Decompensated Liver Cirrhosis By Dr. Doaa Kamal

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

Causes of liver cirrhosis: 1) Viral Hepatitis B, C. 2) Alcoholic liver disease. 3) Non-alcoholic fatty liver disease (NAFLD). 4) Autoimmune hepatitis. 5) Primary biliary cirrhosis. 6) Secondary biliary cirrhosis (associated with chronic extrahepatic bile duct obstruction). 7) Primary sclerosing cholangitis. 8) Hemochromatosis 9) Wilson disease. 10) Alpha-1 antitrypsin deficiency. 11) Granulomatous disease (eg, sarcoidosis). 12) Type IV glycogen storage disease. 13) Drug-induced liver disease (eg, methotrexate, alpha methyldopa, amiodarone). 14) Venous outflow obstruction (eg, Budd-Chiari syndrome, veno-occlusive disease). 15) Cardiac cirrhosis: chronic right-sided heart failure, tricuspid regurgitation.

Causes of hepatic decompensation: Alkalosis. Hypokalemia. GIT bleeding. Hypotension. Hepatotoxic drugs. Infection. Diuretic therapy. General anesthesia. Surgery and general anesthesia place the cirrhotic liver at risk for decompensation. Why? Anesthesia reduces cardiac output, induces splanchnic vasodilation and causes a 30-50% in hepatic blood flow.

Pathophysiology and clinical picture of liver cell failure: Hyper-bilirubinemia (d.t ↓ secretory function of the liver). Hypo-albuminemia (d.t ↓ synthetic function) → tissue edema, ascites, pleural effusion. Elevated liver enzymes as a result of hepatocellular damage.

2) GIT: Portal hypertension: defined as a pressure gradient of > 10 mmHg between the portal vein and IVC. It is a major contributory factor for ascites and esophageal varices. Variceal Bleeding Ascites: as a result of portal HTN. It is a transudate in nature with protein concentration less than 2.5 mg/dL. SBP: appears to be caused by the translocation of GI tract bacteria across the gut wall and also by the hematogenous spread of bacteria. The most common causative organisms are Escherichia coli, Streptococcus pneumoniae, Klebsiella, and other gram-negative enteric organisms. C/P: abdominal pain, fever, leukocytosis, and worsening hepatic encephalopathy.

3) Renal: Hepato-renal Syndrome It is the occurrence of acute renal dysfunction in patients with preexisitng liver failure in the absence of primary renal disease. May be caused by an imbalance between renal vasoconstrictors (eg. Angiontensin, ADH, NE) and vasodilators (eg. PGE2, PGI2, ANF). Plasma levels of vasoconstrictors are elevated resulting in decreased renal perfusion. NSAIDS inhibit PG synthesis and hence potentiate renal vasoconstriction with a resulting drop in glomerular filtration. Thus the use of NSAIDS is contra indicated in patients with decompensated cirrhosis. It is diagnosed by: Creatinine clearance < 40 ml/min Serum creatinine > 1.5 mg/dL Oliguria urine volume < 500 ml/day Urine Na < 10 mlEq/L

(A) Hepato-pulmonary Syndrome (HPS) This is the presence of abnormal intrapulmonary vascular dilatation that can cause profound hypoxemia and can be very difficult to treat. It may be explained by decreased hepatic clearance of endogenous vasodilators (eg. NO). HPS is marked by the symptom of platypnea (shortness of breath occurring more in the upright position) and othrodeoxia (O2 desaturation occurring more in the upright position). It can be diagnosed by echocardiography. Pts are diagnosed when their PaO2 is less than 70 mmHg. Some cases may be corrected by liver transplantation and pts may receive a speedy course to liver transplantation if their PaO2 is less than 60 mmHg.

(B) Porto-pulmonary hypertension (PPHTN) PPHTN is defined as the presence of a mean PAP greater than 25 mmHg in the presence of normal PCWP. It results from excessive pulmonary vasoconstriction and vascular remodelling that eventually leads to right-heart failure. It is also diagnosed by Doppler echocardiography. Many liver transplantation programs rule out the presence of PPHTN in pts on the transplant waiting list. Pts who develop PPHTN require aggressive medical therapy in effort to stabilize PAP and decrease perioperative mortality

5) CNS changes: Hepatic encephalopathy Hepatic encephalopathy is a syndrome marked by personality changes, intellectual impairment, and a depressed level of consciousness occurring as a result of diversion of portal blood into the systemic circulation (porto-systemic shunting). It is believed to be caused by the passage of neurotoxins which bypass hepatic detoxification and reach the brain via porto-systemic shunting. Neurotoxins include short-chain fatty acids, mercaptans, false neurotransmitters (eg, tyramine, octopamine), ammonia (NH3), and gamma-aminobutyric acid (GABA). Patients may have altered brain energy metabolism and increased permeability of the blood-brain barrier. Today it is believed that neurosteroids may play a key role in hepatic encephalopathy. They are elevated in patients with encephalopathy and are capable of binding to their receptor within the neuronal GABA receptor complex and can increase inhibitory neurotransmission. Acute encephalopathy occurs in fulminating hepatic failure. There is cerebral edema and increased ICP.

Symptoms are graded on the following scale: Grade 0 - Subclinical; normal mental status, but minimal changes in memory, concentration, intellectual function, coordination. Grade 1 - Mild confusion, euphoria or depression, decreased attention, slowing of ability to perform mental tasks, irritability, disorders of sleep pattern (ie. inverted sleep cycle). Grade 2 - Drowsiness, lethargy, gross deficits in ability to perform mental tasks, obvious personality changes, inappropriate behaviour, intermittent disorientation (usually for time). Diminished short term memory and concentration. Asterixis on physical examination. Grade 3 - Somnolent but arousable, unable to perform mental tasks, disorientation to time and place, marked confusion, amnesia, occasional fits of rage, speech is present but incomprehensible. Grade 4 - Coma, with or without response to painful stimuli.

