LIVE R

With this anatomy, there is no

mixing of the bile and the
blood under normal
circumstances.
 laboratory.
1) Carbohydrate metabolic function = assessed by
measuring the
Random Blood Sugar.
2) Synthetic function = monitored by measuring the
levels of albumin and coagulation factors (pro-
time and activated partial thromboplastin time).
3) Excretory function = assessed by measuring the
levels of bilirubin.
4) Integrity of the liver cells = assessed by measuring
liver enzymes.
5) Storage function = assessed by using different
Bileserum Iron tests.
6)
250-1,500 ml of bile
Detoxification produced
of blood and secreted
= monitored by the
by measuring
liverthe
everyday.
levels of excreted drugs & foreign compounds.
Components of bile in decreasing order of
concentration: bile acids (cholic acid and
chenodeoxycholic acid), lecithin, cholesterol,
bilirubin, urobilinogen, and electrolytes (Na +, K+, Cl-, &
Bilirubin
Synthesis amino
acids
spleen, senescent red hemoglo globin released
bone cells within bin
&
marrow & mononuclear molecule
heme enter
liver phagocytes breakdow
amino
iron
hemenoxygenase
Stercobilin acid pool
component
= color of Biliverdi of heme
feces Urobilinogen in biliverdin reductasen brought to
small intestine iron stores
free bilirubin (B1) (ferritin)
bacterial binds w/
20% -glucuronidases ligandin 1 mole of
reabsorbed & & Z protein albumin
uridine diphosphate glucuron binds
enter
glucuronosyl-transferaseic acid w/ 2 moles
enterohepatic
(UDPGT) of bilirubin
circulation In bile
conjugated bilirubin
Urobilin (bilirubin
= urine color diglucuronide or B2)
delta () bilirubin = forms covalent bond with the
protein
= explains the persistence of jaundice, in the absence
of bilirubinuria, even during resolution of liver
Residing at the crossroads between the digestive tract
and the rest of the body, the liver has the enormous
taskof maintaining the bodys metabolic homeostasis.
Thus, the liver is vulnerable to a wide variety of
metabolic, toxic, microbial, and circulatory insults.
Jaundiceis an almost invariablefinding of hepatic
problems.
Jaundice (Icterus)
= yellowish pigmentation of the skin, mucous
membrane and sclera of the eyes, due to
accumulation of either free or conjugated bilirubin
or both.
= Bilirubin has a high affinity with the elastin of sclera.

The normal concentration of bilirubin (mostly free

type) in the blood is within the order of 0.2 1.2
mg/dL. Jaundice becomes clinically evident at 2
Pre-hepatic Jaundice (Hemolytic or Retention
jaundice)
= due to excessive destruction of red blood cells.
1) Hemolytic Disease of Fetus & Newborns (HDFN) =
Erythroblastosis Fetalis
= Mother Rh(-); Father Rh(+)
2) Malaria
3) Hemolytic Anemias
a) thalassaemia = severity depends on how many
of the 4 genes foralpha globinor 2 genes
forbeta globinare missing
b) sickle cell anaemia = HgbS (glutamic acid at
-globin gene, substituted byvalineat position 6
= rigid,sickle-like shape RBC)
c) hereditary spherocytosis = mutationsin
genes relating to membrane proteins =
erythrocytes are sphere-shaped (spherocytes)
rather than the normal biconcave disk shaped.
 SPHEROCYTOSIS

schistocyte

HEMOLYTIC ANEMIA

THALASSAEMIA
 B. Hepatic uptake of bilirubin may be decreased as in
prolonged fasting and in intake of drugs.
C. Bilirubin conjugation is decreased (i.e., decreased
activity of UDP- glucuronyl transferase) as in
Physiologic Neonatal Jaundice (until about 2 weeks of
age), Gilberts disease and Crigler- Najjar syndromes I
and II.
Post-hepatic Jaundice (Regurgitative,
Obstructive, or Cholestatic Jaundice)
= elevation of the conjugated bilirubin
A. due to obstruction in biliary flow
(Extrahepatic cholestasis ):
= gallstones (cholelithiasis), strictures, spasms, atresia,
B.parasites
impairment of hepatic excretion
and pancreatitis, or cancer (pancreas,
(Intrahepatic cholestasis):
ampulla of Vater, gallbladder)
1) familial (hereditary) disorders (e.g., Dubin-
Johnson syndrome, Rotor syndrome,)
2) acquired disorders (drug-induced e.g.,
phenothiazines).
3) Primary sclerosing cholangitis; 4) Primary
disease):
= concentration of both unconjugated and
conjugated bilirubin
rises in the blood.

