hepatic disorders - wordpress.com disorders systemic therapeutics 11 ... liver-anatomy and...

6/4/2017

1

Hepatic DisordersSystemic Therapeutics 11

PHCP 402

Dr Maxwell AdibeClinical Pharmacy

Liver - Anatomy and Physiology

Largest organ in the body

Three basic functions• Metabolic• Secretory• Vascular

Major function• Excretion of waste products from bloodstream

by excretion into bile


Location• Upper right quadrant• Four lobes made up of hepatocytes• phagocytic cells

Blood supply• One major vein - portal vein• One major artery - hepatic

6/4/2017

2


Functions of liver• Blood glucose concentration• Synthesis of Enzymes• Protein metabolism• Fat metabolism• Storage functions• Drug metabolism• Ammonia conversion

Metabolic Profile of the Liver

The primary function of the liver is to regulate themetabolism.

It metabolizes the intake of carbohydrates, fats, andproteins.

It accomplishes this function by working closely with othersystems such as lymphatic system, circulatory system, as andendocrine system.

In order for the liver to metabolize the fats, carbohydrates,and proteins, it must be healthy and free of any diseases.

Bile Production Liver produces and secretes a product called bile.

This is what makes it possible for metabolize the intake of fats,proteins, and carbohydrates.

This fluid is a very important presence in the body due to the factthat it aids in the elimination of contaminants in the body, suchas drugs.

The bile system is also responsible for re-circulating red bloodcells.

6/4/2017

3

Failure to Produce Bile It is possible for a type of liver disease to cause the liver to stop

the secretion of bile.

When this happens, the liver loses the capability to metabolizethe fats, carbohydrate, and proteins.

The only way fats can be absorbed into your blood system is ifbile is present.

This is why it would be impossible for the body to absorb thefat-soluble vitamins without bile.

Liver diseases

HYPERBILIRUBINEMIA

Increased plasma concentrations ofbilirubin (> 3 mg/dL) occurs when there is animbalance between its production andexcretion

Recognized clinically as jaundice

6/4/2017

4

Red Blood Cell System Another important function the liver performs is

that it cleanses the body from the damaged, orold, red blood cells.

The liver will also store iron in your body, as wellas breakdown hemoglobin.

This is the reason why many people who sufferfrom liver disease may suffer from anemia.

Hepatitis Acute or Chronic Inflammation of the parachymal

cells of the liver which may to Hepatic necrosis Caused by a variety of infective agents like Viruses,

Bacteria, and drugs or chemicals. Viral hepatitis is the most common type: A, B, C,

D and E. Two main types are HAV and HBV. Noninfectious hepatitis may be caused by drugs

and chemicals

Hepatitis – Clinical Manifestations

Preicteric or Prodromal phase• Precedes jaundice• Lasts 1 – 21 days• Maximal infectivity for hepatitis A• Symptoms

Anorexia, right upper quadrant pain,constipation or diarrhea, malaise, fever,headache, arthralgias, weight loss

6/4/2017

5

Etiology Infection Alcohol Autoimmune Cholestatic Infiltrative Metabolic Vascular Drugs

Complications

Ascites GI bleed SBP Edema Hepatoma Encephalopathy Hepatorenal syndrome

Lab Tests Elevated Alkaline phosphatase

Elevated with bone and liverdisorders

Elevated SGOT/AST

Elevated SGPT/ALT

Elevated serum globulin

Elevated LDH

Decreased albumin

Increased prothrombin time

Blood ammonia level• Increased due to decreasedmetabolism of ammonia tourea by the liver

6/4/2017

6

Treatment is based on Cause ( Etiology) Complication Mgt is usually symptomatic as dx does not

warrant complex drug therapy Bed rest – allows inflamed cells to recover Diet- balance diet with/out protein restriction Colestipol and Cholestyramine (4g tds/qid x

2/52 )– to manage prutitis. SE- GIT disturbances, absorption of fat soluble

vit ADEK

plasma conc of thiazide, tetracycline, warfarin,phenobarbital, phenylbutazone and digitoxin

Anti-histamines e.g diphenhydramine, hydroxyzine –relieve pruritis.

SE – Drowsiness may affect the clinical status of thepts

Antibiotics – not usually given unless HE occurs andthere is need to decrease Ammonia.

