Decompensated Liver Decompensated Liver CirrhosisCirrhosis

By Dr. Doaa KamalBy Dr. Doaa Kamal

DefinitionDefinition::

Cirrhosis is defined histologically as a Cirrhosis is defined histologically as a diffuse hepatic process characterized diffuse hepatic process characterized by fibrosis and the conversion of by fibrosis and the conversion of normal liver architecture into normal liver architecture into structurally abnormal nodules.structurally abnormal nodules.

Causes of liver cirrhosisCauses of liver cirrhosis::1) Viral Hepatitis B, C. 1) Viral Hepatitis B, C. 2) Alcoholic liver disease.2) Alcoholic liver disease.3) Non-alcoholic fatty liver 3) Non-alcoholic fatty liver

disease (NAFLD).disease (NAFLD).4) Autoimmune hepatitis.4) Autoimmune hepatitis.5) Primary biliary cirrhosis.5) Primary biliary cirrhosis.6) Secondary biliary cirrhosis 6) Secondary biliary cirrhosis

(associated with chronic (associated with chronic extrahepatic bile duct extrahepatic bile duct obstruction).obstruction).

7) Primary sclerosing 7) Primary sclerosing cholangitis.cholangitis.

8) Hemochromatosis 8) Hemochromatosis

9) Wilson disease.9) Wilson disease.10) Alpha-1 antitrypsin 10) Alpha-1 antitrypsin

deficiency.deficiency.11) Granulomatous disease (eg, 11) Granulomatous disease (eg,

sarcoidosis).sarcoidosis).12) Type IV glycogen storage 12) Type IV glycogen storage

disease.disease.13) Drug-induced liver disease 13) Drug-induced liver disease

(eg, methotrexate, alpha (eg, methotrexate, alpha methyldopa, amiodarone).methyldopa, amiodarone).

14) Venous outflow obstruction 14) Venous outflow obstruction (eg, Budd-Chiari syndrome, (eg, Budd-Chiari syndrome, veno-occlusive disease).veno-occlusive disease).

15) Cardiac cirrhosis: chronic 15) Cardiac cirrhosis: chronic right-sided heart failure, right-sided heart failure, tricuspid regurgitation.tricuspid regurgitation.

Causes of hepatic decompensationCauses of hepatic decompensation:: Alkalosis.Alkalosis. Hypokalemia.Hypokalemia. GIT bleeding.GIT bleeding. Hypotension.Hypotension. Hepatotoxic drugs.Hepatotoxic drugs. Infection.Infection. Diuretic therapy.Diuretic therapy. General anesthesia.General anesthesia. Surgery and general anesthesia place the cirrhotic Surgery and general anesthesia place the cirrhotic

liver at risk for decompensation. Why? Anesthesia liver at risk for decompensation. Why? Anesthesia reduces cardiac output, induces splanchnic reduces cardiac output, induces splanchnic vasodilation and causes a 30-50% in hepatic blood vasodilation and causes a 30-50% in hepatic blood flow.flow.

Pathophysiology and clinical picture of Pathophysiology and clinical picture of liver cell failureliver cell failure::

1) 1) LiverLiver:: Hyper-bilirubinemia Hyper-bilirubinemia (d.t ↓ secretory function (d.t ↓ secretory function

of the liver).of the liver). Hypo-albuminemiaHypo-albuminemia (d.t ↓ synthetic function) (d.t ↓ synthetic function)

→ tissue edema, ascites, pleural effusion.→ tissue edema, ascites, pleural effusion. Elevated Elevated liver enzymesliver enzymes as a result of as a result of

hepatocellular damage.hepatocellular damage.

2) 2) GITGIT:: Portal hypertensionPortal hypertension: defined as a pressure gradient : defined as a pressure gradient

of of > 10 mmHg> 10 mmHg between the between the portal veinportal vein and and IVCIVC. It . It is a major contributory factor for ascites and is a major contributory factor for ascites and esophageal varices.esophageal varices.

