Lecture

1 - Introduc.on to Liver Cirrhosis and Liver Anatomy and Physiology

Life Sciences 3A03 - Module 3: Cirrhosis of the Liver Alex Zimmer

Why am I teaching you about liver cirrhosis?

The liver is preHy cool and few courses available at McMaster discuss its physiology and the disorders related to this organ It is a disorder of one organ which can lead to complica.ons of several other systems (cardiovascular, respiratory, renal), which makes it interes.ng to study in terms of whole-body physiology/homeostasis

Why am I teaching you about liver cirrhosis?

Maybe this informa.on might be useful in future self diagnosis

What should you expect over the next 2 weeks?

My background is in physiology, so most of the lectures will be geared towards understanding the physiological processes which underlie a variety of these disorders

I will cover some of the complica.ons of liver cirrhosis and discuss their physiological basis

What is Liver Cirrhosis?

Cirrhosis of the liver is described as the buildup of hepa.c scar .ssue (as a result of increased brogenesis) which occurs with chronic liver injury Cirrhosis can result from a number of dierent factors: Viruses Autoimmune dysfunc.on Drugs Alcohol Metabolic diseases For the purposes of this module, we will talk mainly about cirrhosis in general as opposed to the many ways in which it can develop

Epidemiology of Liver Cirrhosis

Diagnosis of liver cirrhosis may be dicult nearly 40% of liver cirrhosis cases are asymptoma.c. Once complica.ons arise (e.g., ascites, variceal hemorrhage, encephalopathy), there is a 50% 5-year mortality rate if liver transplanta.on does not occur Accounts for 30 000 deaths annually in the United States (not including the 10 000 deaths which occur due to liver cancer which typically leads to liver cirrhosis) Cirrhosis of the liver (predominantly alcoholic) is the fourth most common cause of death in individuals aged 25-64 in the U.S.

Pathology of Cirrhosis
Scar .ssue forma.on (formed mainly of collagen) in acute liver injury is a necessary step in repair and regenera.on of liver .ssue In chronic liver injury, the deposi.on of collagen exceeds breakdown and scar .ssue masses begin to form:

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The Liver
The liver is the largest organ in the human body (other than the skin), weighing approximately 3 lbs It receives over 25% of blood output from the heart at rest and accounts for 20% of total oxygen consump.on (brain accounts for 25% of total oxygen consump.on) It receives dual blood supply from the portal vein and hepa:c artery The liver has many func.ons: Synthesis of plasma proteins Detoxica.on and removal of toxins Secre.on of bile Processing of haemoglobin released from red blood cells Many more!

Basic Liver Vasculature

3 major blood vessels to consider: Inferior Vena Cava Hepa:c Vein

Portal Vein Hepa:c Artery

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Portal Vein System

Portal Vein The splenic (spleen), gastric (stomach), and mesenteric (intes.ne) veins all drain into the portal vein which then enters the liver Why does the liver need an addi:onal supply of blood from the hepa:c artery?

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Liver Vasculature
Portal vein supplies ~60-80% of the livers blood supply Oxygen-poor Contains nutrients/wastes from the spleen, stomach, and intes.ne Hepa:c artery supplies ~20-40% of the livers blood supply Oxygen-rich Supplies oxygen and nutrients to the liver Both vessels enter through the inferior side of the liver (the hillus) Blood exits the liver via hepa:c vein which drain into the inferior vena cava which lies dorsal to the liver

Liver Microvasculature
Liver .ssue is vascularized by branches of both the hepa.c artery and portal vein Both vessels drain into hepa.c sinusoids which eventually drain into a central vein which then drain into the hepa.c vein

Liver Microvasculature

Central vein Sinusoids

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The sinusoids act essen.ally as the capillary bed of the liver They are extremely diuse throughout the liver All hepa.c exchanges occur across the walls of these sinusoids

Biliary System
The liver is also responsible for the produc.on of bile a brownish green substance which is a surfactant and acts to emulsify fats which aids in their diges.on Bile is then stored in the gall bladder for later release into the intes.ne via the bile duct

Bile Duct

Gall Bladder

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AFer ea:ng a meal, the gall bladder is emp:ed to facilitate diges:on and is relled between meals