A. Acute or Chronichepatitis
1) Viral hepatitis (hepatitis A, B, & C).
2) Other infection = leptospirosis,
brucellosis,Coxiella burnetii,
and glandular fever by Epstein-Barr virus)
B. Hepatotoxicity (eg, phosphorous, carbon
tetrachloride and phenol.
C. Drug-induced hepatitis: paracetamol = most
common cause
D. Autoimmune hepatitis (10-20% of chronic
hepatitis).
E. Alcoholic liver disease
F. Cirrhosis
G. Liver cancer http://patient.info/doctor/jaundice-pr
 decreased conjugation and decreased uptake of
bilirubin. In some cases, it is a pre- conjugation
failure. There is increased B1.
2) Criggler-Najjar Syndrome. There are two types of
this syndrome.
In type 1 which is autosomal recessive, there is
absence of the enzyme UDPGT (Uridine Diphosphate
Glucuronyltransferase). There is increased B1 (severe).
This can lead to early death.
In type 2 which is autosomal dominant, there is only
partial defect of the conjugation enzyme. There is
increased B1 (severe) but the patient may survive up to
adulthood.
3) Dubin-Johnson Syndrome. This is characterized by a
decreased hepatic excretion of bilirubin. There is
increased B2 with hepatic pigmentation (melanin)
4) Rotor Syndrome. The cause for this syndrome is
 1) Hepatic
LINICAL Failure, 2) Cirrhosis, 3) Portal
SYNDROMES
Hypertension, 4) Cholestasis
> liver biopsy = gold standard for diagnosis.
I. HEPATIC FAILURE
= end point of progressive damage to the liver, either
through insidious piecemeal destruction or by repetitive
waves of symptomatic parenchymal damage.
80% to 90% of hepatic function lost hepatic failure
ensues.
A decompensation on high demands place on the liver:
= systemic infections, electrolyte disturbances, major
surgery, heart failure, and gastrointestinal bleeding.
Patterns of injury:
1) Acute liver failure = massive hepatic necrosis; most
often caused bydrugsorviral hepatitis; from onset of
symptoms to hepatic encephalopathy within 2 to 3
weeks. (3months = subacute failure)
2)Chronic liver disease= most common route to
hepatic failure and is the end point of relentless
chronic liver damage.
Causes: primarily parenchymal, biliary, or vascular.
= often ends in cirrhosis
3)Hepatic dysfunction without overt necrosis.
= Less common
= hepatocytes viable but unable to perform their
normal metabolic function.
e.g. a) mitochondrial injury in Reye syndrome,
b) acute fatty liver of pregnancy,
c) some drug- or toxin-mediated injuries.

SSx =
= Jaundice& Cholestasis (from impaired bileflow
due to hepatocellular dysfunction = common both
in Acute & Chronic
A. Acute liver failure: with encephalopathy
B. Chronic Liver Failure:
1) Hypoalbuminemia = peripheral edema & ascitis.
Albumin = 2/3 of the total plasma proteins.
= regulates intravascular oncotic pressure.
Normally, the A/G (albumin:globulin) ratio is
between
1.3 to 3:1.
> A reversal in the A/G ratio is seen in liver diseases,
infectious diseases, multiple myeloma, and
nephritis. The total proteins
include:
albumin (3.2-4.5
g/dL)
globulin(2.3-3.5
g/dL),
fibrinogen(0.2-0.4
g/dL).
function).
= leads to Hepatic Encephalopathy
3)palmar erythema(a reflection of local
vasodilatation)
andcutaneous spider angiomas(central, pulsating,
dilated arteriole from which small vessels radiate).
4) Impaired estrogen metabolism and consequent
hyper- estrogenemia=
hypogonadismandgynecomastiain men.
5) Coagulopathydevelops (impaired hepatic synthesis
of blood clotting factors) = bleeding tendency
elsewhere

A rapid downhill course

with death in
80% of cases.