Variceal BleedingVariceal Bleeding AscitesAscites: as a result of portal HTN. It is a transudate in : as a result of portal HTN. It is a transudate in

nature with protein concentration less than 2.5 nature with protein concentration less than 2.5 mg/dL.mg/dL.

SBPSBP: appears to be caused by the translocation of GI : appears to be caused by the translocation of GI tract bacteria across the gut wall and also by the tract bacteria across the gut wall and also by the hematogenous spread of bacteria. The most common hematogenous spread of bacteria. The most common causative organisms are Escherichia coli, causative organisms are Escherichia coli, Streptococcus pneumoniae, Klebsiella, and other Streptococcus pneumoniae, Klebsiella, and other gram-negative enteric organisms. C/P: abdominal gram-negative enteric organisms. C/P: abdominal pain, fever, leukocytosis, and worsening hepatic pain, fever, leukocytosis, and worsening hepatic encephalopathy.encephalopathy.

3) 3) RenalRenal: Hepato-renal Syndrome: Hepato-renal Syndrome It is the occurrence of acute renal dysfunction in patients with It is the occurrence of acute renal dysfunction in patients with

preexisitng liver failure in the preexisitng liver failure in the absence of primary renal absence of primary renal disease.disease.

May be caused by an imbalance between renal May be caused by an imbalance between renal vasoconstrictorsvasoconstrictors (eg. Angiontensin, ADH, NE) and (eg. Angiontensin, ADH, NE) and vasodilatorsvasodilators (eg. PGE (eg. PGE22, PGI, PGI22, ANF). Plasma levels of , ANF). Plasma levels of vasoconstrictors are elevated resulting in decreased renal vasoconstrictors are elevated resulting in decreased renal perfusion. NSAIDS inhibit PG synthesis and hence potentiate perfusion. NSAIDS inhibit PG synthesis and hence potentiate renal vasoconstriction with a resulting drop in glomerular renal vasoconstriction with a resulting drop in glomerular filtration. Thus the use of NSAIDS is contra indicated in filtration. Thus the use of NSAIDS is contra indicated in patients with decompensated cirrhosis.patients with decompensated cirrhosis.

It is diagnosed by:It is diagnosed by: Creatinine clearance < 40 ml/minCreatinine clearance < 40 ml/min Serum creatinine > 1.5 mg/dLSerum creatinine > 1.5 mg/dL Oliguria urine volume < 500 ml/dayOliguria urine volume < 500 ml/day Urine Na < 10 mlEq/LUrine Na < 10 mlEq/L

4) 4) PulmonaryPulmonary::(A) (A) Hepato-pulmonary SyndromeHepato-pulmonary Syndrome (HPS) (HPS)

This is the presence This is the presence of abnormal of abnormal intrapulmonary vascular intrapulmonary vascular dilatationdilatation that can cause profound that can cause profound hypoxemiahypoxemia and can be and can be very difficult to treatvery difficult to treat. It may be explained by decreased . It may be explained by decreased hepatic clearance of endogenous vasodilators (eg. NO).hepatic clearance of endogenous vasodilators (eg. NO).

HPS is marked by the symptom of HPS is marked by the symptom of platypneaplatypnea (shortness of (shortness of breath occurring more in the upright position) and breath occurring more in the upright position) and othrodeoxiaothrodeoxia (O (O22 desaturation occurring more in the upright desaturation occurring more in the upright position). position).

It can be diagnosed by It can be diagnosed by echocardiographyechocardiography. Pts are . Pts are diagnosed when their PaOdiagnosed when their PaO22 is less than 70 mmHg. Some is less than 70 mmHg. Some cases may be corrected by liver transplantation and pts may cases may be corrected by liver transplantation and pts may receive a speedy course to liver transplantation if their PaOreceive a speedy course to liver transplantation if their PaO22 is less than 60 mmHg.is less than 60 mmHg.

(B) (B) Porto-pulmonary hypertensionPorto-pulmonary hypertension (PPHTN) (PPHTN) PPHTN is defined as the presence of a PPHTN is defined as the presence of a mean PAP mean PAP

greater than 25 mmHggreater than 25 mmHg in the presence of normal in the presence of normal PCWP.PCWP.

