الفهرس 
HEPATIC CIRRHOSIS AND ITS RELATION TO ASICTES FORMATIONOnly 14 pages are availabe for public view
 |  | from | 215 |  |  |
| | | from | 215 | | |
Abstract
HORHONAL STUDIES IN CHILDHOOD CIRRHOSIS
This study was performed on 53 cirrhotic children (42 of them had ascites) and 11 normal
healthy control children, whose ages ranged from 2 to 12 years, so as to investigate the role
of the renin angiotensin aldosterone system and the plasma cortisol concentration in
cirrhotic ascites formation.
Diagnosis of cirrhosis was achieved by thorough history, clinical examination, liver
function tests , and ultrasonography; and was confirmed by liver biopsy in 15 cases.
Laboratory determination was done (to all the studied cirrhotic and control children) for
serum electrolytes (sodium and potassium) concentrations and urinary sodium excretion using
flame photometry, and also for the plasma cortisol concentration, the plasma renin activity,
and the plasma aldosterone concentration using radioimmunoassay.
No statistically significant change was found in the plasma cortisol concentration between
the control group and both the cirrhotic children with or without ascites. A
aldosterone concentration. Arroyo et al. (1981} found that the plasma sodium concentration
is normal in cirrhotics. Bernardi et al. (1383} found that cirrhotics without ascites showed a
normal plasma sodium concentration, whereas cirrhotics with ascites showed either a normal
(in over 50\ of cases} or decreased (in the rest of cases} plasma sodium concentration. They
found also an inverse correlation between the plasma sodium concentration and both the plasma
renin activity and the plasma aldosterone concentration in
cirrhotics
showing ascites
The
present results showed also a significant increase
in the serum potassium concentration in cirrhotics with ascites, as compared to cirrhotics
without ascites. On the other hand, Arroyo et al. (1981) and Bernardi et al. (1983) showed a
normal plasma potassium concentration ln cirrhotics. The difference may be due to
the young age of our studied patients.
In summary, our results suggest an important role of a stimulated renin angiotensin aldosterone
system ln the pathogenesis of childhood cirrhotic ascites formation.
-143-
of children. Wilkinson et al. (1979 a) found an inverse correlation between the urinary sodium
excretion and the plasma aldosterone concentration in cirrhotics. Arroyo et
al. (1979); Bosch et al. (1980), and Bernardi et al. (1983)
found an excretion cirrhotics
inverse and with
correlation between the urinary sodium the plasma aldosterone concentration in ascites. Bernardi et
al. (1983) attributed
this correlation to an enhanced renal tubular sensitivity to aldosterone which increased with the
progress of the disease; as well as to a deficient synthesis and release of the natriuretic factor.
Rosoff et al. (1979l found that the urinary sodium excretion was directly proportional to the
outer cortical renal plasma flow in cirrhotics. Jimenez et al. (1985) found an inverse correlation
between the urinary sodium excretion and the urinary aldosterone excretion in rats with
experimental cirrhosis.
In our study, the serum sodium concentration showed a significant increase in cirrhotics with
ascites, as compared to the control group. Wernze et al. (1978) showed that the plasma sodium
concentration was normal in cirrhotics, and got reduced only under diuretic therapy. They found
also an inverse correlation between the plasma sodium concentration and both the plasma renin
activity and the plasma
-142-
Our results showed a significant decrease in the urinary sodium excretion in cirrhotics
with ascites, as compared to both cirrhotics without ascites and the control group. This
indicates an enhanced renal sodium retention in cirrhotics with ascites. Arroyo et al. (1979)
found that the
urinary sodium excretion
was either normal or decreased in
cirrhotics
with ascites.
Wilkinson et al. (1979 a) found
that the cirrhotics.
urinary
Bosch et
sodium excretion was decreased in al. (1980) found that the urinary
sodium excretion was decreased in cirrhotics with ascites. Arroyo et al. (1981) found that the
urinary sodium excretion was either normal or decreased in cirrhotics with ascites. Bernardi et
al. (1983) found that cirrhotics without ascites
showed an cirrhotics
increased urinary sodium excretion; whereas with ascites showed either a normal (in over SO\
of cases) or a decreased (in the rest of cases) urinary sodlu• excretion. Jimenez et al.
(1985) showed a decreased urinary sodium excretion in rats with experimental cirrhosis.