SPIDER ANGIOMA
Cholestasis is characterized by the following:
1) Hyperbilirubinemia with bilirubinuria
2) Elevatedalaninetransaminase(ALT) and
aspartatetransaminase(AST)
3) Elevations of alkaline phosphatase (ALP), -
glutamyl transferase (GGT), 5nucleotidase
(5NT), and leucine aminopeptidase (LAP)
activities
4) Hypercholesterolemia (as high as 1000 mg/dL)
where xanthomas appear
5) High serum bile salts (cholate and
chenodeoxycholate)

Clinically, the patient with cholestasis manifests dark

urine, intense itching over the skin, pale and fatty
stools, and jaundice.
Aspartate aminotransferase (AST) catalyzes the
following reversible reaction. (Serum glutamic
oxaloacetic transaminase)
AST
Aspartate + -ketoglutarate Oxaloacetate +
Glutamate

AST (SGOT) is rich in the cardiac muscle, liver

mitochondria, skeletal muscle, kidney, and pancreas.

Alanine aminotransferase (ALT) catalyzes the

following reversible reaction. (Serum glutamic pyruvic
transaminase)
ALT
Alanine + -ketoglutarante Pyruvate + Glutamate
ALT (SGPT) is rich in the liver cytosol, kidney, heart,
skeletal muscle, and pancreas.
 AST: 5-30 U/L at 37 C
ALT: 6-37 U/L at 37 C

Interpretation of AST/ALT Ratio (De Ritis Ratio)

[SGOT/SGPT ratio]
= normally less than 1.0
1) If the ratio <1 = acute viral hepatitis (due to high
ALT).
reversed De Ritis ratio
2) If > 1.0 but <2.0 = cirrhosis or non viral hepatitis
3) If De Ritis ratio >2.0 = alcoholic liver disease, (3-4:1)
AST
concentrations are higher

However, the AST/ALT ratio is less useful in scenarios

where the liver
enzymes are not elevated, or where multiple
conditions co-exist.
 Applications of ALT Levels.
ALT is more specific in detecting liver diseases in
non-alcoholic
asymptomatic patients
Increased levels prompts diagnosis of acute
hepatitis.
Applications of AST Levels.
It is increased
AST = used to in heart failure
monitor therapy with attendant
of potentially
hepatic necrosis.
hepatotoxic drugs.
= used for diagnosis of chronic hepatitis.
= also increased 4-10 times during acute MI.
It can be used for diagnosis of hepatocellular
destruction (both AST and ALT may increase with an
AST/ALT ratio < 1).
 The two phosphatases differ in their pH optima.
Alkaline phosphatase has a pH9 as optimum while acid
phosphatase has optimum activity at pH5.
Alkaline Phosphatase
Physiologic increase is observed in growing children,
pregnant women (3rd trimester), and healing
fractures.
Decreased ALP levels: hypophosphatasia and
malnutrition.
Liver ALP rises rapidly (2x the upper limit of normal) in
cholestasis, space-occupying lesions, passive liver
congestion, viral hepatitis, and alcoholic cirrhosis
* Liver and bone isoenzymes contribute mainly to
serum ALP. It is necessary to differentiate between
ALP rise due to liver disease and that due to the bone
disease.
*5'-NT (5-nucleotidase) = intrinsic membrane
glycoprotein; more liver-specific enzyme; increased in
post- & intrahepatic cholestasis, and infiltrative lesions
of liver. (NV: 2 to 17 U/L)
* Leucine aminopeptidase (LAP) = proteolytic
enzyme; highest increase in obstructive biliary
disease; also increase = last trimester of pregnancy.
(NV: M=: 80 to 200 U/mL; F = 75 to 185 U/mL)
*GGT (Syn: Gamma-glutamyl transpeptidase, GGTP)
= involved in intestinal absorption of amino acids;
increased in chronic hepatitis, and intake of drugs
(phenytoin); (NV: F= 0 - 45 U/L
Hepatic Encephalopathy
= a spectrum of brain dysfunction ranging from subtle
behavioral abnormalities to marked confusion and
stupor, to deep coma and death.
= may progress over hours or days in fulminant
hepatic failure
= other neurologic signs: rigidity, hyperreflexia,
nonspecific electroencephalographic changes,
seizures.
= characteristic is asterixis (flapping tremor),
- a pattern of non-rhythmic, rapid extension-flexion
movements of the
head and extremities,
best seen when arms
are held in extension
w/ dorsiflexed wrists.

