[4.5& 4.6 p1] 6131 LEC -Toxic Responses of the Liver and Kidney part 1

LIVER

• primary elimination organs

Metabolism/ Biotransformation

LIVER

• Substances (drugs, toxins, nutrients) are absorbed in the GI tract → portal vein → liver,

• where they are metabolized into either less active (detoxified) or active/more toxic forms (metabolic activation)

Liver metabolism is NOT always detoxification.

It can convert substances into active or more toxic forms (metabolic activation/intoxication), rather than inactive, excretable compounds.

LIVER

• Converts substances into

• inactive, water-soluble forms to enhance renal excretion.

Lipid-soluble substances

remain in circulation

water-soluble forms

are easily eliminated in urine

KIDNEY

• primary elimination organs

• Excretion (urinary)

KIDNEY

• Insult or injury to either organs can

decrease toxicant elimination and eventually prolong and/or intensify the the effect of a toxicant that successfully enters the body

KIDNEY

• functions (primary eliminating organs)

Excretes waste products and performs hormonal and metabolic functions, including erythropoietin production and activation of vitamin D.

Common lab markers for liver damage

• liver function test (ALT & AST)

• ALP

• Bilirubin

• ammonia

 ALT 

alanine aminotransferase

Liver-specific enzyme; ↑ indicates liver injury

 AST

aspartate aminotransferase

• Found in liver, heart, and skeletal muscle and other tissues

ALP

• Alkaline Phosphatase

• ↑ suggests cholestasis (impaired bile flow or formation)

Bilirubin

• product of old RBC breakdown. The liver processes and excretes it via bile into the intestine → eliminated in feces (gives stool its brown color). 

Ammonia

• byproduct of protein metabolism. 

• the liver converts it to urea, which is excreted by the kidneys in urine

Ammonia

• In liver dysfunction, ammonia

• accumulates in blood, crosses the blood-brain barrier, and can cause altered mental status

The liver

first filters blood from the intestines, then processes, stores, detoxifies, and excretes substances.

The kidneys

filter a large portion of the blood, removing drugs, toxicants, and metabolic waste

The liver and kidneys are the body’s main eliminating organs and major targets for toxicants, both organs are prone to injury. When they are damaged,

elimination is compromised, leading to accumulation of drugs, toxins, protein metabolism products, and RBC breakdown products, which can worsen toxicity in the body

LIVER

• Is the main organ where exogenous chemicals are metabolized and eventually excreted

• First organ to encounter ingested nutrients, vitamins, metals, drugs, and environmental toxicants and waste products

• Maintain the metabolic homeostasis of the body 

LIVER Maintain the metabolic homeostasis of the body 

• Help keep the body’s internal environment stable, regulates nutrients and energy, processes chemicals, and removes waste products

[LIVER'] Efficient scavenging or uptake processes

extract these absorbed materials from the blood for catabolism, storage, and/or excretion into bile; 

if the kidneys cannot eliminate unwanted substances,

they can be removed via bile

Adequate bile formation

is essential for the uptake of lipid nutrients from the small intestine, protection of the small intestine from oxidative insults, and excretion of endogenous and xenobiotic compounds

hepatocytes

produce bile, which carries waste products of liver metabolism, such as protein metabolites and bilirubin from RBC breakdown into the stool

bile duct

connects the liver and gallbladder to the intestine.

Fatty foods

stimulate bile release.

Bile metabolizes

fats in the intestine; some lipids are reabsorbed into the portal vein and processed again by the liver

Gallbladder

stores bile; bile flows through the bile duct into the intestine, carrying liver waste products like bilirubin

Hepatocytes begin the process by

transporting bile acids including xenobiotics and their metabolites, into the canalicular lumen

All unconjugated bile acids are conjugated

before being transported across the canalicular membrane

Hepatocytes metabolize substances and secrete waste into bile,

which passes through canaliculi (small green ducts in the liver) to the bile duct

Blocked or damaged bile flow (due to hepatotoxic drugs or alcoholism)

causes cholestasis, leading to accumulation of bilirubin in blood → jaundice, pale stools (bilirubin not excreted), and dark urine

Biliary secretion

is usually a prelude to urinary or fecal excretion

Biliary secretion is usually a prelude to urinary or fecal excretion

• When a substance is not released into the intestine and eliminated through the stool, it will undergo processes

• If it is in the blood, then it will be eliminated through the kidneys and into the urine

