Transcript Myasthenia Gravis

Learning objectives
• To understand the pathophysiologic basis
for vasoactive therapies for HRS
• To become familiar with the diagnostic
criteria for HRS
• To learn about therapeutic options for
patients with HRS
1.
Sinusoidal portal hypertension, in
the presence of severe hepatic
decompensation
2.
Leads to splanchnic and systemic
vasodilatation-role of NO
3.
Decreased effective arterial blood
volume
4.
Activation of systemic vasoactive
factors, such as the reninangiotensin system, the
sympathetic nervous system, and
vasopressin aimed at restoring
arterial filling pressure.
5.
Renal vasoconstriction increases
concomitantly (leukotrienes and
endothelins), counterbalanced by
the intrarenal hyperproduction of
vasodilating prostaglandins. When
this balance is lost renal
hemodynamics worsens, and
hepatorenal syndrome develops
39-year-old man with a history of heavy alcohol abuse
and cirrhosis but no other significant past medical
problems was admitted for treatment of increasing
ascites.
He had no known history of kidney disease
He had jaundice, tense ascites, severe leg edema, and
mild to moderate encephalopathy.
He had no signs of fluid loss, such as bleeding or
diarrhea.
The patient was not taking any nephrotoxic
medications.
His AST and ALT were 202 U/L and 68 U/L, respectively, and his
initial serum creatinine level was 62 micromoles/L and Na 123.
Results of serologic testing for antibody to hepatitis C virus,
hepatitis B surface antigen, IgM antibody to hepatitis A virus,
antinuclear antibodies, and antibody to Sm nuclear antigen
were negative.
The patient had no detectable paracetamol level, and his
ceruloplasmin level was normal.
Between day 5 and day 14 of the patient's hospitalization, his
serum creatinine level increased from 230 micromoles/L.
No improvement in renal function after volume expansion with 1.5L
isotonic saline solution
Microscopic examination of his urine revealed fewer than 50 red
blood cells per high-power field. Urine and serum osmolality
values were 354 mOsm/kg H2O and 246 mOsm/kg H2O
Urine protein excretion was 246 mg/24 hr, and spot urine sodium
level was 7 mmol/L.
Renal ultrasound was normal.
Serum-ascites albumin gradient was 2.1 g/dL, and PMN count 2
International Ascites Club diagnostic criteria for HRS
Major criteria
1. Chronic or acute hepatic disease and liver failure with portal
hypertension
2. Serum creatinine level >133 micromoles/L or 24-hr creatinine clearance
<40 mL/min
3. Absence of shock, ongoing bacterial infection, recent use of nephrotoxic
drugs, excessive fluid or blood loss
4. No sustained improvement in renal function after volume expansion with
1.5 L isotonic saline solution
5. Proteinuria <500 mg/day and no ultrasonographic evidence of renal tract
or parenchymal disease
Minor criteria
1. Urine volume <500 mL/day
2. Urine sodium <10 mEq/L
3. Urine osmolality greater than plasma osmolality
4. Urine red blood cell count <50 per high-power field
5. Serum sodium <130 mEq/L
Types of HRS
• Type I HRS is the more serious type
defined by a rise in creatinine level to over 221
micromoles/L in less than 2 weeks (or at least a 50
percent lowering of the creatinine clearance to a
value below 20 mL/min) median survival of 2
weeks
• Type II HRS is defined as less severe renal
insufficiency than that observed with type I
disease; it is principally characterized by ascites
that is resistant to diuretics. median survival of
3-6 months.
Other Problems to be Excluded:
•
Prerenal azotemia from volume depletion(diuretic/GI
bleed/LVP)
•
Systemic infection/SBP(HRS type 1 develops in 15% )
•
Drug-induced nephrotoxicity: aminoglycosides, diuretics,
iodine-containing contrast agents, and nonsteroidals. ACE
inhibitors, demeclocycline, and dipyridamole.
•
Postrenal azotemia from outflow obstruction
•
Renal vascular disease
•
Glomerulonephritis, nonstreptococcal postinfectious
PRERENAL HRS
ATN
SPOT Na
<10
<10
>30
Urine
sediment
Nil
Nil
Positive
Fluid
challenge
Responds
Nil
Nil
HEPATORENAL SYNDROME
Incidence
• HRS occurs in approximately 4% of
patients with cirrhosis who are
decompensated,
• With a cumulative probability of 8%
per year, which increases to 39% at
5 years.
• In hospitalized patients with ascites,
the incidence rate is 7-15%.
Assessing renal perfusion
• Creatinine production may be substantially reduced in
this setting, due to the liver disease and to decreased
muscle mass and protein and meat intake.