Neomycin (2-4g orally 3-4 times daily)– non-systemicantibiotic is adm to sterilize the gut against bacteriametabolizing protein to Ammonia

Steroids (Prednisone 40-60mg daily)– controversial –except in acute hepatitis and life threatening cases

For chronic HBV – Goals are to limitinflammation and progression to complications

Interferons (IFN-α2b), Lamivudine, Adefovir (IFN-α2b), Lamivudine are first line but the

latter is favored due to cost and less SE but ishighly susceptible to drug resistance

Preventive prophylaxis of HAV and HBV-Vaccine and immunoglobulins, with formerproviding long-lasting active immunity and lattera short acting passive immunity against HBVinfection

6/4/2017

7

Other treatments Hepatitis B Nucleoside analogues Lamivudine Adefovir Telbivudine Entecavir Tenofovir Interferon

Hepatitis C Alfa interferon Pegylated interferon Ribavirin

Autoimmune hepatitis Prednisone Azathioprine New drugs• Budesonide• Cyclosporine• Tacrolimus• Rapamycin• Mycophenolate mofetil

Alcohol Abstinence Fatty liver Liver transplant

Wilson disease Penicillamine Trientine Zinc acetate Tetrathiomolybdate• Family screening

6/4/2017

8

Hemochromatosis Phlebotomy Family screening Alpa1 antitrypsin deficiency 4-phenylbutyric acid Liver transplant Genetic counseling

CIRRHOSISA chronic difused liver dix characterized by lose of livercells, collapsed and fibrosis of the reticulum net-work

with distortion of the vascular bed and nodularregeneration of the remaining cell mass

Lose of normal lobular archecture of the livercells adversely affects:

Blood vessels and bile duct out-flow withsequalae of: Obstruction Jundice Ascites Portal hypertension Oesophageal varices

6/4/2017

9

Pathophysiology

Irreversible chronic injury of the hepaticparenchyma

Extensive fibrosis - distortion of the hepaticarchitecture

Formation of regenerative nodules

Clinical Manifestations Fever, Nausea, vomiting, jaundice right flank pain,

and tenderness Malaise, flu-like symptoms of weakness, fatigue,

anorexia, weight loss, ankle edema, and protuberantabdomen

Spider angiomas Palmar erythema Nail changes Muehrcke's nails Terry’s nails

Gynecomastia Loss of libido, impotence and Testicular atrophy

Clinical Manifestations

Muehrcke's nails Terry’s nails

6/4/2017

10

Clinical Manifestations Fetor hepaticus Jaundice Asterixis Pigment gallstones Parotid gland

enlargement

Cruveilhier-Baumgartenmurmur

Hepatomegaly Splenomegaly Caput medusa

Laboratory Studies most common measured laboratory test

classified as LFTs include the enzyme tests (principally the serum

aminotransferases, alkaline phosphatase, and gammaglutamyl transpeptidase), the serum bilirubin

tests of synthetic function (principally the serumalbumin concentration and prothrombin time)

Radiologic Modalities

Can occasionally suggest the presence ofcirrhosis, they are not adequately sensitive orspecific for use as a primary diagnostic modality

Major utility of radiography in the evaluation ofthe cirrhotic patient is in its ability to detectcomplications of cirrhosis

6/4/2017

11

Diagnosis

Liver biopsy Obtained by either a percutaneous, transjugular,

laparoscopic, or radiographically-guided fine-needleapproach

Sensitivity of a liver biopsy for cirrhosis is in therange of 80 to 100 percent depending upon themethod used, and the size and number of specimensobtained

Diagnosis not necessary if the clinical, laboratory, and

radiologic data strongly suggest the presence ofcirrhosis

liver biopsy can reveal the underlying cause ofcirrhosis

Complications

Ascites Spontaneous Bacterial Peritonitis Hepatorenal syndrome Variceal hemorrhage Hepatopulmonary syndrome

6/4/2017

12

Complications

Other Pulmonary syndromes Hepatic hydrothorax Portopulmonary HTN

Hepatic Encephalopathy Hepatocellular carcinoma

Liverinsufficiency

Liverinsufficiency

VaricealhemorrhageVaricealhemorrhage

Complications of Cirrhosis Resultfrom Portal Hypertension or Liver

Insufficiency

Complications of Cirrhosis Resultfrom Portal Hypertension or Liver

Insufficiency

CirrhosisCirrhosisAscitesAscites

EncephalopathyEncephalopathy

JaundiceJaundice

Portalhypertension

Portalhypertension Spontaneous

bacterialperitonitis

Spontaneousbacterialperitonitis

HepatorenalsyndromeHepatorenalsyndrome

COMPLICATIONS OF CIRRHOSIS

Variceal hemorrhage

6/4/2017

13

Portal Hypertension An increase in portal venous pressure due to increased

resistance to blood flow in the portal system. Caused obstruction by nodular regeneration and

distortion of vascular architecture in the cirrhotic liver Complications of PH: Dev of venous collaterals btw portal and systemic

circulation (causes formation of varices at lower end ofoesophagus and the fundus of the stomach)

Hyperspleenism Ascitis Hepatic Encephalopathy

Variceal haemorrhage

Acute GIT bleeding is most imp complicationof PH emanating from varices.