Reabsorption leads to

enterohepatic recycling

Reabsorption leads to enterohepatic recycling

• Bile salts from the bile duct go to the intestine to be reabsorbed again and breakdown dietary fats

LIVER IS Important in homeostasis of many metals,

including toxic ones

[liver] Inability to export

may pose problems (ex. copper in Wilson’s disease)

Inability to export may pose problems (ex. copper in Wilson’s disease)

• The transport system of copper is compromised in Wilson’s disease,

• which lets the metal accumulate to several tissues and organs, making it a problem

In neonates

where bile formation is underdeveloped, accumulation can occur (ex. drugs that displace bilirubin → jaundice)

LIVER INJURY

• Biliary secretion is usually a prelude to urinary or fecal excretion

• Reabsorption leads to enterohepatic recycling

• Important in homeostasis of many metals, including toxic ones

• Inability to export may pose problems (ex. copper in Wilson’s disease)

• In neonates where bile formation is underdeveloped, accumulation can occur (ex. drugs that displace bilirubin → jaundice)

DIFFERENT FORMS OF LIVER INJURY

• Cell Death

• Canalicular Cholestasis

• Bile Duct Damage

• Fatty Liver

• Fibrosis and Cirrhosis

• Tumors

• Hepatic encephalopathy

2 types of cell death

• apoptosis

• necrosis

Canalicular Cholestasis

• canalliculi lumen

• first pathway of bile being formed by the hepatocytes

Bile Duct Damage

• The bile, together with the waste products,

is excreted through the bile duct that is connected to the intestine

Sinusoids

- capillaries that bring blood to the liver; also where the exchange of components happen

Fatty Liver

• steatosis

high triglycerides in the liver

Fibrosis and Cirrhosis

FIbrosis comes first and if the injury keeps happening, then it becomes cirrhosis

Tumors

Can be caused by the

proliferation of cells

Hepatic encephalopathy

Encephalopathies are concerned with

the brain

Necrosis

• Characterized by

• cell swelling

• leakage

• nuclear disintegration (karyolysis)

• influx of inflammatory cells

Necrosis

• Can be detected biochemically by

• assaying plasma (or serum) for liver cytosol-derived enzymes 

• AST or ALT or GGT

Necrosis

• Unprogrammed and unregulated

• Liver cell membranes are disrupted and the contents leak out, causing inflammation and ultimately, cell death

Apoptosis

• Characterized by

• cell shrinkage

• nuclear fragmentation

• formation of apoptotic bodies

• lack of inflammation

Apoptosis

• Controlled and regulated

• No leaking of cell contents occur, allowing a cleaner cell death without inflammation

Canalicular Cholestasis

• Decrease in the volume of bile formed or an impaired secretion of specific solutes into bile

• problem with bile flow or when the amount of waste products is not transported enough to the bile

Canalicular Cholestasis

• Characterized biochemically by

• elevated serum levels of compounds normally concentrated in bile, particularly bile salts and bilirubin

Canalicular Cholestasis

• elevated bile salts & bilirubin leads to

•  jaundice; Dark urine and pale stools (less stercobilin)

• Cholestasis - problem with bile flow; can lead to jaundice, dark urine, and pale stool because the bilirubin (RBC breakdown waste product) is not properly excreted by the body

• Since it will not be excreted, it will be reabsorbed in the blood, which will deposit to different parts of the body, resulting in jaundice

• High amounts of bilirubin in the blood also leads to excretion via the kidneys, resulting in a dark-colored urine

  Bile Duct Damage

• Damage to the intrahepatic bile ducts (which carry bile from the liver to the GI tract) is called

• cholangiodestructive cholestasis

Cholangio-

- refers to the bile duct attached to the intestine (which opens when we eat fatty foods, since bile breaks down fat)

  Bile Duct Damage

• indicated by

•  a sharp elevation in serum alkaline phosphatase (ALP) activity; ↑ALP and bilirubin, which are indicators of cholestasis

Bile duct damage can lead to

firbrosis & cirrhosis

The sinusoid is a

specialized capillary with numerous fenestrae (holes) for high permeability

function of sinusoid

• brings blood into the liver (connected to the central vein)

location of sinusoid

•  between the hepatocytes

Fenestrae -

where exchange of nutrients, oxygen, and other components between the blood and liver happen

