Thursday, October 22, 2009

Liver, Brain and Kidney

In my last posting but one I described the clinical features of liver failure. It is interesting that many problems in the management of liver failure are caused by the secondary failure of other organs, especially the brain and kidney. The direct consequences of liver failure - jaundice, blood clotting defects, low blood glucose and low body temperature - are less threatening or are easily treated.


Secondary brain and kidney failure occur together, though one may more severe. If the liver goes down it takes brain and kidney down with it.

Perhaps brain and kidney functions are impaired by the same abnormality, caused by loss of liver function.

If liver function recovers, naturally or after transplant, brain and kidney recover too. The problems are functional, not structural.


I have seen a woman in liver coma for five days recover consciousness in less than twelve hours after a successful liver transplant.


What do brain and kidney have in common? How might liver, brain and kidney interact?

Liver function is central to these questions: kidney failure from other causes does not affect liver or brain function; similarly, coma from other causes does not affect liver or kidney.


High blood flow is a common feature of these three organs. Each takes about a quarter of cardiac output at rest - over a litre per minute in each case. Reduced blood flow may be a factor in the secondary failure of the kidney, but not for the brain.


Brain and kidney also share a dependency on the sodium-potassium pumps in their cell membranes. These produce the chemical and osmotic gradients fundamental to kidney function, and the electrical potentials on which the brain depends.


The conventional wisdom is that liver failure is an intoxication, Substances accumulate in the blood which poison brain and kidney.

Ammonia is the traditional culprit. The problem is that clinical severity does not correlate with blood ammonium values, and washing out ammonium by dialysis does not improve the patient.

The ammonium ion is physically similar to the potassium ion: it is conceivable that ammonium could interfere with sodium-potassium pumps.


There is a long list of other candidate toxins, including methionine and tyrosine or derivatives, diazepam-like substances, and bacterial endotoxins. The same problems apply: poor correlation of biochemical values and clinical state, and failure to improve on dialysis.

These objections weaken if the toxin binds to plasma proteins, or is itself a protein or other macromolecule. But exchange transfusion is no benefit either.


The intoxication hypothesis is strengthened by the undoubted improvement after emptying the colon: patients in stupor or early coma may be aroused by purging or enema. 'Bowel sterilisation' using antibiotics may also be beneficial. Unfortunately these manoeuvres fail if the liver failure is severe.

[A doctor prescribing an enema for a patient in liver coma should do it himself.]


Deficiency is the alternative to intoxication. The liver produces substances essential for brain and kidney function: loss of these essentials causes the secondary organ failures.

Glucose is an obvious example. Reduced blood glucose content will certainly impair and eventually damage the brain, but most patients in liver coma have adequate blood glucose, naturally or by infusion.


The rapid start-up of brain and kidney after transplant does suggest the restoration of something vital for brain and kidney cell function, either a substrate or an activator of a metabolic process.


Poor activity of membrane sodium-potassium pumps can be demonstrated in white blood cells from patients in liver failure. Incubating the cells in normal plasma rapidly restores full activity.

Such depressed pump activity resembles the effect of digoxin on normal cells. Patients in liver failure do not show the ECG changes familiar after digoxin dosage.

But, it is legitimate to ask, why do membrane sodium-potassium pumps have a receptor for digoxin? The same question asked of the brain and morphine led to the discovery of endorphins.


Digoxin and bile acids share the unusual 5-beta steroid nucleus. So far as I know, this type of steroid is produced only by the liver in humans. Bile acids accumulate in the blood if the bile duct is obstructed. They cause intense itching, and may affect the ECG, but brain and kidney functions are maintained.


So this is my hypothesis. The liver produces a regulating activator of the sodium-potassium pumping enzymes in cell membranes, especially in brain and kidney. Perhaps other ion transporting enzymes are similarly regulated. Function of these enzymes is impaired if supply of the liver activator fails, with consequent encephalopathy and nephropathy.

The activator may be a 5-beta steroid molecule, similar to a bile acid. It may be short lived in the body, so constant synthesis is necessary. The activator binds to the digoxin receptor on the enzyme, and increases its activity. Digoxin binds but does not activate, and blocks access of the activator.


Cerebral oedema is a lethal complication of liver coma. It must happen because the pumping of salt and water out of brain cells has collapsed. This is a hint that membrane pumps are failing, but of course other causes must be considered.


And. of course, the putative activator might not be a 5-beta steroid, but some other substance produced by the liver, maybe a peptide, maybe an active vitamin such as adenosyl-cobalamin, or something else entirely.

May be it is another metabolic pathway which is activated, such as ATP production. Ion pumps need ATP.


I have studied liver failure for many years. I have seen theories and treatments come and go. I perceive that there is a fatigue in liver research at present, especially in the mechanisms and management of liver failure. I suspect the subject needs a breakthrough in understanding of liver function, especially its interactions with other organs.


If I had a research facility, my priority would be liver-kidney interactions - much easier to study than the liver-brain axis. Membrane ion pumps would be my first focus.











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