Ascites and peripheral edema can occur asresult of fluid localization

Varices/Variceal

Hemorrhage

Varices/Variceal

Hemorrhage

Varicealobliteration

Varicealobliteration

Portalpressure

Portalpressure

Resistanceto portal flowResistance

to portal flow

CirrhosisCirrhosis

Resistanceto portal flowResistance

to portal flowSplanchnicarteriolar

resistance

Splanchnicarteriolar

resistance

Portal bloodinflow

Portal bloodinflow

Variceal BandLigation or

Sclerotherapy

Variceal BandLigation or

Sclerotherapy

MECHANISM OF ACTION OF ENDOSCOPIC THERAPY IN PORTAL HYPERTENSION

6/4/2017

14

Treatment of Varices / VaricealHemorrhage


RecurrenthemorrhageRecurrent

hemorrhage

Varicealhemorrhage

Varicealhemorrhage

VaricesNo hemorrhage

VaricesNo hemorrhage

No varicesNo varices

Management depends onthe size of varicesManagement depends onthe size of varices

MANAGEMENT OF PATIENTS WITH VARICES WHO HAVE NEVER BLED




hemorrhage

Varicealhemorrhage

Varicealhemorrhage

Medium/ large varicesNo hemorrhage


Small varicesNo hemorrhage



1) -blockers (propranolol, nadolol)indefinitely

2) Endoscopic Variceal Ligation inpatients intolerant to -blockers

1) -blockers (propranolol, nadolol)indefinitely

2) Endoscopic Variceal Ligation inpatients intolerant to -blockers

MANAGEMENT OF PATIENTS WITH MEDIUM/LARGE VARICES WITHOUT PRIOR HEMORRHAGE



Two goals:1. Control of hemorrhage

2. prevention of recurrent hemorrhage

Two goals:1. Control of hemorrhage

2. prevention of recurrent hemorrhage


hemorrhage

Varicealhemorrhage

Varicealhemorrhage






CONTROL OF ACUTE VARICEAL HEMORRHAGE

6/4/2017

15

Treatments Treatment of acute variceal hemorrhage includes general

and specific therapies. General management includes establishing intravenous

access and fluid resuscitation. Vigorous fluid resuscitation and transfusion to hemoglobin

levels >8 g/dL should be avoided as this could precipitateearly variceal rebleeding.

Prophylactic antibiotic therapy should be institutedpromptly in any cirrhotic patient with gastrointestinalhemorrhage.

Specific therapy includes pharmacological therapy,endoscopic therapy and shunt therapy.

Treatment of Acute VaricealHemorrhage

Treatment of Acute VaricealHemorrhage

General Management: IV access and fluid resuscitationDo not over transfuse (hemoglobin ~ 8 g/dL)Antibiotic prophylaxis

Specific therapy: Pharmacological therapy:

Terlipressin, Somatostatin and analogues (Octreotide is

commonly used), Vasopressin (iv bolus of 20U followed by infusion

0.2 -0.4U/min in 100ml of 5% dex) V asopressin + Nitroglycerin, vit K.

General Management: IV access and fluid resuscitationDo not over transfuse (hemoglobin ~ 8 g/dL)Antibiotic prophylaxis

Specific therapy: Pharmacological therapy:

Terlipressin, Somatostatin and analogues (Octreotide is

commonly used), Vasopressin (iv bolus of 20U followed by infusion

0.2 -0.4U/min in 100ml of 5% dex) V asopressin + Nitroglycerin, vit K.

TREATMENT OF ACUTE VARICEAL HEMORRHAGE

Propranolol - 20-180mg daily Endoscopic therapy: Ligation, Sclerotherapy Shunt therapy: TIPS, surgical shunt

6/4/2017

16

Endoscopic Variceal BandLigation

Endoscopic Variceal BandLigation

Bleeding controlled in 90%

Rebleeding rate 30%

Compared with Sclerotherapy:Less rebleedingLower mortalityFewer complicationsFewer treatment sessions

Bleeding controlled in 90%

Rebleeding rate 30%

Compared with Sclerotherapy:Less rebleedingLower mortalityFewer complicationsFewer treatment sessions

ENDOSCOPIC VARICEAL BAND LIGATION

THE TRANSJUGULAR INTRAHEPATICPORTOSYSTEMIC SHUNT

Portal hypertension can be corrected by creatinga communication between the hypertensiveportal system and low-pressure systemic veins,bypassing the liver, i.e., the site of increasedresistance.