Also, our results showed a significant inverse correlation between the urinary sodium
excretion and the plasma aldosterone concentration in all the studied groups
-141-
found that the plasma aldosterone concentration was either normal or increased in cirrhotics with
ascites. They found also a close direct correlation between the plasma aldosterone
concentration and the plasma renin activity. Wilkinson et al. (1979 a) found that the plasma
aldosterone concentration was reduced in cirrhotics. Bosch et al. (1980) found that the plasma
aldosterone concentration was raised in cirrhotics with ascites and that it was closely and
directly correlated with the plasma renin activity. Wilkinson and Williams (1980) stated that
cirrhotics without ascites showed a reduced plasma aldosterone concentration; whereas cirrhotics
with ascites showed either a normal (in two thirds of cases) or an increased (in one third of
cases) plasma aldosterone concentration. Arroyo et al. (19811 found that the plasma aldosterone
concentration was either normal or increased in cirrhotics with ascites; and that it correlated
closely and directly with the plasma renin activity. Bernardi et al. (1983) found that cirrhotics
without ascites showed a reduced plasma aldosterone concentration; whereas cirrhotics with
ascites showed either
a normal (in over 50\ of cases) or an increased (in the rest of cases) plasma aldosterone
concentration. They found also a close direct correlation between the plasma aldosterone
concentration and the plasma renin activity.
-140-
effective hypovolemia caused by arterial hypotension, decreased peripheral resistance,
and increased cardiac o tput characteristic of advanced hepatic diseases. Bernardi et al. (1983)
found that cirrhotics without ascites showed a reduced plasma renin activity due to blood volume
expansion; whereas cirrhotics with ascites showed either a normal (in ever 50% of cases) or an
increased (in the rest of cases) plasma renin activity. They found also that the plasma renin
activity was inversely correlated with the renal perfusion in cirrhotics with ascites.
The plasma aldosterone study showed a significant
concentration in the present increase in cirrhotics with
ascites, as
the control
compared to both cirrhotics without ascites and group. The present results also showed a
significant positive correlation between the plasma renin activity and the plasma
aldosterone concentration in cirrhotic children without ascites as well as in all the studied
children. Rosoff et al. (1975) found that the plasma aldosterone concentration was increased in
cirrhotics with ascites. They attributed this increase to both an increased secretion rate
(mainly) and a reduced metabolic clearance rate [partly). Wernze et al. (1978) found that the
plasma aldosterone concentration was normal in cirrhotics, and got elevated only under diuretic
therapy. Arroyo et al. (1979)
to fill the dilated splanchnic veins, and so, the rest of the plasma volume (which had a
normal value) was unable to stimulate the volume receptors leading to increased plasma renin
activity. The second way suggested that the elevated wedged hepatic venous pressure
implied increased intrahepatic pressure which caused the release of a hepatic humoral agent
which increased the plasma renin activity. The third way suggested that the elevated wedged
hepatic venous pressure stimulated a neurogenic splanchno renal reflex which increased the
plasma renin activity. Bosch et al. (1980) also considered the opposite situation which
implied that the elevated wedged hepatic venous pressure was due to elevated plasma
angiotensin II level produced by the
increased plasma renin between the increased perfusion. Wilkinson
activity. They found no correlation plasma renin activity and renal and Williams (1980)
stated that
cirrhotics without ascites showed a reduced plasma renin activity; whereas cirrhotics with
ascites showed either a normal (in two thirds of cases), or an increased (in one third of
cases) plasma renin activity. They attributed the latter increase to a reduced effective
extracellular fluid or blood volume. Arroyo et al. (1981) found that the plasma renin activity
was either normal or increased in cirrhotics with ascites. They attributed the latter
increase to
-138-
hepatic fai”ure to produce angiotensinogen retarded renin activity to produce the vasopressor
angiotensin II. TJ1e
=esultant hypotension and renal hypoperfusion continued to stimulate excessive renal renin
synthesis and release leading to increased plasma renin activity. Wernze et al. (1978) found the
plasma renin activity to be normal ln cirrhotics, and got elevated only under diuretic therapy.
Arroyo et al. (1979) found the plasma renin activity to be either normal or increased in
cirrhotics with ascites. They found that the plasma renin activity was closely related to the renin
secretion rate; while it was not related to the renal perfusion (assessed by the glomerular
filtration rate and the renal plasma flow). Wilkinson et al. (1979 b) found the plasma renin
activity to be reduced in cirrhotics without ascites. They also found the plasma renin activity in
cirrhotics with ascites to be either normal or reduced in more than half of the cases, while, it
was raised in the rest of cases who exhibited renal impairment as a result of renal hypoperfusion.
Bosch et al. (1980) found the plasma renin activity to be elevated in cirrhotics with ascites. They
attributed this elevation to the increased wedged hepatic venous pressure as explained in three
ways. The first way suggested that the elevated wedged hepatic venous pressure implied that
increased plasma volume was required
-137-
for by the reduced production rate of coritsol caused by the pituitary adrenal negative feed
back mechanism. However, Zumoff et al. (1967) found the cortisol production rate to be normal
in cirrhotics. Me Cann and Fulton (1975) also found that the cortisol secretion rate was
normal in cirrhotics. They found also that cirrhotics showed a slightly reduced total
plasma 11-hydroxycorticosteroids and an elevated plasma non-protein bound 11-
hydroxycorticosteroids. They attributed the latter elevation to both impaired metabolism and
reduced protein binding of steroids.
our results also showed a significant positive correlation between the plasma
cortisol concentration and the urinary sodium excretion in the control group. The explanation
for this needs further investigations.
