BUN) should average 8–20 mg/dL.

Creatinine should be 0.8–1.2 mg/dL for males, and 0.6–0.9 mg/dL for females.

Uric acid levels for males should be 3.5–7.2 mg/dL and for females 2.6–6.0
mg/dL.
Interpretation of the results
Low clearance values for creatinine indicate a diminished ability of the kidneys to
filter waste products from the blood and excrete them in the urine. As clearance levels
decrease, blood levels of creatinine, urea, and uric acid increase. Because it can be
affected by other factors, an elevated BUN, alone, is suggestive, but not diagnostic for
kidney dysfunction. An abnormally elevated plasma creatinine is a more specific
indicator of kidney disease than is BUN. The inability of the kidneys to concentrate
the urine in response to restricted fluid intake, or to dilute the urine in response to
increased fluid intake during osmolality testing, may indicate decreased kidney
function. Because the kidneys normally excrete almost no protein in the urine, its
persistent presence, in amounts that exceed the normal 24-hour urine value, usually
indicates some type of kidney disease.
Chronic Kidney Disease Treatment
General dietary guidelines:
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
Protein restriction: Decreasing protein intake may slow the progression of
chronic kidney disease. A dietitian can help you determine the appropriate
amount of protein for you.

Salt restriction: Limit to 4-6 grams a day to avoid fluid retention and help
control high blood pressure.

Fluid intake: Excessive water intake does not help prevent kidney disease. In
fact, your doctor may recommend restriction of water intake.

Potassium restriction: This is necessary in advanced kidney disease because
the kidneys are unable to remove potassium. High levels of potassium can
cause abnormal heart rhythms. Examples of foods high in potassium include
bananas, oranges, nuts, and potatoes.

Phosphorus restriction: Decreasing phosphorus intake is recommended to
protect bones. Eggs, beans, cola drinks, and dairy products are examples of
foods high in phosphorus.
Other important measures that you can take include:

Carefully follow prescribed regimens to control your blood pressure and/or
diabetes.

Stop smoking.

Lose excess weight.
In chronic kidney disease, several medications can be toxic to the kidneys and may
need to be avoided or given in adjusted doses. Among over-the-counter medications,
the following need to be avoided or used with caution:

Certain analgesics: Aspirin; nonsteroidal antiinflammatory drugs (NSAIDs,
such as ibuprofen.

Fleets or phosphosoda enemas because of their high content of phosphorus.

Laxatives and antacids containing magnesium and aluminum such as
magnesium hydroxide.

Ulcer medication H2-receptor antagonists: cimetidine (Tagamet), ranitidine
(Zantac), (decreased dosage with kidney disease)

Decongestants such as pseudoephedrine (Sudafed) especially if you have high
blood pressure
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
Herbal medications
Medical Treatment
There is no cure for chronic kidney disease. The four goals of therapy are to:
1. Slow the progression of disease;
2. Treat underlying causes and contributing factors;
3. Treat complications of disease; and
4. Replace lost kidney function.
Strategies for slowing progression and treating conditions underlying chronic kidney
disease include the following:

Control of blood glucose: Maintaining good control of diabetes is critical.
People with diabetes who do not control their blood glucose have a much
higher risk of all complications of diabetes, including chronic kidney disease.

Control of high blood pressure: This also slows progression of chronic
kidney disease. It is recommended to keep your blood pressure below 130/80
mm Hg if you have kidney disease. It is often useful to monitor blood pressure
at home. Blood pressure medications known as angiotensin converting enzyme
(ACE) inhibitors or angiotensin receptor blockers (ARB) have special benefit
in protecting the kidneys.

Fluid retention: can be treated with any of a number of diuretic medications,
which remove excess water from the body. However, these drugs are not
suitable for all patients.

