Disorders in Liver Disease

(1)

Professor of Medicine, Department of Medicine, Chief, Division of Nephrology and Hypertension, Rutgers New Jersey Medical School, Newark, NJ, USA

Keywords

HypoalbuminemiaMetabolic alkalosisRespiratory alkalosisHigh anion gap (AG) metabolic acidosisNormal anion gap (AG) metabolic acidosisRenal tubular acidosis (RTA)Respiratory acidosis

The role of the liver in acid-base regulation is often neglected because of the importance given to the lungs and kidneys. This negligence is partly related to few studies of acid-base disorders in liver disease. In Chap. 2, the roles of the lungs and kidneys in acid-base regulation were discussed. In this chapter, a brief discussion on the role of the liver in acid-base balance and its disorders in liver disease is presented. The role of the liver in acid-base balance is divided into four categories:

Role of the Liver in Acid-Base Balance

The liver has the following important roles in maintaining acid-base balance:

1.

Lactate metabolism
2.

Ketogenesis
3.

HCO₃ ⁻ and NH₄ ⁺ metabolism
4.

Albumin synthesis

Lactate metabolism

The body generates approximately 1300 mmol of lactate (Chap. 5) and an equal number of H⁺ daily. These H ions titrate tissue and blood HCO₃ ⁻ so that the pH is maintained at normal level. Lactate is removed mostly in the liver (above 722 mmol) by gluconeogenesis to glucose and by oxidation to CO₂ and water. Both processes generate HCO₃ ⁻, which buffers acids produced during normal life, such as exercise or other activities. In this way, the liver functions as a regulatory organ in acid-base balance. If gluconeogenesis is impaired, lactate accumulates, and metabolic acidosis develops. Also, lactic acidosis develops due to excess production and/or decreased removal from the liver. In these cases, addressing the cause for lactic acidosis improves patient care.

Ketogenesis

Another source of H⁺ and HCO₃ ⁻ is inadequate oxidation of fatty acids and formation of ketone bodies, namely, acetoacetic acid and β-hydroxybutyric acid (Chap. 6). In the fed state, only small concentrations of ketones are formed. However, large quantities are formed in conditions such as starvation, insulin deficiency, and alcohol use even in the presence of normal liver. Following correction of these conditions, the ketones are oxidized to CO₂ and water. Thus, the liver regulates metabolism of ketones.

HCO₃ ⁻ and NH₄ ⁺ metabolism

Another major function of the liver is disposal of HCO₃ ⁻ formed from amino acids from protein diet. Approximately 1000 mmol each of HCO₃ ⁻ and NH₄ ⁺ are formed from 100 g protein intake, assuming that the protein diet contains only neutral amino acids. This huge load of HCO₃ ⁻ must be consumed; otherwise, as a buffer, it may have tremendous effect on acid-base balance. Such high amounts of both HCO₃ ⁻ and NH₄ ⁺ cannot be excreted by the kidneys because of limitation in urine production. The major pathway for elimination (consumption) of these two products is their utilization in hepatic urea synthesis. The liver is the only organ that generates urea via urea cycle enzymes. The generated urea is subsequently excreted in the urine. Urea is generated according to the following equation:

$\begin{array}{l}2{HCO_3}^{-}+2{NH_4}^{+}\to \mathrm{Urea}+{CO}_2+3{\mathrm{H}}_2\mathrm{O}\\ {}\mathrm{or}\\ {}2{HCO_3}^{-}+2{NH_4}^{+}\to \mathrm{Urea}+\kern0.5em {CO}_2+{\mathrm{H}}_2\mathrm{O}+2{\mathrm{H}}^{+}\end{array}$

In the above equation, HCO₃ ⁻ and NH₄ ⁺ are consumed in the same stoichiometry as they are produced during protein breakdown. Thus, consumption or detoxification of NH₄ ⁺ occurs during urea genesis. Note that for each mol of urea synthesized, 2 mol of H⁺ are produced. This H⁺ eventually titrates HCO₃ ⁻.