In our study, the plasma renin activity showed a significant increase in cirrhotics with
ascites, as compared to both cirrhotics without ascites and the control group. Rosoff et al.
(1975) found a raised plasma renin activity amongst cirrhotics with ascites. Rosoff et al.
(1979) described an inverse relationship between the raised plasma, renin activity and the
outer cortical renal blood flow amongst cirrhotics. Ziegler (1976) postulated that cirrhotic
-136-
urinary sodium excretion. At approximately 8 a.m., while the patients were standing up, fasting
venous blood samples were drawn by venipuncture for the estimation of the serum electrolytes
(sodium and potassium) concentrations, the
plasma cortisol concentration, and the plasma aldosterone
the plasma renin activity, concentration. The serum
electrolytes (sodium and potassium) concentrations and the urinary sodium excretion were
measured by the flame photometric method using the atomic absorption spectrophotometer. The
plasma cortisol concen-tration, the plasma renin activity, and the plasma aldosterone
concentration radioimmunoassay.
were measured using a
sensitive
As well, eleven normal healthy children of the same age group were subjected to the same
investigations carried on the studied cirrhotic children to serve as a control group.
our results showed no significant change in the plasma cortisol concentration (total) between
the control group and cirrhotics with and without ascites. This coincides with the results of
Peterson (1960) and Zumoff et al. (1967). Peterson (1960) attributed this result to the fact
that the reduced metabolic clearance rate of cortisol was compensated
-135-
secretion rate, a reduced urinary cortisol excretion, a slightly reduced total plasma
11-hydroxycorticosteroids, and an elevated plasma non-protein bound 11- hydroxycorticosteroids.
They attributed the latter elevation to both impaired metabolism and reduced protein binding of
steroids.
The present study was performed to assess, in a series of cirrhotic children, the role
played by the renin
angiotensin aldosterone system as well as
the plasma
cortisol concentration ln cirrhotic ascites formation.
the pathogenesis
of childhood
Fifty three children (35 males and 18 females), suffering from hepatic cirrhosis were
studied. Their ages ranged from 2 to 12 years. Fourty two of them had ascites at the time of the
study. The diagnosis of cirrhosis was accomplished by careful history, thorough
physical
examination, liver was confirmed by azotemic and none
function tests, and ultrasonography; and liver biopsy in 15 cases. No patient was had evidence of
cardiovascular or renal
disease. All patients were taking an average normal dietary sodium intake. A twenty four
hours’ urine volume was collected from each patient for the determination of the
-134-
The liver has also a major role in cortisol metabolism (Bondy, 1985). Peterson (1960) had
demonstrated that radioactive cortisol was cleared more slowly in cirrhotics than in normal
subjects. Cirrhotics show impaired A ring reduction, abnormal glucosiduronate production, and
probably a defect in the transport or binding of cortisol to its intracellular metabolic
sites (Zumoff et al., 1967). Clinical evidence of endogenous hypercortlclsm (for example
acne, hirsutism, obesity, moon face, and striae livida) may be seen in some cirrhotics (Me
Cann and Fulton, 1975; and conn and Atterbury, 1987).
However, the plasma cortisol concentration has been found to lie in the normal range
amongst cirrhotics (Peterson, 1960); and it has been suggested that this normal result was
maintained by the pituitary adrenal negative feed
back mechanism
producing
a reduced adrenocortical cortisol
secretion rate.
This
concept was disputed by other
investigators who found the cortisol production rate to be normal amongst cirrhotics (Zumof£
et al., 1967); and in one study the plasma cortisol concentration though normal in the morning
failed to decrease in the evening resulting in an elevated mean value (Tucci et al., 1966). Me
cann and Fulton (1975) demonstrated in cirrhotics a normal cortisol
-133-
investigators
who had previously found that the plasma
aldosterone cirrhotics
concentration may be normal or reduced in many with ascites (Wernze et al., 1978; and Wilkinson
et al., spite of
1979 a), and that sodium retention may persist in lowering the plasma aldosterone concentration to
normal (Rosoff et al., 1975). These conflicting observations reflect the existing difficulty of
properly investigating the renin angiotensin aldosterone system in cases of cirrhosis (Jimenez
et al., 1985). Wilkinson and Williams (1980) stated that approximately two thirds of cirrhotics
with ascites did not have a stimulated renin angiotensin aldosterone system, and in those without
clinical evidence of fluid retention, the renin angiotensin aldosterone system was actually
suppressed. Sodium retention found in the latter patients was attributed to an enhanced renal
tubular sensitivity to aldosterone.
Bledsoe et al. (1962) and Coppage et al. (1962) had demonstrated that the liver was the major
organ for aldosterone metabolism. Increased plasma aldosterone concentration seen in some cases
of decompensated cirrhosis may be due to increased secretion rate (mainly) as well as reduced
metabolic clearance rate (partly) (Rosoff et al.,
1975).