Myasthenia Gravis

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(No Transcript)
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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

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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 renin-angiotensin 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

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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.
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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.
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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
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International Ascites Club diagnostic criteria
for HRS

• Major criteria
• Chronic or acute hepatic disease and liver
  failure with portal hypertension
• Serum creatinine level gt133 micromoles/L or 24-hr
  creatinine clearance lt40 mL/min
• Absence of shock, ongoing bacterial infection,
  recent use of nephrotoxic drugs, excessive fluid
  or blood loss
• No sustained improvement in renal function after
  volume expansion with 1.5 L isotonic saline
  solution
• Proteinuria lt500 mg/day and no ultrasonographic
  evidence of renal tract or parenchymal disease
• Minor criteria
• Urine volume lt500 mL/day
• Urine sodium lt10 mEq/L
• Urine osmolality greater than plasma osmolality
• Urine red blood cell count lt50 per high-power
  field
• Serum sodium lt130 mEq/L

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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.

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Other Problems to be Excluded

• Prerenal azotemia from volume depletion(diuretic/G
  I 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

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PRERENAL HRS ATN
SPOT Na lt10 lt10 gt30
Urine sediment Nil Nil Positive
Fluid challenge Responds Nil Nil
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• HEPATORENAL SYNDROME

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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.

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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.

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Treatment options

• OLT
• Haemodialysis
• TIPSS
• Vasoactive Medical treatment

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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

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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.

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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.

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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).

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Vasoactive therapy

• Midodrine- octreotide- albumin regime
• Terlipressin plus albumin

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• 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
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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 renin-angiotensin 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

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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)

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Terlipressin plus albuminregime

• 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
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• 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
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• 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
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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

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• Thank you