Mx = brain edema and

an astrocytic reaction.
ASTERIXIS
*Pathogenesis:
Severe loss of hepatocellular function
Shunting of blood from portal to systemic circulation
around the
chronically diseased liver
* Acute: Elevation in blood ammonia= impairs
neuronal function and promotes generalized brain
edema.
* Chronic: deranged neurotransmitter productions:
a) monoaminergic system,
b) opioidergic system,
c) -aminobutyric acid (GABA)-ergic system,
d) and endocannabanoid system,

= leading to neuronal dysfunction.

= among the top 10 causes of death in the Western
world.
= Major causes: (a) chronic viral infections,
(b) alcoholic or nonalcoholic steatohepatitis
(NASH),
(c) auto-immune diseases,
(d) iron overload.

# Mx =
Fibrous septain the form of delicate bands or broad
scars around multiple adjacent lobules.
Parenchymal nodules,3mm (micronodules) to >1
cm (macro- nodules), encircled by thesefibrous
bands.
Nodules are made up of (1) replicative senescent
Hepatocytes; and (2) newly formed stem/progenitor
hepatocytes
= accompanied by proliferating endothelial cells,
myofibroblasts, & inflammatory cells.
*Pathogenesis
(1) Death of Hepatocytes
= Damaged hepatocytes produce reactive oxygen
species, growth factors, & cytokines (tumor necrosis
factor (TNF), interleukin-1 (IL-1), & lymphotoxins)
(2) Extracellular Matrix Deposition
= Types I and III collagen and other extracellular
matrix (ECM) interstitial collagens (fibril-forming
collagen types I, III, V, and XI) are deposited in the
space between sinusoidal endothelial cells and
hepatocytes (space of Disse) due to activation of
perisinusoidal stellate cells (Ito cells).
(3) Vascular Reorganization
= Inflammation and thrombosis of portal veins,
hepatic arteries, and/or central veins may lead to
alternating zones of parenchymal hypoperfusion (=
 Major vascular lesions:
a) loss of sinusoidal
endothelial cell
fenestrations
b) development of portal
SSx = vein
hepatic vein and hepatic
Symptoms nonspecific:
Complication==anorexia, artery
weight loss, weakness, frank
debilitation.
a) Progressive liver failure portal vein vascular
b)Complications related toshunts.
portal
hypertension
c)Development of hepatocellular
 III. Portal Hypertension
* Dominant intrahepatic causes:
a) cirrhosis= due to fibrosis and expanded parenchymal
nodules
b)noncirrhotic portal hypertension (schistosomiasis,
massive fatty change, diffuse granulomatous diseases
(e.g., sarcoidosis, miliary tuberculosis), and diseases
affecting the portal microcirculation (nodular
regenerative hyperplasia).
c) hyperdynamic circulation:
By
absorb intrahepatic
Bacterial DNA passe
ed fr. shunting of blood
s
gut from portal to
Kupffe
systemic
increased r cells
increase arterial circulation
production of
in portal vasodilation reduced
nitric
venous in the clearan
oxide(NO) in
bloodflo splanchnic ce
the vascular
w circulation
*Ascitesbecomes clinically detectable when at least
500mL excess peritoneal fluid have accumulated;
= containing as much as 3 g/dLof protein (largely
albumin); scant number of mesothelial cells and
mononuclear leukocytes.
neutrophils = secondary infection; red cells=
metastatic cancer.
long-standing ascites= seepage of
peritonealfluid through trans-
diaphragmatic lymphatics
= hydrothorax, (more on right)

Pathogenesis
a)Increased movement of intravascularfluid into the
extravascular space of Disse, caused by sinusoidal
hypertension and hypoalbuminemia.
b) hepatic lymphaticflow may exceed thoracic duct
capacity
Portosystemic Shunt
= develop wherever systemic and portal circulations
share capillary beds.
Principal sites:
a) veins around and within the rectum (hemorrhoids),
b) Cardioesophageal junction (esophagogastric
varices), 65% massive
hematemesis
c) retro-peritoneum, & falciform ligament of the liver
(periumbilical and abdominal wall collaterals=
caput medusae/ palm tree sign).

