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Toxicology > Lecture 7 > Flashcards

Lecture 7 Flashcards

1
Q

Liver facts

A
  • Second largest organ in our body!
  • The liver holds about one pint (13%) of the
    body’s blood supply at any given moment.
  • It is located in the right upper quadrant (RUQ)
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2
Q

Porta hepatis, or hilum of the liver, is the…

A

fissure running transversely on the underside of the liver where most of the vessels enter or leave.

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3
Q

What is the hepatic lobule

A

The hepatic lobule is the anatomic unit of the liver. Each lobule is made up of numerous liver cells, called hepatocytes. A hexagon-like structure where the central vein is located at the center and the hepatocytes form radiating cords from the central vein.

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4
Q

What is the bile canaliculi

A

Bile canaliculi also known as bile capillaries are thin tubes that receive bile secreted by
hepatocytes. The bile canaliculi eventually merge and form bile ductules.

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5
Q

Functions of the liver

A
  • Metabolism/Catabolism (break-down) of toxins, nutrients, alcohol, drugs, hormones
  • Carbohydrate metabolism (Glucose⇌Glycogen)
  • Lipid metabolism (Phospholipids, Cholesterol)
  • Protein metabolism
  • Synthesis of plasma proteins such as Albumin, Prothrombin, Fibrinogen)
  • Urea formation (old proteins -> amino acids -> urea)
  • Storage of vitamins and minerals
  • Breaking down erythrocytes (bilirubin clearance)
  • Producing bile
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6
Q

Functions of hepatic bile

A

1) Primary pathway for elimination of water-insoluble bilirubin, excess cholesterol & xenobiotics
2) Emulsification of dietary fat in gut lumen

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7
Q

What is the liver made of

A

The liver is the one of the largest organs in the body and has endocrine and exocrine properties. It is composed of 60% parenchymal cells, i.e., hepatocytes, and 30% to 35% non-parenchymal cells, i.e., Kupffer
cells (KCs), hepatic stellate cells (HSCs) and liver sinusoidal endothelial cells (LSECs).

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8
Q

Kupffer cells are…

A

resident liver macrophages and play a critical role in maintaining liver functions. They localize within the lumen of the liver sinusoids and are adherent to the endothelial cells that compose the blood vessel walls. Under physiological conditions, they are the first innate immune cells and protect the liver from bacterial infections. Most of them
are responsible for phagocytosis of large
particles.
They also participate in the metabolism of
multiple compounds such as protein complexes, small particles, and lipids, and
in removing apoptotic cells from the circulation.

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9
Q

Histologic patterns of hepatic injury

A
  • Inflammation: acute or chronic hepatitis; portal or lobular
  • Degeneration: ballooning, foamy, steatosis
  • Necrosis: coagulative or lytic (hydropic); Councilman bodies; centrilobular, focal, piece-
    meal, bridging, submassive, massive
  • Cholestasis
  • Fibrosis: portal, central, bridging
  • Cirrhosis: regenerative nodules surrounded by fibrosis
  • Cancer (hepatoma)
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10
Q

Steatosis

A

is the infiltration of liver cells with fat, associated with disturbance of the metabolism by, for example, alcoholism, malnutrition, pregnancy, or drug therapy.

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11
Q

Hepatocyte swelling

A
  • Swelling or hydropic change is a result of defects in membrane and/or mitochondrial function.
  • It is presumed to be caused mostly by membrane damage, which allows influx of fluid into the cell or by damage to cytoskeleton, leading to loss of cell shape.
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12
Q

What is homeostasis

A

Homeostasis is any self-regulating process by which an organism tends to maintain stability while adjusting to conditions that are best for its survival.

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13
Q

What is coagulative necrosis

A

Coagulative necrosis is a type of cell death that occurs when blood flow to cells stops or slows (ischemia). It can occur anywhere in the body except the brain. Many conditions can cause ischemia, including atherosclerosis.

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14
Q

What are Councilman bodies

A

In pathology, a Councilman body, also known as a Councilman hyaline body or apoptotic body, is an eosinophilic globule of apoptotic hepatocyte cell fragments. Ultimately, the fragments are taken up by macrophages or adjacent parenchymal cells. They are found in the liver of individuals suffering from acute viral hepatitis, yellow fever, and other viral syndromes.

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15
Q

What is lytic necrosis

A

hepatocytes swell &
rupture

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16
Q

What are hepatocytes

A

Liver cells

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17
Q

Paracetamol Toxicity

A

*The most common drug implicated in drug-induced liver injury is acetaminophen.

  • Paracetamol overdose is one of the
    leading causes of acute liver failure.
  • > 150mg/kg = Lethal
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18
Q

What is Glutathione (GSH)

A

Glutathione is an antioxidant found naturally in your body. Also known as GSH, it is produced by the liver and nerve cells in the central nervous system and is made from three amino acids: glycine, L-cysteine, and L-glutamate. Glutathione can help metabolize toxins, break down free radicals, support immune function, and more.