It results from It results from excessive pulmonary excessive pulmonary vasoconstriction vasoconstriction and vascular remodelling that and vascular remodelling that eventually leads to right-heart failureeventually leads to right-heart failure..

It is also diagnosed by It is also diagnosed by Doppler echocardiographyDoppler echocardiography.. Many Many liver transplantation liver transplantation programs rule out the programs rule out the

presence of PPHTN in pts on the transplant waiting presence of PPHTN in pts on the transplant waiting list. Pts who develop PPHTN require aggressive list. Pts who develop PPHTN require aggressive medical therapy in effort to stabilize PAP and medical therapy in effort to stabilize PAP and decrease perioperative mortality decrease perioperative mortality

5) 5) CNS changesCNS changes: Hepatic encephalopathy: Hepatic encephalopathy Hepatic encephalopathy is a syndrome marked by personality Hepatic encephalopathy is a syndrome marked by personality

changes, intellectual impairment, and a depressed level of changes, intellectual impairment, and a depressed level of consciousness occurring as a result of diversion of portal consciousness occurring as a result of diversion of portal blood into the systemic circulation (porto-systemic shunting).blood into the systemic circulation (porto-systemic shunting).

It is believed to be caused by the passage of neurotoxins which It is believed to be caused by the passage of neurotoxins which bypass hepatic detoxification and reach the brain via porto-bypass hepatic detoxification and reach the brain via porto-systemic shunting. Neurotoxins include short-chain fatty acids, systemic shunting. Neurotoxins include short-chain fatty acids, mercaptansmercaptans, false neurotransmitters (eg, tyramine, , false neurotransmitters (eg, tyramine, octopamine), octopamine), ammoniaammonia (NH (NH33), and gamma-aminobutyric acid ), and gamma-aminobutyric acid ((GABAGABA). Patients may have altered brain energy metabolism ). Patients may have altered brain energy metabolism and increased permeability of the blood-brain barrier.and increased permeability of the blood-brain barrier.

Today it is believed that Today it is believed that neurosteroids neurosteroids may play a key role in may play a key role in hepatic encephalopathy. They are elevated in patients with hepatic encephalopathy. They are elevated in patients with encephalopathy and are capable of binding to their receptor encephalopathy and are capable of binding to their receptor within the neuronal GABA receptor complex and can increase within the neuronal GABA receptor complex and can increase inhibitory neurotransmission.inhibitory neurotransmission.

Acute encephalopathy occurs in fulminating hepatic failure. Acute encephalopathy occurs in fulminating hepatic failure. There is There is cerebral edemacerebral edema and and increased ICPincreased ICP..

Symptoms are graded on the following scaleSymptoms are graded on the following scale:: Grade 0Grade 0 - Subclinical; normal mental status, but minimal - Subclinical; normal mental status, but minimal

changes in memory, concentration, intellectual function, changes in memory, concentration, intellectual function, coordination.coordination.

Grade 1Grade 1 - Mild confusion, euphoria or depression, decreased - Mild confusion, euphoria or depression, decreased attention, slowing of ability to perform mental tasks, attention, slowing of ability to perform mental tasks, irritability, disorders of sleep pattern (ie. inverted sleep cycle).irritability, disorders of sleep pattern (ie. inverted sleep cycle).

Grade 2Grade 2 - Drowsiness, lethargy, gross deficits in ability to - Drowsiness, lethargy, gross deficits in ability to perform mental tasks, obvious personality changes, perform mental tasks, obvious personality changes, inappropriate behaviour, intermittent disorientation (usually inappropriate behaviour, intermittent disorientation (usually for time). Diminished short term memory and concentration. for time). Diminished short term memory and concentration. Asterixis on physical examination.Asterixis on physical examination.

Grade 3Grade 3 - Somnolent but arousable, unable to perform mental - Somnolent but arousable, unable to perform mental tasks, disorientation to time and place, marked confusion, tasks, disorientation to time and place, marked confusion, amnesia, occasional fits of rage, speech is present but amnesia, occasional fits of rage, speech is present but incomprehensible.incomprehensible.