This communication can be created surgically orby the transjugular placement of an intrahepaticstent that connects a branch of the portal veinwith a branch of a hepatic vein, a proceduredesignated transjugular intrahepatic porto-systemic shunt (TIPS).

TIPS is performed by advancing a catheterintroduced through the jugular vein into ahepatic vein and into a main branch of theportal vein.

An expandable stent is then introducedconnecting hepatic and portal systems, andblood from the hypertensive portal vein andsinusoidal bed is shunted to the hepatic vein.

The procedure is highly effective in correctingportal hypertension but can be associated withcomplications related to diversion of blood flowaway from the liver, namely portal-systemicencephalopathy and liver failure.

6/4/2017

17

Transjugular Intrahepatic Portosystemic Shunt

Transjugular Intrahepatic Portosystemic Shunt

HepaticveinHepaticvein

Portal veinPortal veinSplenicveinSplenicvein

Superior mesentericveinSuperior mesentericvein

THE TRANSJUGULAR INTRAHEPATIC PORTOSYSTEMIC SHUNT

Transjugular intrahepaticportosystemic shunt (TIPS)

ASCITES

Ascites

Accumulation of fluid within the peritonealcavity

It is as a result of combination of pathologic,physiologic and compensatory mechnisms

Most common complication of cirrhosis Two-year survival of patients with ascites is

approximately 50 percent

6/4/2017

18

Pathophysiology Formation of ascetic fluid is a combination of: Increased hydrostatic pressure in the portal vein against Low plasma oncotic pressure due to decreased albumin Hydrostatic > oncotic = fluid movement from vascular

to extra-vascular compartment into the peritoneal cavity The overall fluid depletion causes reduced blood flow

blood flow activating the RAAS. Resutant hyperaldosteronism increase distal tubular

reabsorption of Na and H2O, increasing total body H2O This compensatory mechanism + increased blood flow

may worsen PH with increased splanchnic blood volume Thus, a vicious cycle is set up.

Ascites Assessment of ascites

Grading Grade 1 — mild; Detectable only by Ultra Sound Grade 2 — moderate; Moderate symmetrical distension of the

abdomen

Grade 3 — large or gross ascites with marked abdominal distension

Older system -subjective 1+ minimal, barely detectable 2+ moderate 3+ massive, not tense 4+massive and tense

Ascites

Imaging studies for confirmation of ascites Ultrasound is probably the most cost-effective

modality

6/4/2017

19

Who gets a belly tap?

Treatments

Goals: to reduce excess fluid and Na and H2O Treatment aimed at the underlying cause of the

hepatic disease and at the ascitic fluid itself Bed rest Dietary sodium restriction Limiting sodium intake to 60 to 90 meq (approx.

1500 to 2000 mg) per day

Fluid restricted to 1L per day – pt with dilutionalhyponatremia – low Na (< 130 mmol/L) in thepresence of edema and/or ascites.

K deficiency should be corrected NSAID use minimized - as they can reduce the

effect of diuretics, caused renal vesocontrictionand acute renal failure

6/4/2017

20

Management of Uncomplicated AscitesManagement of Uncomplicated AscitesDefinition: Ascites responsive to diuretics in theabsence of infection and renal dysfunctionDefinition: Ascites responsive to diuretics in theabsence of infection and renal dysfunction

Sodium restriction Effective in 10-20% of cases Predictors of response: mild or moderate ascites, Urine Na

excretion > 50 mEq/dayDiuretics

Should be spironolactone-based – aldosterone antagonist, spares Kwhile depleting Na with low and gradual diuresis

100 to 400mg daily, initiated with 4 times daily, thereafter, oncedaily due its long half life.

The onset of action is gradual (3 to 4 days as a result ofaccumulation of canrenone - and active metabolite)

A progressive schedule (spironolactone furosemide) requiresfewer dose adjustments than a combined therapy (spironolactone+ furosemide)

WHAT ARE THE SIDE EFFECTS OF SPIRONOLACTONE?

Sodium restriction Effective in 10-20% of cases Predictors of response: mild or moderate ascites, Urine Na

excretion > 50 mEq/dayDiuretics

Should be spironolactone-based – aldosterone antagonist, spares Kwhile depleting Na with low and gradual diuresis

100 to 400mg daily, initiated with 4 times daily, thereafter, oncedaily due its long half life.

The onset of action is gradual (3 to 4 days as a result ofaccumulation of canrenone - and active metabolite)

A progressive schedule (spironolactone furosemide) requiresfewer dose adjustments than a combined therapy (spironolactone+ furosemide)

WHAT ARE THE SIDE EFFECTS OF SPIRONOLACTONE?