Bile is produced by liver cells (hepatocytes) and is secreted into biliary canaliculi

Biliary System

Biliary Canaliculi
Walls of canaliculi are made up of the membranes of adjacent hepatocytes

Hepatocytes Canaliculus

Sinusoids

Sinusoid Architecture
Bile canaliculi Space of Disse space between sinusoid and hepatocytes (analogous to inters..al uid) Endothelial cell fenestrae allow for exchange between blood and hepatocytes

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Liver Cell Types

Hepatocytes: Make up ~80% of total liver volume Perform the majority of liver func.ons including bile synthesis, protein synthesis, metabolism of drugs and toxins, etc. Kuper cells: Found inside the sinusoidal space Responsible for phagocytosis of blood-borne toxicants and par.culates (e.g., bacteria) and produc.on of some host defence substances

Liver Func.on: Cell Types

Sinusoidal endothelial cells: Form a leaky barrier between the sinusoid and adjacent hepatocytes Allows for rapid exchange between sinusoidal uid and hepatocytes Stellate cells: Responsible for storage of fat-soluble vitamins (e.g., vitamin A) Produce collagen when ac.vated by liver damage **important for cirrhosis**

Sinusoid Architecture

What are these structures?

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 In healthy livers, acute liver damage is met with the forma.on of scar .ssue which helps protect the liver against any further damage:

How Does Cirrhosis Occur?

Response to Liver Damage

1. Villi of the hepatocytes are lost 2. Endothelial fenestra.ons are lost 3. Stellate cells are ac.vated Leads to constric:on of sinusoid and collagen deposi:on 4. Kuper cells are ac.vated

Stellate cells are the most integral cell-type in this damage response

Stellate Cells are Key in the Development of Cirrhosis

Stellate cells are found throughout the space of Disse and normally func.on only to store vitamin A in quiescent state In response to acute liver injury they go through a series of events to help protect the liver: 1. Constric:on occurs which helps divert blood away from injured area 2. Fibrogenesis occurs to prevent any leakage of bile into the blood 3. Secre.on of factors which appear to induce cell division in hepatocytes to replace damaged cells Following repair of damaged .ssue, stellate and Kupfer cells help in the eventual breakdown of collagen

Stellate Cell Ac.va.on

Stellate cells are believed to be ac.vated by a number of dierent pathways: Various cytokines (signalling molecules) from hepatocytes, Kupfer cells, endothelial cells, or even stellate cells themselves in response to damage or to dierent toxicants Reac.ve oxygen species (ROS) released from necro.c hepatocytes Pro-inammatory agents from Kupfer cells and white blood cells in response to injury Platelets also release a host of cytokines which ini.ate the ac.va.on of stellate cells The pathway of ac.va.on will depend on the ini.al cause of injury (i.e., alcohol abuse, viral infec.on, physical injury)

Consequences of Cirrhosis
The complica.ons of liver cirrhosis are two-fold in that some of the disorders associated with this condi.on are related to (1) impaired liver func:on (due to a destruc.on of hepatocytes) and others are related to (2) hypertension of the liver portal circula:on (due to obstruc.on of sinusoids by collagen deposi.on or constric.on)

Jaundice
Jaundice is the most common sign of liver disorder It is characterized by a yellowing of the skin or whites of the eyes

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Bilirubin
The yellowing seen in jaundice is due to a buildup of the chemical bilirubin. Bilirubin is a product of hemoglobin breakdown (heme groups are converted to bilirubin by phagocy:c monocytes found mainly in the spleen and liver (Kupfer cells!) Bilirubin is delivered to hepatocytes where it is conjugated and released into bile canaliculi to be eliminated from the body via the intes.ne

Bilirubin
When the liver is damaged and hepatocyte func.on is lost, bilirubin cannot be excreted into the bile and this leads to its accumula.on in the body and eventually leads to the yellowing of the skin and eyes Plasma bilirubin levels are used as a diagnos.c tool for cirrhosis or other liver diseases

Whats Next in This Module?

Lecture 2: Ascites and varices Lecture 3: Hepa.c encephalopathy Lecture 4: Liver transplanta.on and regenera.on