Sinusoidal damage

• Functional integrity of the sinusoid can be compromised by

• dilation or blockade of its lumen or destruction of its endothelial cell wall

Sinusoidal damage

• Blockade will occur when

• red blood cells become caught in the sinusoids (”veno-occlusive disease / sinusoidal obstruction syndrome”)

Blockade will occur when red blood cells become caught in the sinusoids (”veno-occlusive disease / sinusoidal obstruction syndrome”)

• Ex. Pyrrolizidine alkaloids in some herbal teas

• Functional integrity of the sinusoid can be compromised by dilation or blockade of its lumen or destruction of its endothelial cell wall

• Ex. APAP

Triglycerides (comprised of fatty acids) increase when:

• There is an increase in the synthesis of fats in the liver

• Fats are not metabolized correctly

Process to metabolize fats in the liver by

beta oxidation

Metabolized fats are sources of energy

(mitochondria is a cell component that is responsible for  metabolizing fats)

Damaged mitochondria

= no source of energy = increase in fats

Triglycerides in the liver are escorted into the bloodstream in order to be used as energy in the form of

very low density lipoprotein (VLDL)

• If not converted to VLDL = accumulate in the liver

Appreciable increase in the hepatic lipid content,

(Default: <5% of the weight of normal human liver)

Fatty Liver (aka Steatosis)

• common causes

• Insulin resistance from central obesity/sedentary lifestyle

• Hepatotoxicants like carbon tetrachloride 

• Ethanol

• Drugs (ex. amiodarone, tetracycline)

Insulin resistance from central obesity/sedentary lifestyle

= adipose fats will undergo lipolysis = fats will go to the blood = fats will accumulate in the liver

Hepatotoxicants like carbon tetrachloride

• Converted to a reactive species 

• Increases the synthesis of fats

Ethanol

Worst

Ethanol

• 3 ways to increase the fats:

• (a) increases synthesis of fats,

• (b) inhibits beta oxidation (cannot breakdown fats), and

• (c) inhibits exportation of triglycerides via VLDL

Alcoholic people (e.g. drinks gin bilog everyday)

have a high fat concentration in the liver

Drugs (ex. amiodarone, tetracycline)

• Both inhibit metabolism of fats

• Compromise exportation of triglycerides via VLDL

Hepatic fibrosis

is the accumulation of extensive amounts of collagen fibers in response to direct injury or to inflammation

Fibrosis can be induced by

chronic lists xenobiotic causes of fibrosis and cirrhosis such as

• CCl₄

• ethanol

• thioacetamide

• vitamin A

• vinyl chloride.

• exposure to drugs and chemicals, especially ethanol and heavy metals.

When fibrous scars subdivide the remaining liver mass into nodules →

cirrhosis

• Not reversible, has a poor prognosis for survival

• May progress to liver cancer

The primary cause of hepatic fibrosis/cirrhosis is

viral hepatitis, but can also be drugs, ethanol, and heavy metals

Progression of Liver Disease

• healthy liver

• fatty liver

• fibrosis liver

• cirrhosis liver

• liver cancer

Fatty Liver

• the liver is enlarged due to fatty deposits in the cells

Fibrosis Liver

• liver tissue begins to be replaced by connective tissue

Cirrhosis Liver

• excessive development of connective tissue, restructuring of the liver and vascular system, formation of areas of necrosis

Liver Cancer

• as a result of malignant transformation of hepatocytes, liver cancer is formed

Tumors

• Can start from various types of hepatic cells

• Cellular proliferation

• Formation of reactive species such as hepatotoxin (bind to sulfhydryl of the DNA and proteins of people with high risk of cancer)

Tumors

• linked to

• chronic abuse of androgens, alcohol, and aflatoxin-contaminated diets

• Also increased risk in patients with viral hepatitis, hemochromatosis, and a1-antitrypsin deficiency

Hepatic Encephalopathy

• Reversible condition due to liver dysfunction

  • Often due to ammonia build-up when the liver cannot metabolize it to urea (accumulates in the blood if the liver is damaged)

  • Ammonia passes to the brain and increases permeability of the BBB > entry of other neurotoxins such as free fatty acids

  • Effect is more on functional rather than structural, so it is reversible

Hepatic Encephalopathy

• manifested as

• altered mental state, mood, asterixis, and even stupor to deep coma

Hepatic Encephalopathy

• common antidote

lactulose

lactulose

• Converts bacteria/organism into an organic acid

• Acidic the intestine → ammonia will be converted to a form that will not be reabsorbed in the blood (ammonium) → excreted via the feces