Liver

• Normal adult liver weight

  1,400 to 1,600 grams
• Liver blood supply


  • Portal Vein supplies 60-70% of the blood flow
  • Hepatic Artery supplies 30-40% of the blood flow
• The blood supply enters the liver via porta hepatis and travel within parallel tracts, ramifying through 17-20 branches
• Hepatic microarchitecture


  • Liver is divided into 1-2mm diameter lobules that are oriented around the terminal tributaries of the hepatic vein (central vein), with portal tracts at the lobule's periphery
  • Lobules are often drawn as hexagon in shape
  • Centrilobular - those near the periphery of the terminal branch of the hepatic vein (central vein)
  • Periportal - those near the portal tract
• Between trabecular plates of hepatocytes are vascular sinusoids where blood traverses and exits via the terminal hepatic vein
• Sinusoids


  • Lined by fenestrated endothelial cells
  • Beneath the endothelial cells is the space of Disse, into which protrude abundant hepatic microvilli
• Kupffer cells

  • Attached in the luminal face of the endothelium
• Hepatic Stellate Cells


  • Found in the space of Disse, they are fat-containing myofibroblastic cells
• Bile drainage


  Between hepatocytes are bile canaliculi which are channels that drain into the canals of Herring that connect to bile ductules in the periportal region which ultimately empties into the terminal bile duct
• Major diseases of the liver

  • Viral Hepatitis
  • Non-alcoholic Fatty Liver Disease (NAFLD)
  • Alcoholic Liver Disease
  • Hepatocellular Carcinoma (HCC)
• Liver disease can occur secondary to some most common diseases such as heart failure, cancer, and extrahepatic infections
• With exception of acute liver failure, liver disease is insidious and may heal without clinical detection
• Steatosis


  Ballooning degeneration of hepatocytes
• Cholestasis


  Feathery degeneration of hepatocytes
• Hepatocyte Necrosis


  1. Cellular swelling due to defective osmotic regulation at cell membrane leads to rupture

  2. Before rupture, membrane blebs form, carrying off cytoplasmic contents into the extracellular compartment
• Hepatocyte Apoptosis

  Active form of programmed cell death resulting in hepatocyte shrinkage, nuclear chromatin condensation (pyknosis), fragmentation (karyorrhexis), and cellular fragmentation into acidophilic apoptotic bodies
• When there is widespread parenchymal loss, there is often evidence of confluent necrosis; a severe, zonal loss of hepatocytes may be seen in toxic, ischemic injuries, severe viral or autoimmune hepatitis
• Regeneration


  Occurs primarily by mitotic replication of hepatocytes adjacent to the lost ones
• Hepatocytes are almost stem cell-like in their ability to continue to replicate even in the setting of years of chronic injury and thus stem cell replenishment is usually NOT a significant part of repair
• Hepatic Stellate Cells


  • In its quiescent form it is a lipid (Vit. A) storing cell
  • In several acute and chronic injuries, the cells are activated and converted into highly fibrogenic myofibroblasts
  • Myofibroblasts express platelet-derived growth factor receptors
• Scar formation


  1. Kupffer cells release cytokines that modulate gene expression in stellate cells particularly TGF-β, MMP-2, and TIMP-1

  2. Myofibroblasts are contractile and stimulated by endothelin-1

  3. Stellate cell activation may originate from chronic inflammation, cytokine and chemokine production by Kupffer cells, response to disruption of the ECM, or direct simulation of the stellate cells from toxins

  4. Zones of parenchymal loss transform into dense fibrous septa through a combination of the collapse of underlying reticulin and activated stellate cells

  5. Eventually these septa encircle surviving hepatocytes in late chronic disease give rise to diffuse scarring termed cirrhosis
• Scar regression

  If the chronic injury is interrupted, the stellate cell activation stops and the scars condense and thin out then can be reversed
• Antigens in the liver

  • Taken up by APC such as Kupffer cells and blood-derived dendritic cells
  • TLRs detect host molecules and foreign invaders that lead to production of pro-inflammatory cytokines
• Liver failure

  The most severe consequence of liver disease, may be result of sudden, massive destruction (acute liver failure) or more often, a chronic liver failure which follows upon years or decades of insidious, progressive liver injury
• 80-90% of hepatic functional capacity must be lost before hepatic failure ensues
• Transplantation offers the best hope for survival, mortality rate without transplant is about 80%
• Acute Liver Failure


