14. Cirrhosis. Causes, mechanisms and consequences. Hepatic cachexia.

Cirrhosis?

Chronic degenerative disease of the liver

- Functioning liver parenchyma is replaced by connective scar tissue

- Is the final pathway of many chronic liver diseases

- The development takes years

- Abnormal nodules are formed in the liver

- Involves chronic injury to hepatocytes that stimulates scarring

- As the parenchyma is filled w/ scar tissue, will the liver start to lose its function - FAILURE

The causes of cirrhosis?

- Chronic hepatitis viral infection (mostly hepatitis C)

- Alcoholic liver disease

- Non-alcoholic fatty liver disease

- Cholestasis

- Congestion (right-sided heart failure)

- Cystic fibrosis

- Metabolic disorders (Wilsons, hemochromatosis, a1-antitrypsin deficiency)

- Cryptogenic cirrhosis

- Primary sclerosing cholangitis

- Autoimmune hepatitis

- Budd Chiari syndrome

- Parasitic infection (malaria)

- Medication (e.g. acetaminophen)

- Aflatoxin ingestion (Aspergillus)

What usually develops first in chronic liver disease?

Steatosis hepatis often develops first

- Later will the hepatocyte injury stimulate fibrosis and inflammation

- Ito cells (stellate cells) are converted into myofibroblasts that start to proliferate & deposit collagen

Stages of development of cirrhosis?

- Pre-inflammatory (steatotic) phase

- Inflammatory phase

- Post-inflammatory phase

Pre-inflammatory (steatotic) phase?

Hepatocyte injury leading to (reversible) lipid accumulation → steatosis

↓ β-oxidation → suppress protein synthesis → reducing hepatocytes ability to release lipids in lipoproteins

Inflammatory phase?

The injured, fat-filled hepatocytes produce free radicals

= Stimulate stellate cells to convert into myofibroblasts

- They proliferate and produce C.T and cytokines -> which further stimulate Kupfer macrophages, which produce inflammation

= Remodeling of the parenchyma has started

- Necrotic cell debris from dead hepatocytes also stimulate inflammation

What happens to the sinusoids in the inflammatory phase?

The newly built C.T starts to compress the sinusoids - increasing the pressure in them

- The endothelial cells of the sinusoids will be damaged -> which increases the fenestration of them -> allowing for more proteins & inflammatory cytokines to enter the interstitium

Post-inflammatory phase?

Most stellate cells are converted into myofibroblasts at this point

- Continous C.T. proliferation -> compressing the liver parenchyma & damages hepatocytes

What does the damaged hepatocytes produce in the post-inflammatory phase?

y-glutamyl transferase (GGT)

- High levels of this indicates that there is a damage to the liver, or the bile ducts

Symptoms of cirrhosis (end-stage of the post-inflammatory phase)?

Cirrhosis may not cause symptoms initially

- If not treated, it will progress and show symptoms like jaundice and edema

Liver failure will eventually occur, with more severe symptoms

What is cirrhosis a risk factor for?

hepatocellular carcinoma

Liver failure?

When liver loses some or all of its functions

- Is a spectrum

Some liver functions are lost as soon as liver parenchyma is lost

- The liver failure may progress until liver function is severely decreased -> at this point it is called end-stage liver disease

Can occur acutely, but more commonly has a chronic development

Common causes of acute liver failure?

- Viral hepatitis

- Toxins - mushroom, organic solvents

- Hepatotoxic drugs - halothane, isoniazid, paracetamol

- Tumors

Common causes of chronic liver failure?

Cirrhosis

What are the consequences of liver failure?

Hypoglycemia

- In acute- or end-stage liver failure

Decreased protein synthesis

- Hypoalbuminemia

- Coagulopathy -> due to decreased clotting factor

Cholestasis

- Jaundice

Hepatopulmonary syndrome

Hepatorenal syndrome

Portal hypertension

- Hypersplenism/splenomegaly

- Malabsorption

Edema, ascites

Hepatic encephalopathy

Hepatic cachexia

Hepatic cachexia occurs due to?

A combination of:

- Hypermetabolism due to inflammation

- Malabsorption due to portal hypertension and porto-caval anastomoses

- Decreased appetite due to ascites, inflammation and hepatic encephalopathy

What contributes to ascites and edema in liver failure?

The hypoalbuminemia

What contributes to the hepatic encephalopathy?

When the liver fails, its ability to eliminate ammonia via the urea cycle is impaired

- Ammonia is toxic to the brain, and contributes to the hepatic encephalopathy

What have you acquired if you are considered to be in end-stage liver disease?

- Ascites

- Hepatic encephalopathy

- Hepatorenal syndrome