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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
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)
# 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.
*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