  Defined as an acute liver illness associated with encephalopathy and coagulopathy that occurs within 26 weeks of the initial liver injury, in the absence of pre-existing liver disease
• Acute Liver Failure is caused by massive hepatic necrosis, most often induced by drugs or toxins
• Mechanism may be direct toxic damage (e.g. acetaminophen) or more often variable combination of toxicity and immune-mediated hepatocyte destruction (hepatitis viral infection)
• Morphology of Acute Liver Failure

  • Massive hepatic necrosis with broad regions of parenchymal loss surrounding islands of regenerating hepatocytes
  • Toxic injuries usually take place within hours to days, too brief to allow scar formation or regeneration
  • Acute Viral infections may cause failure over weeks or months, regeneration is often demonstrable
  • Diffuse poisoning of the liver cells without obvious cell death and parenchymal collapse such as diffuse microvesicular steatosis related to fatty liver of pregnancy
  • In states of immunodeficiency, non-hepatic viruses such as HSV, CMV, and adenovirus can cause fulminant liver failure
• Clinical course of Acute Liver Failure

  1. Manifests first with nausea, vomiting, and jaundice, followed by life-threatening encephalopathy and coagulation defects

  2. Serum liver transaminases are markedly elevated

  3. Liver is initially enlarged due to swelling and edema, as it the parenchyma is destroyed it shrinks dramatically

  4. Decline of serum transaminases are not a sign of improvement but rather an indication that there are few viable hepatocyte left

  5. Alterations of bile formation and flow become evident as a yellow discoloration of the skin (jaundice) and sclera (icterus) due to retention of bilirubin

  6. Hepatic encephalopathy ranges from subtle behavioral abnormalities to marked confusion and stupor to coma & death

  7. Asterixis, a particular sign, is a non-rhythmic, rapid extension-flexion movement of head and extremities

  8. Elevated ammonia levels in the blood and CND correlate with impaired neuronal function and cerebral edema

  9. Easy bruisability is the earliest sign of coagulopathy

  10. Portal hypertension develops when there is diminished flow to the portal venous system

  11. Hepatorenal Syndrome – sodium retention, impaired free water excretion, & decreased renal perfusion and glomerular filtration
• Leading causes of Chronic Liver Failure and Cirrhosis

  • Chronic Hepatitis B and C
  • Non-alcoholic fatty liver disease
  • Alcoholic liver disease
• Cirrhosis


  A condition marked by disffuse transformation of the entire liver into regenerative parenchymal nodules surrounded by fibrous bands and variable degrees of vascular shunting (usually portosystemic)
• Not all cirrhosis leads to chronic liver injury and not all liver injury is cirrhotic
• Child-Pugh classification of cirrhosis

  • Class A - well-compensated cirrhosis
  • Class B - partially decompensated
  • Class C - decompensated
• Morphology of Cirrhosis


  • Narrow, densely compacted fibrous septa separated by large islands of hepatic parenchyma have less portal hypertension
  • Broad bands of dense scar, often with dilated lymphatic spaces, with less intervening parenchyma are likely to be progressing to portal hypertension and to end-stage disease
  • In chronic liver disease, ductular reactions increase with advancing stage and are usually most prominent in cirrhosis
  • Role of liver stem cells in parenchymal regeneration increases as the preexisting hepatocytes undergo replicative senescence after year sof high turnover
  • Ductular reactions may incite scarring in chronic liver disease and may have negative effect on progressive liver disease
• Regression of fibrosis, although uncommon, may occur
• Clinical features of Chronic Liver Failure and Cirrhosis

  1. 40% are asymptomatic until the most advanced stage

  2. Present with non-specific manifestations such as anorexia, weight loss, and weakness

  3. Ultimate cause of death, whether cirrhotic or not, include those seen in acute liver failure and additional frim outcomes such as development of HCC

  4. Hepatic encephalopathy, esophageal varices and bacterial infections are often terminal events

  5. Pruritus can occur in the setting of chronic jaundice

  6. Impaired estrogen metabolism and hyperestrogenemia in males can give rise to palmar erythema and spider angiomas of skin

  7. In men, it can result to hypogonadism and gynecomastia

  8. Hypogonadism can occur in females due to disruption of the hypothalamic-pituitary axis function
• Causes of Portal Hypertension

  • Prehepatic
  • Intrahepatic (dominant cause is cirrhosis)
  • Posthepatic
• Increased resistance to portal flow in cirrhosis

  Due to contraction of vascular smooth muscle and myofibroblasts, and the disruption of blood flow by scarring and formation of nodules