Splenomegaly
* Long-standing congestion = cause congestive
splenomegaly.
* Massive splenomegaly = induce hematologic
Hepatorenal Syndrome
= Appears withsevere liver disease
= developmentof renal failure without primary
abnormalities of the kidneys themselves.
= Kidney function promptly improves if hepatic
failure is reversed.

* Pathogenesis:
Splanchnic vasodilatation and systemic
vasoconstriction= leading to a severe reduction in
renal bloodflow, particularly to the cortex.
SSx:
=a drop in urine output;
= rising blood urea nitrogen and creatinine
values.
= ability to concentrate urine is retained,
= producing a hyperosmolar urine devoid of proteins
*Urea is the major excretory product of protein
UREA
catabolism.
Over 90% of urea is excreted through the kidney,
where it is readily filtered from the plasma by the
glomerulus.
Considerable glomerular destruction, as much as 70%
to 80%, must occur before an increase in the level of
plasma urea is observed.
In assessing renal function, utility of serum urea
measurements is greatly enhanced when urea results
are considered together with the results of serum
creatinine determinations.

In addition, the concentration of urea in the plasma is

an assessment of renal function and perfusion,
dietary intake of protein, and the level of protein
metabolism.
Clinicopathologic Correlation
= An increased level of urea in the blood is called
azotemia.
Prerenal azotemia = inadequate perfusion
= eventually fatal if not treated by dialysis.
The elevated blood urea nitrogen (BUN) varies in
magnitude but usually is in excess of 100 mg / dL,
or approaching
200 mg/dL with deep stupor or coma.
Postrenal azotemia = urinary tract obstruction and a
consequent increase in the back-diffusion of urea
from the renal tubule into the circulation.
A significantly decreased plasma or serum urea
concentration occurs in: Poor nutrition, high fluid
intake, or excessive administration of intravenous
(IV) fluids (overhydration), pregnancy, severe liver
disease.
*To enhance the clinical interpretation, it is
recommended to calculate the BUN /creatinine (B/C)
ratio.

The reference interval for the B/C ratio is between 10:1

and 20:1, with values for most individuals being
between 12 and 16.

a) High ratio with normal creatinine levels is typically

associated with Prerenal Azotemia;
(congestive heart failure;dehydration;
hypoperfusion);

b) High ratio with elevated creatinine is seen in

Postrenal Azotemia;

c) Low B/C ratios are seen in conditions associated with

Intrarenal Azotemia (due to reduced reabsorption of
BUN); liver disease(due to decrease in the formation of
*Reference interval

Urea in blood is usually reported as BUN and expressed

in mg/dL.

The System International dUnites (SI)system

recommends that results be expressed as millimoles per
liter.

The factor for converting BUN in milligrams per deciliter

to urea in millimoles per liter is 0.357. ( (10 dL/1 L)/
(28 mg ofN/mmol of urea) = 0.357 )

The reference interval for serum or plasma urea nitrogen

of healthy adults is 8 to 20 mg/dL (2.8 to 7.1 mmol of
urea per liter).
The normal urinary excretion or urea nitrogen for
adults ingesting an average-protein diet is in the
range of 17 -20 g /24 h.
CREATINE AND CREATININE

Muscle cells contain about 98% of the total body

creatine pool (the main storage compound of high-
energy phosphate needed for the muscle
metabolism).
Under physiologic conditions, creatine loses water
spontaneously, to form its cyclic amide, creatinine.
Once formed, creatinine is not reused in the bodys
metabolism and thus functions solely as a waste
product.
Creatine is filtered by the glomeruli but is largely or
completely reabsorbed by the proximal tubules.
Creatinine is freely filtered by the glomeruli but is not
reabsorbed.
*Clinicopathologic Correlation
Decreased creatinine clearance + increased serum
creatinine
= impaired renal function; decrease in glomerular
filtration rate (GFR)
Serum or plasma creatine concentration and urinary
creatine excretion are increased significantly by
skeletal muscle necrosis or atrophy.

