PR2155 IC2 pathophys

What are the seven fundamental functions of the liver?

MESSSDI

Metabolism

Excretion

Storage

Synthesis

Secretion

Detoxification

Immune function

What is the storage function in the liver?

Storage of blood

Nutrient-rich blood flows through the liver before entering systemic circulation.

What is the role of the liver in nutrient metabolism?

The liver is involved in **carbohydrate, lipid, and protein** metabolism, including

* glucose buffer function → maintaining blood glucose levels,
* lipid oxidation and synthesis
* protein synthesis and degradation (deamination→ urea cycle)

What is glucose buffer function?

The liver stores glucose as glycogen

blood glucose levels are **high**: Glucose → glycogen (stored)

blood glucose levels are **low**: Glycogen → glucose, amino acid→ glucose (gluconeogenesis)

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This helps to maintain stable blood glucose levels.

What is the role of the liver in lipid metabolism?

The liver is involved in the

* **oxidation of fatty acids**, lipolysis (breaking down of fats to supply energy),


* synthesis of fats from proteins and carbohydrates
* synthesise cholestrol, phospholipids, lipoproteins

What is oxidative deamination?

Liver **removes the nitrogenous content** of amino acids to form urea (amino acid) and uric acid (DNA), which are **excreted** in urine and feces.

What is the role of the liver in protein synthesis?

The liver synthesizes

* albumin and plasma proteins
* blood coagulation factors.

What are the blood coagulation factors synthesized by the liver?

Fibrinogen, prothrombin, factor VII

What are some markers for poor liver function → poor protein synthesis?

1. low albumin level → affects oncotic pressure
2. prothrombin time, clotting ability of the patient

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Which vitamin is needed in the formation of prothrombin, factor VII, IX, X

Vitamin K

Where is factor VII produced?

Liver sinusoidal endothelial cells, overall endothelial cells

What is bilirubin?

Bilirubin is a **bile pigment that** is produced from the **breakdown of haemoglobin by microphage**

It is excreted by the liver and can cause jaundice if it accumulates in the blood.

What is the enterohepatic circulation of bile salts?

95% Bile salts are reabsorbed in the **terminal ileum** and then transported back to the liver through the portal vein.

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This process is known as the enterohepatic circulation of bile salts.

what is the difference between conjugated and unconjugated bilirubin?

1. Unconjugated bilirubin → not polar, not excreted in the urine
2. Conjugated bilirubin → polar, more easily excreted

How does the liver detoxify?

Phase I

Phase II


1. Main purpose is to make the metabolites more polar and hydrophiliic so they can be excreted more easily 

What is the role of the liver in the storage of vitamins and minerals?

The liver stores fat-soluble vitamins A, D, E, and K, as well as minerals like iron and copper.

How does the liver involve in immune function?

1. Remove bacterial from blood coming from portal vein (from small intestine, bacteria present) 
2. **Hepatic macrophage system** 


1. **Kuffer cells**


1. large phagocytic macrophages
2. Lines the hepatic venous sinuses

What is Jaundice and what is its threshold?

Yellow coloration of skin, sclera, mucous membrane due to **excess level of circulating bilirubin**.

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Bilirubin level exceeds **1.2 mg/dL.**

What are the two mechanisms that cause excess bilirubin in the blood?

Increased production

Decreased excretion

What are the three types of jaundice?

Pre-hepatic, intrahepatic, and obstructive (post-hepatic).

What kind of bilirubin increases in prehepatic jaundice?

Increase in unconjugated

* produced too much
* excess hemolysis of erythrocytes
* normal liver cannot process excess amount of bilirubin

What are some causes of prehepatic jaundice?

Excess RBC hemolysis

* Too much bilirubin from heme 

Reduced hepatic uptake

What kind of bilirubin increases in intrahepatic jaundice?

Increase in unconjuaged (hepatocellular damage cannot conjugate) 

Increase in conjugated (inflammation obstruct flow)

What are some causes of intrahepatic jaundice?

Hepatitis

Cirrohsis

Liver cancer

Reduced liver cells funciton and capacity

What kind of bilirubin increases in Obstructive (post hepatic) jaundice?

Normal unconjugated 

Increased conjugated (obstructed flow to the intestine)

What are some causes of obstructive jaundice?

Onsctruction of outflow 

Gall stones

Tumours

What are the feaces colors for the three different types of jaundice?

Prehepatic → normal or dark

Intrahepatic → variable

Obstructive → light color

What is unconjugated hyperbilirubinemia and what are the causes?

1. Unconjugated hyperbilirubinemia is an excess of unconjugated bilirubin in the blood, which can occur due to drug-induced **immune hemolytic anemia (higher break down of RBC)**

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2. G6PD deficiency.

What is conjugated hyperbilirubinemia and what are the causes?

Conjugated hyperbilirubinemia is an **excess of conjugated bilirubin in the blood**, which can occur due to

* viral hepatitis
* alcoholic liver disease
* non-alcoholic steatohepatitis
* drug-induced liver injury.