Grade 4Grade 4 - - ComaComa, with or without response to painful stimuli., with or without response to painful stimuli.

Diagnosis of hepatic encephalopathyDiagnosis of hepatic encephalopathy::a)a) Elevated free Elevated free serum ammonia serum ammonia level.level.b)b) EEGEEG: shows non-specific high amplitude low frequency waves : shows non-specific high amplitude low frequency waves

and triphasic waves.and triphasic waves.c)c) CT scan and MRI of the brain may be necessary in ruling out CT scan and MRI of the brain may be necessary in ruling out

intracranial lesions. In acute encephalopathy brain edema may intracranial lesions. In acute encephalopathy brain edema may be seen.be seen.

Common precipitating factorsCommon precipitating factors::Renal failure, GIT bleeding, infection, constipation, increased Renal failure, GIT bleeding, infection, constipation, increased dietary protein intake. Opiates, benzodiazepines, anti-depressants dietary protein intake. Opiates, benzodiazepines, anti-depressants and anti-psychotics may also worsen encephalopathy. Hypokalemia and anti-psychotics may also worsen encephalopathy. Hypokalemia and alkalosis (due to vomiting or excessive use of K-losing and alkalosis (due to vomiting or excessive use of K-losing diuretics) increase solubility of NHdiuretics) increase solubility of NH33 thus increase its passage thus increase its passage across the blood brain barrieracross the blood brain barrier..

Differential diagnosis of encephalopathyDifferential diagnosis of encephalopathy (other causes of (other causes of coma): coma):

Intracranial lesions (intracranial hge, tumour, abcess), infections Intracranial lesions (intracranial hge, tumour, abcess), infections (meningitis, encephalitis), metabolic encephalopathy (meningitis, encephalitis), metabolic encephalopathy (hypoglycaemia, uremia, electrolyte imbalance), alcoholic (hypoglycaemia, uremia, electrolyte imbalance), alcoholic encephalopathy, post-seizure encephalopathy.encephalopathy, post-seizure encephalopathy.

6) 6) BloodBlood:: AnemiaAnemia:: may result from folic acid deficiency, may result from folic acid deficiency,

hemolysis, hypersplenism, or GIT bleeding.hemolysis, hypersplenism, or GIT bleeding. ThrombocytopeniaThrombocytopenia:: usually is secondary to usually is secondary to

hypersplenism and decreased levels of hypersplenism and decreased levels of thrombopoietin.thrombopoietin.

CoagulopathyCoagulopathy:: results from decreased hepatic results from decreased hepatic production of coagulation factors. Decreased production of coagulation factors. Decreased vitamin K absorption results in reduction of Vit-vitamin K absorption results in reduction of Vit-K-dependent factors: II, VII, IX, and X. Patients K-dependent factors: II, VII, IX, and X. Patients with cirrhosis also may experience fibrinolysis with cirrhosis also may experience fibrinolysis and DIC.and DIC.

7) 7) Metabolic changesMetabolic changes:: Fasting hypoglycemia: Fasting hypoglycemia: due to reduced glycogen stores.due to reduced glycogen stores.

Electrolytes:Electrolytes: Na and water retention: occurs 2ry to relative : occurs 2ry to relative

hypovolemia and 2ry hyperaldosteronism.hypovolemia and 2ry hyperaldosteronism. Dilutional hyponatremia: occurs due to increased ADH, : occurs due to increased ADH,

2ry hyperaldosteronism, impaired renal handling of free 2ry hyperaldosteronism, impaired renal handling of free water and decreased dietary Na.water and decreased dietary Na.

HypokalemiaHypokalemia: due to diuresis and 2ry hyperaldosteronism.: due to diuresis and 2ry hyperaldosteronism. Hyperkalemia: may occure due to the use of K-sparing : may occure due to the use of K-sparing

diuretics, renal failure and metabolic acidosis.diuretics, renal failure and metabolic acidosis. Hypomagnesemia: due to poor dietary intake, intestinal : due to poor dietary intake, intestinal

malabsorption hyperaldosteronism and diuretic therapy.malabsorption hyperaldosteronism and diuretic therapy.