The human body produces glutathione, but there are also dietary sources. Spinach, avocados, asparagus and okra are some of the richest dietary sources. However, dietary
glutathione is poorly absorbed by the
human body.

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19
Q

Functions of Glutathione (GSH)

A

Functions
* Detoxifying xenobiotics
* Antioxidant cofactor
* Cell proliferation
* Apoptosis
* Immune function
* Fibrogenesis

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20
Q

The injury produced by NAPQI involves
two mechanisms

A
  1. covalent binding to hepatic proteins, which causes damage to cellular membranes and mitochondrial dysfunction, and
  2. depletion of GSH, making hepatocytes more susceptible to ROS-induced injury. Because alcohol induces CYP2E in the liver, toxicity can occur at lower doses in chronic
    alcoholics.

‘Reactive oxygen species’ (ROS)

21
Q

Paracetamol Toxicity phase 1

A

*0.5 – 24 hours after ingestion
*Asymptomatic or nausea / vomiting
*Pallor, diaphoresis, fatigue

22
Q

Paracetamol Toxicity phase 2

A

*18-72 hours after ingestion
*Upper right abdominal pain, nausea / vomiting
*Upper right abdominal pain

23
Q

Paracetamol Toxicity phase 3

A

*72-96 hours after ingestion
*Tender hepatic edge, abdominal pain, nausea/ vomiting
*Jaundice, coagulopathy, hypoglycaemia, hepatic encephalopathy

24
Q

Paracetamol Toxicity antidotes

A
  • Activated charcoal
  • N-acetylcysteine

In serious overdose, liver failure ensues, starting with centrilobular necrosis that may extend to entire lobules; in such circumstances liver transplantation is the only
hope for survival.

25
Q

Jaundice

A

yellowish discoloration of skin & sclera (icterus) due to systemic retention of bilirubin (> 2 mg/dl)

  • Equilibrium between bilirubin production & clearance is disturbed:
  • 1) Excessive production
  • 2) Reduced hepatocellular uptake
  • 3) Impaired conjugation
  • 4) Decreased hepatocellular excretion
  • 5) Impaired bile flow
  • Kernicterus: accumulation of bilirubin in brain
26
Q

Amoxicillin-clavulanate toxicity

A
  • The combination of amoxicillin and clavulanic acid is used to treat certain infections caused by bacteria, including infections of the ears, lungs, sinus, skin, and urinary tract.
  • The liver injury caused by amoxicillin-clavulanate is typically associated with jaundice and can be severe and prolonged (with jaundice lasting 4 to 24 weeks), but rarely results in lasting injury or death.
  • The liver injury may present days or weeks after stopping therapy.
  • The injury is more common in men than women, in the elderly and after multiple
    courses.
  • Deaths due to amoxicillin-clavulanate hepatic injury have been largely in patients with other comorbidities including cirrhosis or with multiple exposures.
  • The cause of amoxicillin-clavulanate hepatotoxicity is unknown, but is probably
    immunoallergic in origin.
27
Q

Cholestasis

A

Cholestasis is a condition where bile cannot flow from the liver to the duodenum.
Bile that can’t flow leaks into your bloodstream and backs up into your organs, causing inflammation. Bile that can’t reach your intestines can also cause problems in your digestive system.

28
Q

Causes of cholestasis

A

Causes may be obstructive or metabolic and include:
Alcoholic liver disease
Amyloidosis
Bacterial abscess in the liver
Lymphoma
Primary biliary cirrhosis
Viral hepatitis B or C can cause primary biliary cirrhosis
Metastatic liver cancer

29
Q

Toxic Hepatitis

A

Hepatitis is the term used to describe inflammation of the liver. It could be the result of a viral infection or liver damage caused by alcohol or drugs (Paracetamol, Aspirin, Ibuprofen).
Chronic liver inflammation leads to fibrosis and cirrhosis, which is the 12th leading
cause of death in the United States.

30
Q

What is cirrhosis

A

Cirrhosis is scarring (fibrosis) of the liver caused by long-term liver damage. The scar tissue prevents the liver working properly.

Cirrhosis is sometimes called end-stage liver disease because it happens after other stages of damage from conditions that affect the liver, such as hepatitis.

Your liver may keep working even when you have cirrhosis. However, cirrhosis can eventually lead to liver failure, and you can get serious complications, which can be life threatening.

Cirrhosis is an increasing cause of morbidity and mortality in more developed countries, being the 14th most common cause of death worldwide but fourth in central Europe.