MANAGEMENT OF UNCOMPLICATED ASCITES

Diuretic TherapyDosage

Spironolactone 100-400 mg/dayFurosemide (40-160 mg/d) for inadequate weight loss or if

hyperkalemia develops Increase diuretics if weight loss <1 kg in the first week and < 2

kg/week thereafter Decrease diuretics if weight loss >0.5 kg/day in patients

without edema and >1 kg/day in those with edema

Side effectsRenal dysfunction, hyponatremia, hyperkalemia,

encephalopathy, gynecomastia

Diuretic TherapyDosage

Spironolactone 100-400 mg/dayFurosemide (40-160 mg/d) for inadequate weight loss or if

hyperkalemia develops Increase diuretics if weight loss <1 kg in the first week and < 2

kg/week thereafter Decrease diuretics if weight loss >0.5 kg/day in patients

without edema and >1 kg/day in those with edema

Side effectsRenal dysfunction, hyponatremia, hyperkalemia,

encephalopathy, gynecomastia

Management of Uncomplicated AscitesMANAGEMENT OF UNCOMPLICATED ASCITES: DIURETIC THERAPY

Definition and Types of Refractory AscitesDefinition and Types of Refractory AscitesOccurs in ~10% of cirrhotic patientsOccurs in ~10% of cirrhotic patients

Diuretic-intractable ascitesTherapeutic doses of diuretics cannot be achievedbecause of diuretic-induced complications

Diuretic-resistant ascitesNo response to maximal diuretic therapy (400 mgspironolactone + 160 mg furosemide/day)

Diuretic-intractable ascitesTherapeutic doses of diuretics cannot be achievedbecause of diuretic-induced complications

Diuretic-resistant ascitesNo response to maximal diuretic therapy (400 mgspironolactone + 160 mg furosemide/day)

20%20%

80%80%

DEFINITION AND TYPES OF REFRACTORY ASCITES

6/4/2017

21

Treatments The most successful therapeutic regimen is the

combination of single morning oral doses ofSpironolactone and Furosemide, beginning with100 mg and 40 mg

Two major concerns with diuretic therapy forcirrhotic ascites: Overly rapid removal of fluid Progressive electrolyte imbalance

Triamterene and amiloride – serve as alternative Spare K but do not antagonize tha aldosterone,

therefore, it should be used in combination withspironolactone

Salt free albumin 25mg per day for few days Prednisone 10 mg 3 times daily for 1/52 for low

serum Na

Others

Paracentesis – 1 to 3 L daily for over 5 hoursrepeated every few days.

Leveen Peritoneojugular Shunt (PJS) Liver transplantation Discuss the advantages and disadvantages of

each of them.

6/4/2017

22

SPONTANEOUS BACTERIALPERITONITIS (SBP)

Spontaneous bacterial peritonitis (SBP) is aninfection of ascitic fluid that occurs in theabsence of a hollow viscus perforation and inthe absence of an intra-abdominal inflammatoryfocus such as an abscess, acute pancreatitis orcholecystitis.

Any cirrhotic patient with ascites(uncomplicated or refractory) is at risk ofdeveloping SBP, a potential precipitating factorof the hepatorenal syndrome.

Spontaneous Bacterial Peritonitis

Infection of ascitic fluid Almost always seen in the setting of end-stage

liver disease The diagnosis is established by A positive ascitic fluid bacterial culture Elevated ascitic fluid absolute polymorphonuclear

leukocyte (PMN) count ( >250 cells/mm3)

Spontaneous Bacterial Peritonitis

Clinical manifestations: Fever Abdominal pain Abdominal tenderness Altered mental status

6/4/2017

23

Spontaneous Bacterial Peritonitis (SBP)Complicates Ascites and Can Lead to Renal

Dysfunction

Spontaneous Bacterial Peritonitis (SBP)Complicates Ascites and Can Lead to Renal

Dysfunction

SBPSBP

HVPG >10 mmHgExtreme VasodilationHVPG >10 mmHgExtreme Vasodilation

HVPG >10 mmHgSevere VasodilationHVPG >10 mmHgSevere Vasodilation

HVPG >10 mmHgModerate VasodilationHVPG >10 mmHgModerate Vasodilation

HVPG <10 mmHgMild VasodilationHVPG <10 mmHgMild Vasodilation

HepatorenalSyndrome

HepatorenalSyndrome

RefractoryAscites

RefractoryAscites

UncomplicatedAscites

UncomplicatedAscites

PortalHypertension

No Ascites

PortalHypertension

No Ascites

SPONTANEOUS BACTERIAL PERITONITIS (SBP) COMPLICATES ASCITES AND CAN LEAD TO RENALDYSFUNCTION

Early Diagnosis of SBPEarly Diagnosis of SBP

Diagnostic paracentesis: If symptoms / signs of SBP occur Unexplained encephalopathy and / or renal

dysfunction At any hospital admission

Diagnosis based on ascitic fluidPolymorphonuclear leukocyte (PMN) count>250/mm3

Diagnostic paracentesis: If symptoms / signs of SBP occur Unexplained encephalopathy and / or renal

dysfunction At any hospital admission

Diagnosis based on ascitic fluidPolymorphonuclear leukocyte (PMN) count>250/mm3

EARLY DIAGNOSIS OF SPONTANEOUS BACTERIAL PERITONITIS (SBP)