*Reference Interval
Serum creatinine = is 0.6 to 1.2 mg/dL (53 to 106
mol/L) for males and 0.5 to 1.0 mg/dL (44 to 88
mol/L) for females.
The sex difference is attributed to differences in the
lean body mass in males and females.
Serum creatinine concentration in children under
12years old
= 0.3 to 1.0 mg/dL (26.5 to 88.4 mole/L) with no
muscle mass or lean body weight:
= that is, 21 to 26 mg/kg body weight/24h (0.18 to
0.23 mmol /kg/ 24 h) for adult males , and 16
to 22 mg/kg body weight/24 h (0.14 to 0.19
mmol/lg/24h) for adult females.
Reference interval for urine creatinine in small
children
= interpreted with caution due to difficulties in
obtaining urine
~~~~~~~~~~~~~000~~~~~~~~~
~~~~~
Serum creatine concentration = more variable
= higher in females than in males that is, 0.2 to 0.6
mg/dL ( 15 to 45 mol/L) for males, and 0.6 to 1.0
mg/dL (45 to 76 mol/L) for females.
Urine creatine = 0 to 40 mg/24 h (0 to 0.35 mmol/24
h) for adult males; and 0 to 100 mg/24 h (0 to 0.88
*Creatinine Clearance CCr
Creatinine clearance (CCr) is calculated from the
creatinine concentration in the collected urine sample
(UCr), urine flow rate (V = urine volume collected usually
for 24-hours), and the plasma concentration (PCr).
CCr = __1.25mg/mL x
CCr = __Ucr x 60mL/60min
V__ 0.01mg/mL
Example: A person
PCr
has a plasma = 1.25mg/mL x

creatinine 1mL/min
concentration of 0.01mg/mL
0.01mg/ml and in 1
hour produces 60ml = 1.25mg/min
of urine with a 0.01mg/mL
creatinine
concentration of = 125mL/min (volume of
1.25mg/mL. blood
 Portopulmonary Hypertension and
Hepatopulmonary Syndrome
1) Causes of liver injury also may damage the lungs
(e.g.,1- antitrypsin deficiency leading to both
cirrhosis and emphysema).
2) Ascites, pressing upward on the diaphragm, and
pleural effusions associated with portal hypertension
can compromise lung capacity.
3) Changes in pulmonary bloodflow occurring
secondary to hepatic failure may lead
toportopulmonary hypertensionor
hepatopulmonary syndrome. HPS SSx =
* PPH SSx a) Platypnea
= (easier
a) dyspnea breathing on
on lying down)
exertion b) orthodeoxia (fall
b) clubbing of arterial blood
of oxygen with
fingers upright posture)
ortopulmonary Hypertension (PPH) :

unmetabolized potentially
liver blood will
toxic substances
disease shunt from
Endothelin- 1
and/or portal to
(vasoconstrictor) and
portal systemic
Serotonin (smooth
hypertensi circulation
muscle hyperplasia &
on
hypertrophy)
= attack pulmonary
pulmonary
circulation
arterial
hypertensi
thickenin on
right-sided
heart g and excessive
failure remodeli pulmonary
ng vasoconstrict
ion
* Hepatopulmonary
syndrome (HPS) unmetabolized potentially
liver blood will
toxic substances
disease shunt from
Endothelin- 1
and/or portal to
(vasoconstrictor) and
portal systemic
Serotonin (smooth
hypertensi circulation
muscle hyperplasia &
on
hypertrophy)
abnormal = attack ventilati
increased Shunting ofpulmonary
intrapulmona circulation on-
pulmonar blood
ry vascular perfusio
y through
dilatation n
bloodflo such
reduced
mismatc
w dilatations
oxygen
h
formation of a diffusion
right-to- sp n e
arterioveno dy severe
left a n d
us sis arterial
shunting a n o
malformatio cy