Acid base disorders:Acid base disorders: Respiratory alkalosis: due to hyperventilation 2ry to : due to hyperventilation 2ry to

ascites and hepatopulmonary $ (most common).ascites and hepatopulmonary $ (most common). Metabolic alkalosis: due to K-losing diuretics, : due to K-losing diuretics,

hyperaldosteronism, or vomiting.hyperaldosteronism, or vomiting. Metabolic acidosis: in renal failure.: in renal failure.

8) 8) CVS changesCVS changes::Hyperdynamic circulatory state due to:Hyperdynamic circulatory state due to: Peripheral vasodilation by endogenous vasodilators that Peripheral vasodilation by endogenous vasodilators that

bypass hepatic metabolism (NO and glucagon).bypass hepatic metabolism (NO and glucagon). Portal and systemic shunts.Portal and systemic shunts.

Child-Turcotte-Pugh classificationChild-Turcotte-Pugh classification::

Child-Turcotte-Pugh Scoring System for Cirrhosis (Child-Turcotte-Pugh Scoring System for Cirrhosis (Child Child Class AClass A=5-6 points, =5-6 points, Child Class BChild Class B =7-9 points, =7-9 points, Child Class Child Class CC=10-15 points).=10-15 points).

Mo’emen Modified Classification of Liver DiseaseMo’emen Modified Classification of Liver Disease::

VariablesScoring Points

1 (Class A)2 (Class B) 3 (Class C)

1) Encephalopathy

0 I, II III, IV

2) Ascites0 Mild

Moderate, severe

3) Serum bilirubin (mg/dL)

< 4.0 4.0-5.0 > 5.0

4) Serum albumin (g/L)

> 3.5 3.5-2.8 < 2.8

5) Prothrombin Time prolonged (seconds)

0 1-4 > 4

6) Serum Sodium (mmol/L)

> 130 130-120 < 120

7) Serum creatinine (mg/dL)

< 1.5 1.5-2.5 > 2.5

8) Leucocytic count (103/mm3)

< 10 10-12 > 12

9) Alveolar/arterial gradient

> 0.75 0.74-0.55 < 0.55

The surgical risk is classified according to the scoring points into: mild (9-10 points), moderate (11-14 points) and severe (15-27 points).

TreatmentTreatment(1) (1) ttt of GIT bleedingttt of GIT bleeding (variceal bleeding): (variceal bleeding):

Upper GIT endoscopy to exclude other causes of hematemesis as peptic ulcer and gastritis.

Gastric lavage through a NG tube using cold saline. Replacement of blood loss by IV fluids and blood products

(anti-shock measures). Vasopressin infusion (or its analogue Terlispressin):

IV infusion: 0.3-0.8 units/min Localised infusion into Superior mesenteric artery (identified

by selective arteriography): 0.15-0.2 untis/min Balloon tamponade by Sengstaken-Blakemoore, Minnesota

tubes. Emergency sclerotherapy. IV nitroglycerin and propranolol can decrease portal pressure. Octreotide:somatostatin analogue that acts as intestinal

vasocontrictor. H2 Blockers: eg. Ranitidine

(2) (2) ttt of Encephalopathyttt of Encephalopathy:: Treatment of the precipitanting factors of hepatic Treatment of the precipitanting factors of hepatic

encephalopathy (eg. metabolic disturbances, GI bleeding, encephalopathy (eg. metabolic disturbances, GI bleeding, infection, constipation).infection, constipation).

LactuloseLactulose is a nonabsorbable disaccharide that is a nonabsorbable disaccharide that stimulates the passage of ammonia from tissues into the stimulates the passage of ammonia from tissues into the gut lumen and inhibits intestinal ammonia production.gut lumen and inhibits intestinal ammonia production.

Other Other catharticscathartics, including , including colonic lavagecolonic lavage also may be also may be effective in patients with severe encephalopathy.effective in patients with severe encephalopathy.