Diagnosis of hepatic encephalopathy: Elevated free serum ammonia level. EEG: shows non-specific high amplitude low frequency waves and triphasic waves. CT scan and MRI of the brain may be necessary in ruling out intracranial lesions. In acute encephalopathy brain edema may be seen. Common precipitating factors: Renal failure, GIT bleeding, infection, constipation, increased dietary protein intake. Opiates, benzodiazepines, anti-depressants and anti-psychotics may also worsen encephalopathy. Hypokalemia and alkalosis (due to vomiting or excessive use of K-losing diuretics) increase solubility of NH3 thus increase its passage across the blood brain barrier. Differential diagnosis of encephalopathy (other causes of coma): Intracranial lesions (intracranial hge, tumour, abcess), infections (meningitis, encephalitis), metabolic encephalopathy (hypoglycaemia, uremia, electrolyte imbalance), alcoholic encephalopathy, post-seizure encephalopathy.

6) Blood: Anemia: may result from folic acid deficiency, hemolysis, hypersplenism, or GIT bleeding. Thrombocytopenia: usually is secondary to hypersplenism and decreased levels of thrombopoietin. Coagulopathy: results from decreased hepatic production of coagulation factors. Decreased vitamin K absorption results in reduction of Vit-K-dependent factors: II, VII, IX, and X. Patients with cirrhosis also may experience fibrinolysis and DIC.

Fasting hypoglycemia: due to reduced glycogen stores. Electrolytes: 7) Metabolic changes: Fasting hypoglycemia: due to reduced glycogen stores. Electrolytes: Na and water retention: occurs 2ry to relative hypovolemia and 2ry hyperaldosteronism. Dilutional hyponatremia: occurs due to increased ADH, 2ry hyperaldosteronism, impaired renal handling of free water and decreased dietary Na. Hypokalemia: due to diuresis and 2ry hyperaldosteronism. Hyperkalemia: may occure due to the use of K-sparing diuretics, renal failure and metabolic acidosis. Hypomagnesemia: due to poor dietary intake, intestinal malabsorption hyperaldosteronism and diuretic therapy.

8) CVS changes: Acid base disorders: Respiratory alkalosis: due to hyperventilation 2ry to ascites and hepatopulmonary $ (most common). Metabolic alkalosis: due to K-losing diuretics, hyperaldosteronism, or vomiting. Metabolic acidosis: in renal failure. 8) CVS changes: Hyperdynamic circulatory state due to: Peripheral vasodilation by endogenous vasodilators that bypass hepatic metabolism (NO and glucagon). Portal and systemic shunts.

Child-Turcotte-Pugh classification: Child-Turcotte-Pugh Scoring System for Cirrhosis (Child Class A=5-6 points, Child Class B =7-9 points, Child Class C=10-15 points).

Mo’emen Modified Classification of Liver Disease: Variables Scoring Points 1 (Class A) 2 (Class B) 3 (Class C) 1) Encephalopathy I, II III, IV 2) Ascites 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) 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).

Treatment (1) ttt of GIT 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) ttt of Encephalopathy: Treatment of the precipitanting factors of hepatic encephalopathy (eg. metabolic disturbances, GI bleeding, infection, constipation). Lactulose is a nonabsorbable disaccharide that stimulates the passage of ammonia from tissues into the gut lumen and inhibits intestinal ammonia production. Other cathartics, including colonic lavage also may be effective in patients with severe encephalopathy. Neomycin and other antibiotics (eg. metronidazole, oral vancomycin) serve as second-line agents. They work by decreasing the colonic concentration of ammoniagenic bacteria. Neomycin dosing is 250-1000 mg orally 2-4 times daily. Rifaximin is a nonabsorbable antibiotic that can decrease colonic levels of ammoniagenic bacteria, with resulting improvement in symptoms of hepatic encephalopathy. Flumazenil: a benzodiazepine receptor antagonist that has been tried successfully in hepatic encephalopathy.

(3) ttt of Hepatorenal $: Expansion of intravascular volume with albumin & FFP. Proper hydration. Avoid nephrotoxic drugs as: aminoglycosides, cyclosporine and contrast dyes. Mannitol to prevent renal failure. Hemodialysis. Liver transplantation: kidney function usually recovers when patients with cirrhosis and hepatorenal syndrome undergo liver transplantation. If end stage renal failure develops combined liver-kidney transplantation is needed.

 25-30 Kcal/Kg/day of normovolemic BW. (4) Nutrition of hepatic patient: Caloric requirements:  25-30 Kcal/Kg/day of normovolemic BW. Protein 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. Micronutrients: Thiamine, folic acid, Mg, Zn.

(5) Avoidance of heaptotoxic medications: Medications associated with drug-induced liver disease include: NSAIDs Isoniazide valproic acid Erythromycin amoxicillin-clavulanate Ketoconazole chlorpromazine Aminoglycosides are considered obligate nephrotoxins in patients with cirrhosis and should be avoided.

(6) Analgesia in patients with hepatic failure: Although high-dose acetaminophen is a well-known hepatotoxin, most hepatologists permit the use of acetaminophen in patients with cirrhosis at doses up to 2 g/d. NSAID use may predispose patients with cirrhosis to develop GI bleeding. Patients with decompensated cirrhosis are at risk for NSAID-induced renal insufficiency, because of prostaglandin inhibition and worsening of renal blood flow. Opiate analgesics are not contraindicated but must be used with caution in patients with preexisting hepatic encephalopathy.