31
Q

3 histologic features of cirrhosis

A
  1. Bridging fibrous septa
  2. Disruption of entire liver architecture
  3. Parenchymal nodules
32
Q

Etiology

A

Etiology means the cause or origin of disease

33
Q

Etiologic factors of cirrhosis

A

*Alcoholic liver diseases- 60 to 70%
*Viral hepatitis- 10%
*Biliary diseases- 5 to 10%
*Primary hemochromatosis- 5%
*Wilson disease- rare
*Cryptogenic cirrhosis- 10-15%

34
Q

Alcoholic liver disease

A

Alcohol is the fifth leading cause of death in the U.S

Alcohol has adverse effects on liver, GIT (ulcers, gastritis), CNS (peripheral neuropathy & Wernicke- Korsakaff syndrome secondary to thiamine deficiency, cerebral atrophy,
cerebellar degeneration …), CVS (cardiomyopathy, hypertension, HDL), pancreas (pancreatitis), pregnancy (fetal alcohol syndrome)

35
Q

3 forms of alcoholic liver disease

A
  1. Hepatic steatosis
  2. Alcoholic hepatitis
  3. Alcoholic cirrhosis
36
Q

Alcohol-induced hepatocellular steatosis

A
  1. Generation of excess NADH by alcohol dehydrogenase & acetaldehyde dehydrogenase leading to increased lipid biosynthesis
  2. Impaired assembly & secretion of lipoproteins
  3. Increased peripheral catabolism of fat
37
Q

Alcohol-induced hepatocellular damage

A
  1. Induction of cytochrome P450 (particularly the 2E1 isoform)
  2. Generation of free radicals
  3. Direct effect on microtubular & mitochondrial function & memebrane fluidity
  4. Acetaldehyde induces lipid peroxidation & acetaldehyde-protein adduct formation,
    further disrupting cytoskelatal & membrane function
  5. Antigenic alteration of hepatocytes & hepatic proteins, inducing an immunologic attack
38
Q

Alcohol-induced fibrosis

A

Multifactorial and poorly understood

39
Q

Anabolic steroids are…

A

manufactured drugs that copy the effects of the male hormone testosterone.

40
Q

Liver cell adenoma

A

*Adenomas are benign (noncancerous) tumors.
*You should treat adenomas as precancerous
because they may turn into cancer if left
undetected.

  • Mostly in young women with history of oral
    contraceptive pills (OCP) use. [estrogen-based oral contraceptive pills]
  • Hepatic adenomas have also been linked to anabolic steroids.
  • Well-demarcated yellow-tan frequently bile-stained nodule(s), often located beneath capsule, usually small in size but may reach up to 30 cm.
41
Q

Clinical significance of liver cell adenoma

A

Clinical significance:
1) Misdiagnosed as hepatocellular carcinoma
2) May rupture & cause serious intra-abdominal hemorrhage
* May regress on discontinuance of OCPs

42
Q

Hepatocellular carcinoma

A

The most common type of primary liver cancer

43
Q

Cholangiocarcinoma

A

Bile duct cancer

44
Q

Liver angiosarcoma

A

Cancer that forms in the lining of blood vessels and lymph vessels.

45
Q

Aflatoxins

A

are a family of toxins produced by certain
fungi that are found on agricultural crops such as maize (corn), peanuts, cottonseed, and tree nuts.

46
Q

Hepatic failure (liver failure) causes

A
  • Mostly due to progressive, or less often sudden massive hepatic destruction with loss of 80-90% of hepatic functional capacity

Causes:
1. Chronic liver diseases.
2. Massive hepatic necrosis (fulminant failure): viral hepatitis, drug & chemical toxicity (acetaminophen, halothane, rifampicin, MOI antidepressants, CCl4, Amanita mushroom toxins)
3. Hepatic dysfunction without overt necrosis: viable but nonfunctional hepatocytes, e.g. Reye’s syndrome, tetracycline toxicity, acute fatty liver of pregnancy

A variety of stressful events may contribute to onset of failure:
* GI bleeding
* Acute infections
* Electrolyte disturbances
* Major surgery, heart failure, shock
* Treatment: not satisfactory
* Px: 80% mortality rate

47
Q

Symptoms of liver failure

A

*Jaundice
*Easy bleeding
*Swollen abdomen
*Mental disorientation/Confusion/Loss of concentration
*Sleepiness
*Coma
*Pain in the upper right abdomen
*Fluid buildup in legs
*Fluid buildup in the abdomen
*Generalised body swelling

48
Q

Liver Function Tests

A

Tests of hepatocyte integrity
* ASL (SGOT)
* ALT (SGPT)
* LDH

Tests of biliary excretory function
* Serum Bilirubin
* Alkaline phosphatase
* Gamma-glutamyl transpeptidas

Tests of hepatocyte function
* Albumin
* Prothrombine time
* Ammonia
* Aminopyrine breath test; galactose elimination

Toxicology (8 decks)

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