• Creatinine clearance value obtained in patients with
renal insufficiency will tend to overestimate the true GFR
due to increased creatinine secretion
• Noninvasive techniques to assess the degree of renal
vasoconstriction duplex Doppler ultrasonography.A high
resistive index ( 0.70) is indicative of renal
vasoconstriction.
Treatment options
• OLT
• Haemodialysis
• TIPSS
• Vasoactive Medical treatment
OLT
• Liver transplantation carries the best
chance for long-term survival, but the
rapid deterioration associated with type 1
HRS means that many patients die before
an organ becomes available.
• The systemic and neurohumoral
abnormalities associated with HRS also
resolve in the first postoperative month.
• The hepatorenal syndrome is a prerenal
disease, as the kidneys are normal
histologically
Dialysis
• This is used most commonly in patients who are awaiting
liver transplantation, as dialysis improves the priority
score for the transplant.
• Acute and potentially reversible hepatic insult may
benefit from dialysis, since renal function will recover in
parallel with improving hepatic function.
• Hemodialysis is frequently difficult to perform in patients
with hepatorenal syndrome since decompensated
hepatic function is associated with hemodynamic
instability.
TIPSS
• The transjugular intrahepatic portosystemic shunt (TIPS) has been
used in the treatment of refractory ascites. When used in this
setting, there may also be a delayed improvement in renal function
• There is much less information on the use of TIPS in patients who
fulfill criteria for the hepatorenal syndrome
• Overall, these results suggest that, in selected patients with
hepatorenal syndrome, TIPSS may provide short-term benefit.
Given the risks associated with this procedure (particularly the high
incidence of encephalopathy), it should be considered only as a last
resort in patients who are not a candidate for or are awaiting liver
transplantation.
Medical treatment
• Hepatorenal syndrome was recalcitrant to
medical therapy for so many years that it
is still perceived by many physicians as
untreatable.
• Clearly, new therapies have significantly
brightened the short-term outlook for
patients with type 1 hepatorenal
syndrome, and improvement in short-term
survival rates may lead to increased
opportunity for definitive therapy (ie, liver
transplantation).
Vasoactive therapy
• Midodrine- octreotide- albumin
regime
• Terlipressin plus albumin
• Midodrine and octreotide – Growing data
suggest that combination therapy with
midodrine (a selective alpha-1 adrenergic
agonist) and octreotide (a somatostatin
analog) may be highly effective and safe.
• The rationale is midodrine (systemic
vasoconstrictor) and octreotide (inhibitor
of endogenous vasodilator release)will
reverse the pathophysiology
Angelie et al Hepatology 1999
Pomier-Layrargues et al Hepatology 2003
1.
Sinusoidal portal hypertension, in
the presence of severe hepatic
decompensation
2.
Leads to splanchnic and systemic
vasodilatation-role of NO
3.
Decreased effective arterial blood
volume
4.
Activation of systemic vasoactive
factors, such as the reninangiotensin system, the
sympathetic nervous system, and
vasopressin aimed at restoring
arterial filling pressure.
5.
Renal vasoconstriction increases
concomitantly (leukotrienes and
endothelins), counterbalanced by
the intrarenal hyperproduction of
vasodilating prostaglandins. When
this balance is lost renal
hemodynamics worsens, and
hepatorenal syndrome develops
Midodrine- octreotide- albumin
regime
• Midodrine (7.5 mg by mouth every 8
hours)
• Octreotide (100 mg subcutaneously
every 8 hours)
• Albumin (25 mg intravenously per
day)
Terlipressin plus albumin
regime
• Terlipressin bolus(0.5mg/4h)increase every 3 days if no response
to 1-2mg/4h
• Given until creatinine normalizes or
for 15 days
• Albumin 1g/kg on day1,20-60g/d
thereafter
Uriz et al J Hepatol 2000
• In one prospective, nonrandomized
study 21 patients were treated with
terlipressin plus albumin compared
with terlipressin alone.
• The group treated with terlipressin and
albumin had a 3-month survival rate of
50%, compared to 10% for the
terlipressin-only group.
Ortega et al hepatology
2002
• A small cohort of nine patients with
cirrhosis and HRS were given Terlipressin
and albumin until the reversal of
hepatorenal syndrome or for a maximum
of 15 days
• Seven of the nine patients showed a
reversal of hepatorenal syndrome. There
was also a marked improvement in MAP.
Plasma renin activity and plasma
norepinephrine decreased
Uriz et al J Hepatol 2000
PREVENTION
• In patients with spontaneous bacterial peritonitis, the
administration of intravenous albumin (1.5 g/kg) at the
time of diagnosis of infection and another dose of albumin
(1.0 g/kg) on day three of antibiotic treatment may reduce
the incidence of both renal impairment and mortality during
hospitalization and at three months
• Pentoxifylline (400 mg PO TID) may be preventive in
patients with severe alcoholic hepatitis
Thank you