Transcript Metabolic diseases of the liver

Metabolic diseases of the liver
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Central role in metabolism
Causes and mechanisms of dysfunction
Clinical patterns of metabolic disease
Clinical approach to problem-solving
Specific disorders
Liver’s central role in metabolism
Pathways involve CHO, protein, lipid, trace element
and vitamin metabolism
• Synthesis
e.g. serum proteins
• Detoxification/degradation
e.g. ammonia
• Regulation
e..g. blood glucose
Metabolic function of the liver
Reactions disturbed by
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Congenital deficiency of enzymes
Nutritional deficiency/excess of substrate
Toxic/chemical damage to organelles
Hypoxic/ischaemic insult
Secondary to metabolic effects of disease
Metabolic disorders
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of amino acid metabolism
of bile acid synthesis and metabolism
of carbohydrate metabolism
of bile flow and excretion
of mitochondrial function
of peroxisomal function
of copper metabolism
Metabolic dysfunction : inherited disease
• Essential product deficit
e.g. G-6-P deficiency
(Glycogen storage I)
• Precursor accumulation
e.g. OTC deficiency
(Hyperammonaemia)
• Alternative pathway activation
e.g. Aminoacidopathy
• Combinations of above
Mitochondrial damage
• Inhibition of beta oxygenation of fatty acids
leads to microvesicular steatosis
• Interference with oxidative phosphorylation
leads to insufficient ATP generation
• Impairment of the respiratory chain
leads to excess ROS with lipid peroxidation
• Increase in permeability transition
leads to cell death (apoptosis)
Mitochondrial dysfunction
• Inborn enzyme deficiencies involving:
fatty acid oxygenation
organic acids
lactate metabolism
oxidative phosphorylation
urea cycle
Episodic decompensation precipitated by
intercurrent stress
Toxic damage to liver
• Mitochondrial damage
Drugs (antivirals, salicylate, valproate,
tetracycline)
Toxins (hypoglycin, atractyloside)
• Endothelial damage to hepatic veins
Drugs (cytotoxic drugs)
Toxins (Senecio, aflatoxin, pyrrolizidine)
• Glutathione depletion and cell death
Drugs (paracetamol)
Hypoxic ischaemia
Mechanisms of centrilobular necrosis
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Sepsis
Shock induced ischaemia
Congestive heart failure
Toxicity from drugs and poisons
made worse by
Malnutrition
Infection
Fasting
Exercise
Pathologic manifestations of metabolic
disease of the liver
• No structural abnormalities evident but
severe functional disturbance
• Hepatocyte injury leading to apoptosis,
necrosis, cirrhosis or tumours
• Storage of lipid, glycogen or other products
manifesting as hepatomegaly
Clinical patterns of metabolic disease
involving the liver
• Newborn acute metabolic crisis
mimics sepsis
• Severe vomiting and failure to thrive
• Recurrent episodes of vomiting and
encephalopathy with acidosis
• Progressive retardation or seizures with
hepatomegaly
• Hepatomegaly with/without jaundice and failure
to thrive/grow normally
Inherited metabolic disease presenting with
acute onset liver failure “Reye-like”
Typical age
Neonatal to 3 years
Past history
Episodic vomiting since neonatal period, possible
failure to thrive, possible family history
Preceding history
Abnormal stress such as infection, fasting,
exercise
Clinical features
Progressive encephalopathy and anicteric
multisystem failure and acidosis
Inherited metabolic disease presenting with
acute onset liver failure “Reye-like”
Typical biochemical
findings
Hypoglycaemia. Ketosis often absent.
Metabolic acidosis. Transaminases elevated.
Hyperammonaemia. Prolonged prothrombin time.
Decreased serum albumin. Leucocytosis.
Raised acute phase reactants.
Functional
disturbance
Mitochondrial dysfunction
Pathology
Microvesicular steatosis
Treatment
Supportive for liver failure : attend to
hypoglycaemia, acidosis, bleeding tendency,
hyperammonaemia.