NeomycinNeomycin and other antibiotics (eg. and other antibiotics (eg. metronidazolemetronidazole, oral , oral vancomycin) serve as second-line agents. They work by vancomycin) serve as second-line agents. They work by decreasing the colonic concentration of ammoniagenic decreasing the colonic concentration of ammoniagenic bacteria. Neomycin dosing is 250-1000 mg orally 2-4 bacteria. Neomycin dosing is 250-1000 mg orally 2-4 times daily. times daily.

RifaximinRifaximin is a nonabsorbable antibiotic that can decrease is a nonabsorbable antibiotic that can decrease colonic levels of ammoniagenic bacteria, with resulting colonic levels of ammoniagenic bacteria, with resulting improvement in symptoms of hepatic encephalopathy.improvement in symptoms of hepatic encephalopathy.

FlumazenilFlumazenil: : a benzodiazepine receptor antagonist that a benzodiazepine receptor antagonist that has been tried successfully in hepatic encephalopathy.has been tried successfully in hepatic encephalopathy.

(3) (3) ttt of Hepatorenal $ttt of Hepatorenal $:: Expansion of intravascular volume with albumin & Expansion of intravascular volume with albumin &

FFP. FFP. Proper hydrationProper hydration.. Avoid nephrotoxic drugs as: aminoglycosides, Avoid nephrotoxic drugs as: aminoglycosides,

cyclosporine and contrast dyes.cyclosporine and contrast dyes. Mannitol Mannitol to prevent renal failure.to prevent renal failure. HemodialysisHemodialysis.. Liver transplantationLiver transplantation: kidney function usually : kidney function usually

recovers when patients with cirrhosis and recovers when patients with cirrhosis and hepatorenal syndrome undergo liver hepatorenal syndrome undergo liver transplantation.transplantation.

If end stage renal failure develops If end stage renal failure develops combined liver-combined liver-kidney transplantationkidney transplantation is needed. is needed.

(4) (4) Nutrition of hepatic patientNutrition of hepatic patient:: Caloric requirementsCaloric requirements: :

25-30 Kcal/Kg/day of normovolemic BW.

Protein requirementsProtein requirements::

Ptn restriction is controversial but still routinely implemented (esp. in pts with TIPSS). Amount: 40-60 g/day or 0.8g/kg/day (of normovolemic BW).

Type: rich in branched chain (non-aromatic) amino acids.

Some studies support that parentral ptn carries less risk of encephalopathy since not converted by colonic bacteria into NH3.

MicronutrientsMicronutrients: Thiamine, folic acid, Mg, Zn.: Thiamine, folic acid, Mg, Zn.

(5) (5) Avoidance of heaptotoxic medicationsAvoidance of heaptotoxic medications:: Medications associated with drug-induced liver Medications associated with drug-induced liver

disease include:disease include: NSAIDs Isoniazide valproic acid Erythromycin amoxicillin-clavulanate Ketoconazole chlorpromazine

AminoglycosidesAminoglycosides are considered obligate are considered obligate nephrotoxins in patients with cirrhosis and should nephrotoxins in patients with cirrhosis and should be avoided.be avoided.

(6) (6) Analgesia in patients with hepatic failureAnalgesia in patients with hepatic failure:: Although high-dose Although high-dose acetaminophenacetaminophen is a well-known is a well-known

hepatotoxin, most hepatologists permit the use of hepatotoxin, most hepatologists permit the use of acetaminophen in patients with cirrhosis at doses up acetaminophen in patients with cirrhosis at doses up to 2 g/d.to 2 g/d.

NSAIDNSAID use may predispose patients with cirrhosis to use may predispose patients with cirrhosis to develop GI bleeding. Patients with decompensated develop GI bleeding. Patients with decompensated cirrhosis are at risk for NSAID-induced renal cirrhosis are at risk for NSAID-induced renal insufficiency, because of prostaglandin inhibition and insufficiency, because of prostaglandin inhibition and worsening of renal blood flow.worsening of renal blood flow.

OpiateOpiate analgesics are analgesics are not contraindicatednot contraindicated but must but must be used with caution in patients with preexisting be used with caution in patients with preexisting hepatic encephalopathy.hepatic encephalopathy.