# 4.5: Acid-Base Role of the Liver

The liver is important in acid-base physiology and this is often overlooked. It is important because it is a metabolically active organ which may be either a significant net producer or consumer of hydrogen ions. The amounts of acid involved may be very large. The acid-base roles of the liver may be considered under the following headings:

• Carbon dioxide production from complete oxidation of substrates
• Metabolism of organic acid anions (such as lactate, ketones and amino acids)
• Metabolism of ammonium
• Production of plasma proteins (esp albumin)

## 2.5.1: Substrate Oxidation

Complete oxidation of carbohydrates and fat which occurs in the liver produces carbon dioxide but no fixed acids. As the liver uses 20% of the body's oxygen consumption, this hepatic metabolism represents 20% of the body's carbon dioxide production also. The CO2 diffuses out of the liver and reactions in red cells result in production of H+ and HCO3-.

## 2.5.2: Acid Anions

The metabolism of various organic anions in the liver results in consumption of H+ and regeneration of the extracellular bicarbonate buffer. These anions may be:

• Exogenous (eg citrate in blood transfusion, acetate and gluconate from Plasmalyte 148 solution, lactate from Hartmann's solution), or
• Endogenous (eg lactate from active glycolysis or anaerobic metabolism, keto-acids produced in the liver)

The term acid anion is used because they are anions produced by dissociation of an acid.

That is: $$HA \rightarrow H^{+} + A^{-}$$ (where HA is the acid and A- is the acid anion).

The anions are the conjugate base of the acid (Bronsted-Lowry system) and are not themselves acids. This is an important distinction to make because they are often referred to as though they were acids and this leads to confusion.

If the endogenous production of these anions is followed by later consumption in the liver then there is no net production of acid or base because the H+ produced (from the dissociation of the acid) is consumed when the anion is subsequently metabolised by the liver.

When these organic anions are exogenously administered (eg in intravenous fluids), administration of the anion (the conjugate base) without any H+ occurs because the cation involved is Na+. Any subsequent metabolism of these anions in the liver will consume H+ and result in excess bicarbonate production. As an example, a metabolic alkalosis can result after a massive blood transfusion when the citrate anticoagulant is metabolised to bicarbonate. (The alkalosis is only transitory as the kidney normally excretes it rapidly- see Section 7.3). The important point to note is how some of these anions (eg lactate, acetate) are used in IV crystalloid solutions as a bicarbonate source (though this is indirect of course as the bicarbonate is only produced when they are metabolised in the body).

The situation with lactate sometimes causes confusion to students. The key point to remember is that lactic acid is an acid but lactate is a base. The administration of lactate in Hartmann's solution can never result in a lactic acidosis because it is a base and not an acid. The solution contains sodium lactate and not lactic acid. The lactate anion is the conjugate base of lactic acid and represents potential bicarbonate and not potential H+.

#### So does this mean that Hartmann's solution can be used for volume resuscitation in patients with lactic acidosis?

Firstly, consider the following points:

• Hartmann's solution has a high [Na+] (which restricts the fluid to the ECF) so it is a useful ECF replacement solution. Infusion of an appropriate amount can correct an intravascular volume deficiency.
• Lactate cannot buffer H+ (to form lactic acid) at physiological pH as the pKa (3.86) of the reaction is too low.
• Normally, lactate can be metabolised in the liver and this results in the consumption of H+ (or equivalently: production of HCO3-)
• Patients with lactic acidosis have inadequate hepatic metabolism of lactate so the production of HCO3- from the infused lactate is impaired. (So until this problem with hepatic metabolism can be corrected then the infused lactate cannot act as a bicarbonate source).

The serum lactate level is used as an index of the severity of the lactic acidosis as each lactate generally means that one H+ has been produced. If sodium lactate in Hartmann's solution is now given then the lactate level is not as useful a guide as now not all the lactate implies the presence of an equivalent amount of H+ that was produced with it in the body.

So: Hartmann's solution is an excellent ECF replacement solution to correct hypovolaemia. If the circulation improves and hepatic metabolism of lactate returns to normal then bicarbonate will be generated and the solution indirectly assists in correcting the lactic acidosis as well. (But of course if this happened then the body would also metabolise the endogenously produced lactate and this would be the major factor in correction of the acidosis.) However, if this hepatic metabolism does not happen, then the infused lactate just interferes with the usefulness of serial lactate measurements as an serial index of severity of the acidosis.

Overall then, it is generally not the preferred ECF replacement solution. If it is the only solution readily available then it can be used and the infused lactate (a base) cannot worsen the acidaemia. The 'official' recommendation is to not use Hartmann's solution in patients with lactic acidosis. (As a point of interest, you might like to consider whether normal saline which contains the non-metabolisable chloride as the anion could possibly be any better!)