Both urea and glutamine synthesis occur at two different hepatocytes located in the liver: (1) periportal hepatocytes located at the inflow of the sinusoidal bed and (2) perivenous hepatocyte at the acinar outflow. The first hepatocyte contains urea cycle enzymes where urea is synthesized, and the second hepatocyte contains glutamine synthetase where glutamine is synthetized. Glutamine synthesis has a high affinity for NH₄ ⁺; therefore, it acts as a scavenger for the NH₃ that escaped periportal urea synthesis in the first hepatocyte. Thus, NH₄ ⁺ is detoxified by these two mechanisms, namely, urea and glutamine synthesis. Figure 17.1 shows schematically the formation of urea in periportal hepatocyte and glutamine synthesis in perivenous hepatocyte.

../images/480755_1_En_17_Chapter/480755_1_En_17_Fig1_HTML.png — Fig. 17.1

Synthesis of urea and glutamine in hepatocytes. (1) Represents phosphate-dependent glutaminase; (2) represents glutamate dehydrogenase; and (3) represents glutamine synthetase. Both urea and glutamine are taken up by the kidney

The importance of the liver in the regulation of acid-base balance is explained during metabolic acidosis or alkalosis. Whenever acidosis occurs, the liver responds with a decrease in urea synthesis. As a result, HCO₃ ⁻ is retained and subsequently used to correct acidosis. It is estimated that a 10% decrease in urea synthesis retains approximately 100 mEq of HCO₃ ⁻ per day. NH₄ ⁺ that is formed during protein catabolism is taken up by the perivenous hepatocyte and used for glutamine synthesis. Thus, when urea synthesis is switched off during acidosis to conserve HCO₃ ⁻, glutamine synthesis is increased, and this glutamine serves as a nontoxic transport form of NH₃ to the kidney. In the kidney, renal ammoniagenesis increases to help in the excretion of excess H⁺ generated during metabolic acidosis. In this way, the liver and kidney participate in maintaining acid-base balance during metabolic acidosis. Several other factors, which are not discussed here, also contribute to the decrease in urea synthesis during metabolic acidosis.

Conversely, during metabolic alkalosis, the HCO₃ ⁻ produced from protein catabolism does not aggravate alkalosis. This is related to enhanced urea synthesis. As a result, both HCO₃ ⁻ and NH₄ ⁺ are used up, and their amount decreases. Furthermore, degradation of glutamine increases with a supply of NH₄ ⁺ for more urea synthesis. Thus, increased urea synthesis consumes HCO₃ ⁻ during metabolic alkalosis.

Hypoalbuminemia

The liver is the major organ for albumin synthesis. As expected, albumin synthesis is decreased in liver failure. This results in a decrease in total weak acid concentration and an increase in strong ion difference, causing metabolic alkalosis (Chap. 3). Thus, hypoalbuminemia causes metabolic alkalosis. It has been reported that for each gram/dL decrease in albumin from normal, base excess increases by 3.7 mEq/L. This acid-base disorder may not be that significant in a normal individual, but it may have some significance in critically ill patients with severe metabolic acidosis by slightly increasing the pH.

From the above discussion, it is clear that the liver plays an important role in acid-base regulation besides the lungs and kidneys. Let us now discuss the various types of acid-base disorders in liver disease.

Acid-Base Disorders in Liver Disease

Several acid-base disorders have been described in patients with liver disease. Respiratory alkalosis is the predominant acid-base disturbance in patients with liver disease. The incidence and degree of respiratory alkalosis varied with severity of liver disease. For example, about 61% of patients with fulminant hepatic failure had respiratory alkalosis. In patients with stable chronic cirrhosis, the percentage varied from 25% to 83%. However, respiratory alkalosis was documented in 72–86% in patients with hepatic coma. In some of these patients, the reported arterial pH was >7.50. Similarly, the incidence of metabolic alkalosis varied from study to study with percentages from 0% to 36%.