What are some drugs that can cause dose-dependent drug-induced liver injury?

1. Paracetamol, salicylates, tetracycline.

What are some drugs that can cause dose-independent drug-induced liver injury?

1. Anaesthetics (e.g. halothane), anti-depressants (e.g. MAOIs), anti-malarials (e.g. Fansidar), anti-inflammatory (e.g. NSAIDs), statins (e.g. simvastatin).

What are the types of liver injury?

hepatocellular

Cholestatic

* intrahepatic
* Extrahepatic

What are the parameters changes that indicate Hepatocellular liver injury?

Significantly Raised AST ALT levels

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little or no increase in ALP and bilirubin

What are the parameters changes that indicate **intrahepatic cholestatic** liver injury?

little or no increase in AST ALT

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Significantly Raised ALP

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Little or no increase in bilirubin

What are the parameters changes that indicate extrahepatic cholestatic liver injury?

little or no increase in AST ALT

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Significantly Raised ALP

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Significant increase in bilirubin

What are the lab parameter for testing liver synthetic functions?

1. Serum albumin
2. Prothrombin time (clotting factor activity) 

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What are the lab parameter for testing excretory function of the liver?

1. Serum Bilirubin levels 
2. Gamma-glutamyltransferase GGT

What is liver cirrhosis?

 irreversible fibrosis. Scar tissue formation from liver injury. 

What are some general impact of cirrhosis?

* Widespread hepatocyte loss
* Distortion of normal liver architecture
* Disrupts hepatic vasculature (**obstructed blood flow**) → **portal hypertension**

What are some conditions that can cause cirrhosis?

* Hepatitis B, C and D
* NAFLD
* NASH
* Many others

Brief pathogenesis of cirrhosis.

Initiation phase:

* hepatocytes injured → Release cytokines

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Perpetuation phase

* cytokines activate stellate cells →stimulate production of collagen matrix→ fibrosis

What are the two general complication of cirrhosis?

1. progressive hepatocyte dysfunction → affect basic 7
2. Portal hypertension

What are some complication of portal hypertension?

1. Ascites
2. Esophageal varices
3. Rectal varices
4. Distended abdominal veins
5. Splenomegaly

How does ascites happen in cirrhosis?

* high pressure causing fluid to flow out of portal circulation into peritoneal cavity

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mechanism

* Portal hypertension→ **increased hydrostatic pressure** in the portal circulation
* Decreased synthesis of albumin→ **decreasing intravascular oncotic pressure**
* Under-filling of circulation and reduced aldosterone metabolism in the liver→ activation of RAA system

What is portal hypertension?

1. Portal hypertension is a major complication of cirrhosis, caused by an increase in venous pressure in the portal system due to obstructed blood flow.

How does esophageal varices happen?

bleeding, hematemisis and malena→ **buldging** esophageal varices to **relief pressure in the portal vein**, burst if too big

What are some manifestation of hepatic failure (hepatocellular dysfunction?

Coma

* accumulation of ammonia, crossing the BBB, toxic

Jaundice

* accumulation of excess bilirubin 

Bleeding tendencies

* impaired hepatic synthesis of clotting factors

Anemia

Hypoalbuminemia

*  (not able to make enough albumin, periphery odema) 

Hyperammonemia

* cerebral dsyfunction

Impatired **estrogen metabolism**

* Males: hypogonadism & gynecomastia

Describe the stages of alcoholic liver disease.

Alcoholic fatty liver → Alcoholic hepatitis → Cirrhosis

What happens in alcoholic fatty liver?

Fatty change

Perivenular fibrosis 

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**Clinical features** 

Elevated AST and ALT

Hepatomegaly +/-

Reversible and steatosis usually disappears after 3 montjs of abstinence

What happens in alcoholic hepatitis?

Liver cell necrosis

Inflammation

Mallory bodies

Fatty change

Features of protal hypertension

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**Clinical features** 

Jaundice 

Hepatomegaly 

Complications of portal hypertension +/-

AST ALT elevation

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better 5 years survival if you stop drinking

What happens in alcoholic cirrhosis?

Fibrosis

Hyperplastic nodules 

Encephalopathy

Features of portal hypertension

\n **Clinical features** 

Higher risk of developing hepatocellular carcinoma

Varices; hemorrhage

acites

What is the pathophysiology behind NAFLD?

* NAFLD→ insuline resistance. 
* Insulin resistance→ leads to incerase release of free fatty acids from adipocytes due to overactive lipoprotein lipase. 
* which leads to **increased levels of circulating insulin**. Insulin resistance causes the **liver to produce more glucose than it needs,** which leads to an accumulation of fat in the liver

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* **Lipid accumulation** → toxicity (change cell signalling pathways that regulate metabolism and stress response that can potentiate liver cell injury or death) 

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* dyslipidemia, obesity, and a sedentary lifestyle. These factors can lead to the **accumulation of fat in the liver** and promote inflammation, which can further damage liver cells