Liver Functions and Metabolism Quiz

Liver Functions

• The liver is a vital organ with diverse functions including:
  • Metabolism of carbohydrates, fats, and proteins
  • Synthesis of essential compounds
  • Excretion and detoxification

Carbohydrate Metabolism

• The liver maintains blood glucose levels through:
  • Glycogenesis: Synthesis of glycogen from glucose when blood glucose levels are high.
  • Glycogenolysis: Breakdown of glycogen into glucose when blood glucose levels are low.
  • Gluconeogenesis: Synthesis of glucose from non-carbohydrate sources like glycerol, lactate, and amino acids during prolonged fasting.

Lipid Metabolism

• The liver plays a crucial role in lipid metabolism:
  • Oxidation of triglycerides: Produces energy.
  • Ketone body synthesis: Converts fatty acids to ketone bodies which can be used as energy by other tissues.
  • Triglyceride synthesis: Converts excess carbohydrates and proteins into fatty acids and triglycerides.
  • Cholesterol and phospholipid synthesis: Produces cholesterol and phospholipids needed for cell membranes and other functions.
  • Lipoprotein synthesis: Synthesizes very-low-density lipoproteins (VLDLs) to transport triglycerides, cholesterol, and phospholipids to other tissues.

Protein Metabolism

• The liver is essential for protein metabolism:
  • Deamination and transamination: Breakdown of amino acids for energy or conversion to glucose or lipids.
  • Urea synthesis: Removal of ammonia, a toxic byproduct of protein metabolism.
  • Non-essential amino acid synthesis: Produces non-essential amino acids like glutamine.
  • Plasma protein synthesis: Synthesizes most of the plasma proteins including albumin, globulins, and clotting factors.

Vitamin Metabolism

• The liver is involved in the metabolism of Vitamin D:
  • 25-hydroxylation: Converts the precursor form of Vitamin D (cholecalciferol) to its circulating form (25-hydroxy-Vitamin D).

Biosynthetic Products of the Liver

• The liver synthesizes a wide range of essential compounds including:
  • Nutrients: Triglycerides, cholesterol, phospholipids, lipoproteins, glycogen, glucose, and non-essential amino acids.
  • Plasma proteins: Albumin, globulins, clotting factors (e.g., fibrinogen).
  • Haem: Iron-containing molecule crucial for oxygen transport, storage, and metabolism.
  • Bile acids: Aid in fat digestion and absorption.
  • Nucleotide precursors: Building blocks for DNA and RNA.
  • Urea: Waste product of protein metabolism.

Plasma Proteins Synthesized by the Liver

• The liver produces a variety of plasma proteins with diverse functions:
  • Carrier proteins: Bind and transport fat-soluble nutrients, hormones, drugs, and ions (e.g., albumin, globulins).
  • Clotting/Anticlotting factors: Regulate blood coagulation (e.g., fibronectin, components of the complement cascade).
  • Hormones: Regulate metabolism and growth (e.g., fibroblast growth factor, insulin-like growth factor).
  • Apolipoproteins: Enable transport of lipids in the blood.

Albumin

• Albumin is the most abundant protein in the blood:
  • Synthesis: Produced exclusively by hepatic cells.
  • Physiological role:
    • Acts as a carrier protein for many substances including fatty acids, hormones, drugs, and ions.
    • Contributes to maintaining osmotic pressure in the blood.

Haem Synthesis

• Haem is essential for the function of many proteins involved in oxygen transport, storage, and metabolism:
  • Synthesis: Occurs in the liver, muscle, and bone marrow.
  • Process:
    • Starts in the mitochondria with the synthesis of aminolevulinic acid (ALA).
    • Proceeds through a sequence of steps involving various enzymes culminating in the formation of haem.
• Defects in haem synthesis:
  • Can lead to porphyrias, a group of inherited disorders characterized by the accumulation of porphyrins in the body.

Porphyrias

• Porphyrias are a group of genetic disorders affecting the haem synthesis pathway:
  • Causes: Mutations in enzymes involved in haem synthesis leading to a buildup of porphyrin precursors.
  • Symptoms: Vary depending on the deficient enzyme, ranging from mild skin sensitivity to severe abdominal pain, neurological dysfunction, and psychiatric problems.
  • Diagnosis: Based on measuring porphyrins in urine and blood.
  • Treatment: Focuses on managing symptoms and avoiding triggers that exacerbate the condition.

Acute Intermittent Porphyria (AIP)

• AIP is a type of porphyria caused by a deficiency in the enzyme hydroxymethylbilane synthase (also known as porphobilinogen deaminase):
  • Causes: Accumulation of porphyrin precursors δ-aminolevulinate (ALA) and porphobilinogen (PBG).
  • Triggers: Drugs that induce cytochrome P450 enzymes, including barbiturates and progestins.
  • Symptoms: Severe abdominal pain, nausea, vomiting, neurological dysfunction, seizures, and psychosis.
  • Diagnosis: Elevated levels of ALA and PBG in the urine.
  • Treatment: Haematin, a synthetic form of haem, helps to inhibit ALA synthase and reduce the production of ALA and PBG.