Microorganisms Isolated in Spontaneous Bacterial PeritonitisMicroorganisms Isolated in Spontaneous Bacterial Peritonitis

Microorganism % of Cases

Gram-negative bacilli 72

Gram-positive cocci 29

Microorganism % of Cases

Gram-negative bacilli 72

Gram-positive cocci 29

MICROORGANISMS ISOLATED IN SPONTANEOUS BACTERIAL PERITONITIS (SBP)

6/4/2017

24

Treatment of Spontaneous BacterialPeritonitis

Treatment of Spontaneous BacterialPeritonitis

Recommended antibiotics for initial empiric therapy i.v. cefotaxime, i.v. amoxicillin-clavulanic acid avoid aminoglycosides

Minimum duration: 5 days

Recommended antibiotics for initial empiric therapy i.v. cefotaxime, i.v. amoxicillin-clavulanic acid avoid aminoglycosides

Minimum duration: 5 days

TREATMENT OF SPONTANEOUS BACTERIAL PERITONITIS (SBP)

Indications for ProphylacticAntibiotics to Prevent Spontaneous

Bacterial Peritonitis

Indications for ProphylacticAntibiotics to Prevent Spontaneous

Bacterial Peritonitis

Patients who have recovered from SBP (long-term) Norfloxacin 400 mg p.o. daily, indefinitely

Weekly Quinolones

Patients who have recovered from SBP (long-term) Norfloxacin 400 mg p.o. daily, indefinitely

Weekly Quinolones

INDICATIONS FOR PROPHYLACTIC ANTIBIOTICS TO PREVENT SPONTANEOUS BACTERIAL PERITONITIS(SBP)

Hepatorenal Syndrome

6/4/2017

25

Hepatorenal syndrome acute renal failure coupled with advanced hepatic

disease (due to cirrhosis or less often metastatic tumor orsevere alcoholic hepatitis)

characterized by: Oliguria benign urine sediment very low rate of sodium excretion progressive rise in the plasma creatinine concentration

Hepatorenal Syndrome

Reduction in GFR often clinically masked Prognosis is poor unless hepatic function

improves Nephrotoxic agents and overdiuresis can

precipitate HRS

Ascites and Hepatorenal SyndromeAscites and Hepatorenal Syndrome

ASCITES AND HEPATORENAL SYNDROME

The most common complication of cirrhosis that results fromportal hypertension and the consequent vasodilatation is• the development of ascites and,• in its extreme, the development of hepatorenal syndrome.

6/4/2017

26

NATURAL HISTORY OF ASCITES

Ascites does not develop in patients with earlycirrhosis and hepatic venous pressure gradient(HVPG) under 10 mmHg.

Once HVPG is elevated above this thresholdpressure, accumulation of ascites may occur.

Ascites progresses from uncomplicated ascites, torefractory ascites, and eventually to hepatorenalsyndrome (HRS) depending on the severity ofliver disease and the degree of peripheralvasodilatation.

In early cirrhosis, even in the absence of ascites,there is mild vasodilatation.

Uncomplicated ascites is associated withmoderate vasodilatation.

As liver disease progresses further, vasodilatationbecomes more severe and patients developrefractory ascites.

Hepatorenal syndrome develops when there is anextreme systemic vasodilatation, leading tomaximal renal vasoconstriction and renal failure.

Natural History of Ascites(Hepatic venous pressure gradient- HVPG)

Natural History of Ascites(Hepatic venous pressure gradient- HVPG)

HVPG >10 mmHgExtremeVasodilation

HVPG >10 mmHgExtremeVasodilation

HVPG >10 mmHgSevereVasodilation

HVPG >10 mmHgSevereVasodilation

HVPG >10 mmHgModerate VasodilationHVPG >10 mmHgModerate Vasodilation

HVPG <10 mmHgMild VasodilationHVPG <10 mmHgMild Vasodilation

HepatorenalSyndrome

HepatorenalSyndrome

RefractoryAscites

RefractoryAscites

Uncomplicated

Ascites

Uncomplicated

Ascites

PortalHypertension

No Ascites

PortalHypertension

No Ascites

NATURAL HISTORY OF ASCITES

6/4/2017

27

CHARACTERISTICS OFHEPATORENAL SYNDROME (HRS)

The hepatorenal syndrome (HRS) occurs inpatients with advanced cirrhosis.

