Urea cycle - hyperammonaemia

[Phloston]

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Why does hyperammonaemia (e.g. secondary to liver disease) impair the urea cycle? What's the mechanism?

Kaplan QBank tests this, and they don't give an explanation by even the slightest means.

 

[spinesurgery]

Thank you for your valuable information.🙂

 

[Phloston]

A 65M with a long-standing Hx of alcohol abuse and cirrhosis is brought to the ED in a confused and disoriented state. He is started on lactulose and admitted to the hospital, where he is started on a protein-restricted diet. Lactulose acts to minimize a metabolic abnormality that results from decreased function of which of the following processes?

That's the question.

 

[Phloston]

Is that really the mechanism for hyperammonaemia in liver disease? Impaired hepatic synthesis of arginase --> blockage of the urea cycle?

I had always heard that hyperammonaemia impairs the citric acid cycle because of shunting of depletion of alpha-KG.

Now here's a full mechanism (correct me if I'm wrong):

Impaired hepatic synthesis of arginase --> blockage of the urea cycle --> hyperammonaemia --> decreased alpha-KG --> impaired TCA cycle --> encephalopathy.

I guess I'm just a bit shocked that I had never learned that arginase inhibition mechanism earlier, but yet again, that's how everything with Step1 prep goes.

 

[Myxedema]

Is that really the mechanism for hyperammonaemia in liver disease? Impaired hepatic synthesis of arginase --> blockage of the urea cycle?

That may depend on the type of liver disease. In a destructive process like cirrhosis, the entire process would be affected, not just a specific enzyme. In metabolic diseases, lack of ATP production would block urea cycle and create hyperammonemia.

 

[Phloston]

That may depend on the type of liver disease. In a destructive process like cirrhosis, the entire process would be affected, not just a specific enzyme. In metabolic diseases, lack of ATP production would block urea cycle and create hyperammonemia.

Could you please elaborate on the latter portion of your statement?

 

[Myxedema]

Could you please elaborate on the latter portion of your statement?

Sure. One of the causes of hyperammonemia is beta oxidation disorders. There are no common enzymes between the urea cycle and beta oxidation, and beta oxidation defects do not cause overt liver damage and create cirrhosis like viral hepatitis resulting in liver failure and hyperammonemia. So how does hyperammonemia occur in beta oxidation defects? The answer lies with ATP production: Since the primary source of energy production in fasting state in liver is beta oxidation, defects in this pathyway causes decreased ATP production. Since the liver needs ATP for gluconeogenesis and urea cycle, there would be (1) hypoglycemia, (2) hyperammonemia (NH3 can't be excreted as urine), and (3) hypoketonemia (ketones are synthesized as a result of beta oxidation).