Cirrhosis Key features: The parenchymal injury & consequent fibrosis are diffuse. The nodularity is part of the diagnosis  reflects balance between regeneration and scarring. Vascular architecture is re-organized by the parenchymal damage and scarring  formation of abnormal interconnections

Pathogenesis: Progressive fibrosis & re-organization of vascular micro-architecture of liver Collagen deposition (types I & III) in the lobule Loss of fenestration of sinusoidal endothelial cells New vascular channels in the septae Impaired hepatocellular protein secretion (albumin, clotting factors, lipoproteins) Shunting of blood around the parenchyma Create delicate or broad septal tracts

Main characteristics Bridging fibrous septae link portal tracts with one another & portal tracts with terminal hepatic vein Parenchymal nodules contain proliferating hepatocytes encircled by fibrosis micronodules - < 3 mm diameter macronodules - > 3 mm to several cm Disruption of architecture of entire liver

Complications associated with cirrhosis: Hepatic failure ( called decompensation) Multiple coagulation defects Hypoalbuminemia due to decreased albumin synthesis  pitting edema and ascites Hepatic encephalopathy Increased serum ammonia due to defective urea cycle

Complications associated with cirrhosis: Portal hypertension Ascites Congestive splenomegaly Esophageal varices Hemorrhoids, periumbilical collateral circulation

Complications associated with cirrhosis: Hepatorenal syndrome due to decreased renal blood flow Hyperestrinism in males Gynecomastia Spider angiomas Female distribution of hair

Criteria for Diagnosis: liver biopsy or at least three of the following: Hyperglobulinemia, esp. with hypoalbuminemia Low protein (<2.5 g/dL) ascites Evidence of hypersplenism (usu. Thrombocytopenia, often with leukopenia) Evidence of portal hypertension (e.g. varices) Characteristic “corkscrew” hepatic arterioles on celiac arteriography Shunting of blood

Bridging fibrous septae Nodules

HEPATORENAL SYNDROME HRS was found to be part of a cascade of events associated with intense dilatation of the splanchnic arterial vasculature in the setting of cirrhosis or acute liver injury and resulting in profound renal arterial vasoconstriction and progressive renal failure. The diagnostic criteria for HRS( type 2 HRS usually) :(1) cirrhosis with ascites; (2) serum creatinine level higher than 1.5 mg/dL (133 mmol/L); (3) lack of improvement in the serum creatinine level to 1.5 mg/dL (133 mmol/L) or less after at least two days of diuretic withdrawal and volume expansion with albumin (1 g/kg of body weight/day, up to a maximum of 100 g/day); (4) absence of shock, (5) lack of current or recent treatment with nephrotoxic drugs; and (6) absence of parenchymal kidney disease as indicated by proteinuria of more than 500 mg/day, microhematuria (>50 red blood cells/high power field), or abnormal renal ultrasonographic findings . Acute hepatorenal syndrome ( type 1 HRS) can occur in severe acute liver disease and acute liver failure even without ascites.

HEPATOPULMONARY SYNDROME AND PORTOPULMONARY HYPERTENSION Cirrhosis and portal hypertension are accompanied by alterations in the vascular beds of multiple organ systems. In the pulmonary circulation, two distinct clinical entities, termed the hepatopulmonary syndrome (HPS) and portopulmonary hypertension (PPH), have been recognized. HPS is characterized by microvascular alterations and dilatation in the precapillary and capillary pulmonary arterial circulation. In human HPS, the production of vasodilatory substances within the pulmonary vasculature, most notably NO, is increased. Although increased circulating and pulmonary NO levels appear to be features of human HPS, improvement in oxygenation in response to acute inhibition of NO is variable. Classic clinical manifestations of HPS include platypnea (dyspnea worsened by an erect position and improved by a supine position), orthodeoxia (exacerbation of hypoxia and hypoxemia in an upright position), an insidious onset and slow progression of dyspnea, clubbing, and distal cyanosis.