Anemia: can be treated with erythropoiesis stimulating agents such as
erythropoietin or darbepoetin (Aranesp, Aranesp Albumin Free, Aranesp
SureClick). Erythropoiesis stimulating agents are a group of drugs that replace
the deficiency of erythropoietin, which is normally produced by healthy
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kidneys. Often, patients treated with such drugs require iron supplements by
mouth or sometimes even intravenously.

Bone disease: develops in kidney disease due to an inability to excrete
phosphorus and a failure to form activated Vitamin D. In such circumstances,
your physician may prescribe drugs binding phosphorus in the gut, and may
prescribe active forms of vitamin D.

Acidosis: may develop with kidney disease. The acidosis may cause
breakdown of proteins, inflammation, and bone disease. If the acidosis is
significant, your doctor may use drugs such as sodium bicarbonate (baking
soda) to correct the problem.
Renal Replacement Therapies
In end-stage kidney disease, kidney functions can be replaced only by dialysis or by
kidney transplantation. The planning for dialysis and transplantation is usually started
in Stage 4 of chronic kidney disease.
Dialysis
Types:
1) Hemodialysis
2) Peritoneal dialysis.
Dialysis Access
Before dialysis can be initiated, a dialysis access has to be created. A vascular access
is required for hemodialysis so that blood can be moved though the dialysis filter at
rapid speeds to allow clearing of the wastes, toxins, and excess fluid. Peritoneal
access (for peritoneal dialysis): A catheter is implanted into the abdominal cavity
(lined by the peritoneum) by a minor surgical procedure.
Hemodialysis
Hemodialysis involves circulation of blood through a filter or dialyzer on a dialysis
machine. The dialyzer has two fluid compartments and is configured with bundles of
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hollow fiber capillary tubes. Blood in the first compartment is pumped along one side
of a semipermeable membrane, while dialysate (the fluid that is used to cleanse the
blood) is pumped along the other side, in a separate compartment, in the opposite
direction. Concentration gradients of substances between blood and dialysate lead to
desired changes in the blood composition, such as a reduction in waste products (urea
nitrogen and creatinine); a correction of acid levels; and equilibration of various
mineral levels. Excess water is also removed. The blood is then returned to the body.
Peritoneal dialysis
Peritoneal dialysis utilizes the lining membrane (peritoneum) of the abdomen as a
filter to clean blood and remove excess fluid. Peritoneal dialysis may be performed
manually (continuous ambulatory peritoneal dialysis) or by using a machine to
perform the dialysis at night (automated peritoneal dialysis). About 2 to 3 liters of
dialysis fluid are infused into the abdominal cavity through the access catheter. This
fluid contains substances that pull wastes and excess water out of neighboring tissues.
The fluid is allowed to dwell for two to several hours before being drained, taking the
unwanted wastes and water with it. The fluid typically needs to be exchanged four to
five times a day.
Transplantation
Kidney transplantation offers the best outcomes and the best quality of life.
Transplanted kidneys may come from living related donors, living unrelated donors,
or people who have died of other causes. A person who needs a kidney transplant
undergoes several tests to identify characteristics of his or her immune system. The
recipient can accept only a kidney that comes from a donor who matches certain of
his or her immunologic characteristics. The more similar the donor is in these
characteristics, the greater the chance of long-term success of the transplant.
Transplants from a living related donor generally have the best results. Transplant
surgery is a major procedure and generally requires four to seven days in the hospital.
All transplant recipients require lifelong immunosuppressant medications to prevent
their bodies from rejecting the new kidney. Immunosuppressant medications require
careful monitoring of blood levels and increase the risk of infection as well as some
types of cancer.
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Outlook

There is no cure for chronic kidney disease. The natural course of the disease
is to progress until dialysis or transplant is required.

Patients with chronic kidney disease are at a much higher risk than the
general population to develop strokes and heart attacks.

People undergoing dialysis have an overall five year survival rate of 32%.
The elderly and those with diabetes have worse outcomes.

Recipients of a kidney transplant from a living related donor have a two year
survival rate greater than 90%.

Recipients of a kidney from a donor who has died have a two year survival
rate of 88%.
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