It is a functional renal failure, that is, the kidneysof these patients have no significant histologicalabnormalities.

Renal failure occurs as a result of renalvasoconstriction that in turn occurs as a resultof extreme peripheral vasodilatation.

Characteristics of HepatorenalSyndrome

Characteristics of HepatorenalSyndrome

Renal failure in patients with cirrhosis, advanced liverfailure and severe sinusoidal portal hypertension

Absence of significant histological changes in the kidney(“functional” renal failure)

Marked arteriolar vasodilation in the extra-renal circulation

Marked renal vasoconstriction leading to reducedglomerular filtration rate

Renal failure in patients with cirrhosis, advanced liverfailure and severe sinusoidal portal hypertension

Absence of significant histological changes in the kidney(“functional” renal failure)

Marked arteriolar vasodilation in the extra-renal circulation

Marked renal vasoconstriction leading to reducedglomerular filtration rate

CHARACTERISTICS OF HEPATORENAL SYNDROME (HRS)

TYPES OF HEPATORENALSYNDROME (HRS)

The HRS has been divided in 2 types based onclinical characteristics and prognosis.

Type 1 HRS is a rapidly progressive renal failure,in which a doubling of serum creatinine (orhalving of creatinine clearance) occurs within a2–week period.

Type 2 HRS is more slowly progressive and isassociated with refractory ascites.

Arroyo V, et al., Hepatology 1996; 23: 164

6/4/2017

28

Two Types of HepatorenalSyndrome

Two Types of HepatorenalSyndrome

Type 1 Rapidly progressive renal failure (2 weeks) Doubling of creatinine to >2.5

Type 2 More slowly progressive Creatinine >1.5 mg/dL or Creatinine Clearance

< 40 ml/min Associated with refractory ascites

Type 1 Rapidly progressive renal failure (2 weeks) Doubling of creatinine to >2.5

Type 2 More slowly progressive Creatinine >1.5 mg/dL or Creatinine Clearance

< 40 ml/min Associated with refractory ascites

TYPES OF HEPATORENAL SYNDROME (HRS)

Management of Hepatorenal SyndromeManagement of Hepatorenal SyndromeProven efficacy

Liver transplantation

Under investigation Vasoconstrictor + albumin Transjugular intrahepatic portosystemic shunt

(TIPS) Vasoconstrictor + TIPS Extracorporeal albumin dialysis (ECAD)

Ineffective Renal vasodilators (prostaglandin, dopamine) Hemodialysis

Proven efficacy Liver transplantation

Under investigation Vasoconstrictor + albumin Transjugular intrahepatic portosystemic shunt

(TIPS) Vasoconstrictor + TIPS Extracorporeal albumin dialysis (ECAD)

Ineffective Renal vasodilators (prostaglandin, dopamine) Hemodialysis

MANAGEMENT OF HEPATORENAL SYNDROME

Hepatic Encephalopathy (PE)

Hepatic encephalopathy (portal-systemicencephalopathy, hepatic coma) is metabolicdisorder of the CNS often seen an advancedcirrhotic dx.

6/4/2017

29

Clinical manifestations

Spectrum of potentially reversibleneuropsychiatric abnormalities seen in patientswith liver dysfunction

Neurological complications Untidiness, Irritability, Confusion, drowsiness,

slurred speech and stupor to coma. Diurnal sleep pattern pertubation Asterixis Hyperactive deep tendon reflexes Transient decerebrate posturing

Hepatic Encephalopathy

Pathophysiology

Defect in protein metabolism and shortage are themajor causes of encephalopathy.

When the liver lacks the ability to detoxify productsof protein breakdown which enter the portalcirculation from the GIT

Ammonia is the major product of the breakdownby bacterial flora

Also, branched chain amino-acids (against aromaticchain), short-chain fatty acids and some biogenicamines have been found toxic to the brain.

6/4/2017

30

PATHOPHYSIOLOGY OF HEPATICENCEPHALOPATHY

Ammonia, which crosses the blood-brainbarrier, results in up-regulation of astrocyticperipheral-type benzodiazepine receptors whichare the most potent stimulants of neurosteroidproduction.

Neurosteroids are the major modulators ofGABA, which results in cortical depression andhepatic encephalopathy.