### Endogenous Lactate

Some excess lactate is normally produced in certain tissues and 'spills over' into the circulation. This lactate can be taken up and metabolised in various tissues (eg myocardium) to provide energy. Only in the liver and the kidney can the lactate can be converted back to glucose (gluconeogenesis) as an alternative to metabolism to carbon dioxide. The glucose may re-enter the blood and be taken up by cells (esp muscle cells). This glucose-lactate-glucose cycling between the tissues is known as the Cori cycle. Typically there is no net lactate production which is excreted from the body. The renal threshold for lactate is relatively high and normally all the filtered lactate is reabsorbed in the tubules.

The total amount of lactate involved is large (1,500 mmols/day) in comparison to the net fixed acid production (1 to 1.5 mmols/kg/day). The metabolism of lactate in the liver indirectly eliminates the H+ produced subsequent to the tissue production of lactate. Lactic acidosis will result if this hepatic metabolism is not adequate. (See Lactic Acidosis ).

Metabolism of lactate sourced from IV Hartmann's solution also results in a net consumption of H+, but as this lactate was associated with Na+, the overall result is a net bicarbonate production. Effectively, metabolism of this lactate results in generation of an equivalent amount of bicarbonate. The situation is similar with metabolism of citrate and gluconate in other IV fluids.

### Ketones

Keto-acids such as acetoacetate are produced in hepatic mitochondria due to incomplete oxidation of fatty acids. The ketones are released into the blood stream and metabolised in the tissues (esp muscle). Hepatic production of ketoacids produces H+ and the oxidation of the keto-anion in the tissues consumes H+ and thereby regenerates the HCO3- which had buffered it in the blood stream. In severe diabetic ketoacidosis, the keto-acid production may exceed 1,200 mmols/day in an adult! In healthy individuals, a modest amount of excess ketones are produced only with significant fasting. (See also Section 8.2 Ketoacidosis)

### Amino Acids

Amino acids are all dipolar ions (zwitterions) at physiological pH as they all have both COO- and NH3+ groups. These are the groups that participate in formation of the peptide bond. As these groups are present on all amino acids, then the oxidation of these groups in all amino acids will result in a production of equal amounts of bicarbonate and ammonium: typically 1,000 mmol/day of each. This aspect and the acid-base implications has been covered in the previous section 2.4 and will not be repeated here.

Amino acids also have side chains and incomplete metabolism of some of these has acid-base effects - eg side chain metabolism can result in a net fixed acid production. Sulphuric acid is produced from metabolism of methionine and cysteine. This is a major component of the net fixed acid load.

Arginine, lysine and histidine have nitrogen in their side chains so their metabolism generates H+ . Glutamate and aspartate have carboxylic acid groups (COO-) in their side chains so their metabolism consumes H+ (and therefore produces HCO3- ). The balance of these reactions is a net daily production of H+ and acid anions of 50 mmol/day (ie production of 210 mmols/day and consumption of 160 mmol/day). The liver is the major net producer of fixed acids.

## 2.5.3: Metabolism of Ammonium

See section 2.4 for details. The conversion of NH4+ to urea in the liver results in an equivalent production of H+. Infusions of NH4Cl have an acid loading effect because of this hepatic metabolism. H+ cannot be released directly from NH4+ in the body because the high pKa of the reaction means that NH3 is present in only minute quantities at pH 7.4.

## 2.5.4: Synthesis of Plasma Proteins

The liver is the major producer of plasma proteins as nearly all (except the immunoglobulins) are produced here. Albumin synthesis accounts for 50% of all hepatic protein synthesis. The acid-base roles of albumin are:

• it is the major unmeasured anion in the plasma which contributes to the normal value of the anion gap
• extracellular buffer for CO2 and fixed acids
• abnormal levels can cause a metabolic acid-base disorder

Haemoglobin is more important than albumin for buffering H+ produced from CO2. Also, bicarbonate is more important than albumin as a buffer for fixed acids.

The role of low or high albumin levels in causing acid-base disorders is difficult to explain within the traditional framework of acid-base analysis. The role of albumin as the major non-volatile weak acid present in plasma and its significance in acid-base balance is discussed in Section 10. Hypoalbuminaemia causes a metabolic alkalosis.

## 2.5.5: Overview

Consideration of all these factors shows that the liver has an extremely important role in normal acid-base physiology. The traditional emphasis on the lung and kidney as the organs of acid-base regulation should be extended to a new concept of the importance of the lung-liver-kidney complex.

Hepatic disorders are often associated with acid-base disorders. The most common disturbances in chronic liver disease are respiratory alkalosis (most common) and metabolic alkalosis.