Porphyria Cutanea Tarda (PCT)

• PCT is a type of porphyria caused by a deficiency in the enzyme uroporphyrinogen decarboxylase:
  • Causes: Accumulation of uroporphyrinogen, a photosensitive porphyrin that causes skin damage.
  • Triggers: Sunlight exposure, alcohol consumption, and iron deficiency.
  • Symptoms: Skin blistering, photosensitivity, hyperpigmentation, and increased hair growth.
  • Diagnosis: Elevated levels of uroporphyrinogen in urine and blood.
  • Treatment: Avoidance of sunlight, alcohol, and iron supplements. Anti-malarials like chloroquine can be used to bind uroporphyrinogen and increase its urinary excretion.

Albumin

• Albumin is the most abundant protein in the blood plasma
• It is synthesized by the liver and is essential in regulating fluid balance
• Albumin contributes 75-80% of the oncotic pressure in the blood which pulls fluid from the interstitial spaces into the blood vessels
• Hypoalbuminemia, a decrease in albumin levels in the blood, can be caused by impaired hepatic synthesis due to conditions like liver cirrhosis or increased renal excretion due to conditions like nephrotic syndrome
• Hypoalbuminemia leads to decreased plasma oncotic pressure, resulting in edema and ascites

Haem Synthesis by Liver Cells

• Haem is a chemical containing iron chelated in a porphyrin ring
• Haem is synthesized in the liver, muscles, and bone marrow
• Haem functions as a cofactor for hemoproteins which are involved in a range of processes, including oxygen transport, storage, and metabolism
• Haem synthesis is initiated in mitochondria where glycine and succinyl Co-A are converted into aminolevulinic acid (ALA) by the enzyme ALA synthase
• ALA is shuttled into the cytoplasm and converted into porphobilinogen (PBG) by ALA dehydratase, followed by a conversion to hydroxymethylbilane by PBG deaminase
• Hydroxymethylbilane is converted to uroporphyrinogen, then coproporphyrinogen by sequential enzyme actions
• The coproporphyrinogen is re-entered into the mitochondria to form protoporphyrin
• Protoporphyrin is then chelated to iron by the enzyme ferrochelatase to produce haem

Regulation of Haem Synthesis

• Haem levels are the primary factor regulating the rate of haem synthesis
• Haem inhibits both activity and expression of the enzyme ALA synthase in hepatocytes
• Haem also stimulates globin synthesis to maintain low levels of free haem

Defects in Haem Synthesis

• Lead poisoning: Leads to inhibition of ALA dehydratase and ferrochelatase, resulting in a reduction of haem production and increased ALA levels
• Porphyrias: A group of liver disorders due to mutations in enzymes involved in haem synthesis, leading to an accumulation of porphyrins in the body and resulting in red/purple urine

Lead Poisoning

• Exposure to lead can occur through old paint, dust, batteries, and industrial settings
• Symptoms include anemia, constipation, abdominal pain, irritability, seizures, and coma
• Lead poisoning can be treated by removing the source of lead exposure and using chelation therapy with succimer or EDTA

Porphyrias

• Can be hereditary and caused by mutations in haem synthesis enzymes
• Characterized by increased urinary porphyrin excretion
• Symptoms include abdominal pain, vomiting, confusion, fever, constipation, increased blood pressure, and seizures
• Two examples of porphyrias are Acute Intermittent Porphyria (AIP) and Porphyria Cutanea Tarda (PCT)

Acute Intermittent Porphyria (AIP)

• Due to a deficiency in porphobilinogen deaminase (uroporphyrinogen synthase I)
• Attacks are often triggered by drugs, stress, hormones, and fasting
• Symptoms include seizures, psychosis, severe abdominal pain, nausea, vomiting, and coma
• Diagnosis is made by measuring urinary ALA and PBG levels
• Treatment involves using haematin to restore the inhibition of ALA synthase

Porphyria Cutanea Tarda (PCT)

• Results from a deficiency in uropoprhorinigen decarboxylase
• Leads to a build-up of uroporphorinigen and a decrease in haem production
• UPO accumulates in the skin and becomes photoreactive, causing cell damage, inflammation, blistering, and skin discolouration upon sun exposure
• Symptoms include swelling, itching, and blistering of the skin
• Patients need to avoid sunlight, alcohol, and iron supplements
• Treatment utilizes anti-malarials like chloroquine to bind UPO and enhance urinary excretion.