Pathophysiology of HepaticEncephalopathy

Ammonia

Upregulation of astrocytic peripheralbenzodiazepine receptors (PBR)

Neurosteroid production

Modulation of GABA receptor

Hepatic encephalopathy

Ammonia

Upregulation of astrocytic peripheralbenzodiazepine receptors (PBR)

Neurosteroid production

Modulation of GABA receptor

Hepatic encephalopathy

PATHOPHYSIOLOGY OF HEPATIC ENCEPHALOPATHY

Hepatic Encephalopathy isa Clinical Diagnosis

Hepatic Encephalopathy isa Clinical Diagnosis

Clinical findings and history important

Ammonia levels are unreliable

Ammonia has poor correlation with diagnosis

Measurement of ammonia not necessary

Number connection test

Slow dominant rhythm on EEG

Clinical findings and history important

Ammonia levels are unreliable

Ammonia has poor correlation with diagnosis

Measurement of ammonia not necessary

Number connection test

Slow dominant rhythm on EEG

HEPATIC ENCEPHALOPATHY IS A CLINICAL DIAGNOSIS

6/4/2017

31

STAGES OF HEPATIC ENCEPHALOPATHY

ConfusionConfusion

DrowsinessDrowsiness

SomnolenceSomnolence

ComaComa11 22 33 44StageStage

Stages of Hepatic EncephalopathyMental stages progress from confusion through drowsiness and

somnolence to coma.

Stages of Hepatic EncephalopathyMental stages progress from confusion through drowsiness and

somnolence to coma.

Treatment of Hepatic EncephalopathyTreatment of Hepatic Encephalopathy Identify and treat precipitating factor

Infection (such as SBP) GI hemorrhage Prerenal azotemia Sedatives Constipation hypokalemia, and hyponatremia

Reduction of ammoniagenic substrate Lactulose/ lactitol – a non-absorbable synthetic disacharide (lactulose +

Lactose + galatose) – 15 to 30ml 3 times daily adjust to 2-3 bowelmovements/day. Lactulose is broken in lactic, acetic and formic acidswith ultimate production of H ion which converts ammonia toammonium

Protein restriction, short-term (if at all) Zinc and melatonin

Identify and treat precipitating factor Infection (such as SBP) GI hemorrhage Prerenal azotemia Sedatives Constipation hypokalemia, and hyponatremia

Reduction of ammoniagenic substrate Lactulose/ lactitol – a non-absorbable synthetic disacharide (lactulose +

Lactose + galatose) – 15 to 30ml 3 times daily adjust to 2-3 bowelmovements/day. Lactulose is broken in lactic, acetic and formic acidswith ultimate production of H ion which converts ammonia toammonium

Protein restriction, short-term (if at all) Zinc and melatonin

TREATMENT OF HEPATIC ENCEPHALOPATHY

ANTIBIOTICS In combination with lactulose Neomycin sulfate – initiated with1 to 2mg 4times

daily for 1/7, then 2 to 4mg daily as maintenancedose

SE- ototoxicity and nephrotoxicity Metronidazole – 250mg 2 or 3 times daily – not to

be use for a long period, peripheral neuropathy mayresult.

Rifaximin- non-absorbable derivatives of rifampin -400mg 3 times daily, it is as effective as lactulose andneomycin and can be used for long term therapies

6/4/2017

32

Treatment of HepaticEncephalopathy

Treatment of hepatic encephalopathy involves1) identifying and treating the precipitatingfactor, and

2) using lactulose adjusted to produce 2-3 bowelmovements per day.

Protein restriction is carried out typically whenpatients have stage 4 hepatic encephalopathy,but may not be necessary. Long-term proteinrestriction is not required.

A vegetable protein diet is better tolerated thanan animal protein diet.

Liver Transplantation

Liver transplantation is the definitive treatmentfor patients with decompensated cirrhosis

Depends upon the severity of disease, qualityof life and the absence of contraindications

Liver Transplantation

Minimal criteria for listing cirrhotic patients onthe liver transplantation list include Less than 90 percent chance of surviving one year

without a transplant An episode of gastrointestinal hemorrhage related to

portal hypertension An episode of spontaneous bacterial peritonitis

6/4/2017

33

Liver transplant

All patients with end stage liver disease shouldbe assessed for liver transplant when ever isproven to significantly prolong survival andimprove quality of life in a cost effective mannerover natural history of the liver disease andother medical and non transplant surgicalintervention.

Vaccinations

Hepatitis A and B Pneumococcal vaccine Influenza vaccination

Surveillance

Screening recommendations: serum AFP determinations and ultrasonography

every six months

6/4/2017

34

Avoidance of Superimposed Insults

Avoidance of:AlcoholAcetaminophenHerbal medications

hepatic disorders - wordpress.com disorders systemic therapeutics 11 ... liver-anatomy and...

Documents