Metabolic acidosis is not that common compared to alkalosis. High AG metabolic acidosis is rather common in patients with acute-on-chronic liver failure than in patients with stable chronic liver disease. In these acute-on-chronic liver failure patients, lactic acidosis and unmeasured anions accounted for high AG metabolic acidosis. Also, concomitant respiratory alkalosis was present with high AG metabolic acidosis. Arterial pH <7.10 was associated with 100% mortality. In addition to high AG metabolic acidosis, non-AG metabolic acidosis (renal tubular acidosis) has been reported in patients with autoimmune hepatitis. Patients with alcoholic hepatitis seem to develop incomplete renal tubular acidosis.

Mixed acid-base disturbances are also commonly observed in liver disease, particularly in those with chronic severe decompensated liver disease. Indeed such mixed acid-base disturbances were reported in 11 of 14 studies reviewed. Combined respiratory and metabolic alkalosis with hypokalemia is a frequently seen acid-base disturbance in patients with liver disease. Mixed respiratory alkalosis and metabolic acidosis are seen particularly in patients with ketoacidosis or toxic alcohol ingestion. Respiratory acidosis is rather uncommon but is an expected acid-base disturbance in patients with respiratory muscle fatigue due to hypokalemia and hypophosphatemia. Let us discuss briefly each one of these acid-base disorders that occur in liver disease.

Respiratory Alkalosis

As mentioned above, respiratory alkalosis seems to be the major acid-base disorder observed in patients with liver disease. It results from hyperventilation due to stimulation of respiratory center. Pathophysiology of respiratory alkalosis includes (1) hypoxia due to pulmonary ventilation-perfusion defects; (2) increased NH₃ levels; (3) increased progesterone levels; (4) ascites with elevated diaphragm with pleural effusions; (5) sepsis; and (6) catecholamines. Despite systemic alkalosis, intracellular acidosis occurs in the brainstem of patients with liver disease. Furthermore, alkalosis increases brain and liver NH₃ uptake. Both these processes enhance hyperventilation.

One must be cautious in lowering blood pH acutely in patients with hepatic encephalopathy. Studies have shown that lowering pH by administration of acetazolamide or 5% CO₂ inhalation caused further deterioration in neurologic status despite normal systemic NH₃ level. This suggests that care should be taken to lower systemic pH in patients with hepatic encephalopathy .

Metabolic Alkalosis

Metabolic alkalosis has been observed from 0% to 36% of patients with liver disease. However, it is the belief of many acid-base physiologists that metabolic alkalosis is rather uncommon in liver disease unless the patients are treated with diuretics, or taking antacids, or received blood transfusions with citrate as an anticoagulant.

In this connection, the reader is remained of the role of the liver in acid-base balance. A normal liver can handle approximately 1000 mmol of HCO₃ ⁻ daily in the process of urea synthesis. In fulminant hepatic failure or in severe decompensated liver disease, urea synthesis is decreased with underutilization of HCO₃ ⁻ and resultant metabolic alkalosis. However, this mechanism for metabolic alkalosis is disputed. Another mechanism is hypoalbuminemia-induced metabolic alkalosis. Again the clinical significance of hypoalbuminemia-induced metabolic alkalosis is disputed.

Hypophosphatemia and hypokalemia from poor oral intake and respiratory alkalosis may contribute to the development of metabolic alkalosis. Thus, decreased urea synthesis, hypoalbuminemia, hypophosphatemia, and hypokalemia should be considered in the evaluation of metabolic alkalosis in a patient with liver disease in the absence of diuretics or vomiting.

Hyperaldosteronism, which is common in liver disease, alone may not induce metabolic alkalosis because of reduced delivery of Na⁺ to the cortical collecting duct. However, aldosterone can elicit its action once a thiazide or loop diuretic can deliver Na⁺, which is reabsorbed in exchange for K⁺ and H⁺.

High Anion Gap (AG) Metabolic Acidosis

Metabolic acidosis is less common than metabolic alkalosis. It has been reported that metabolic acidosis occurs in 10–15% of patients at later stages of liver disease. Although the liver is the major organ for lactate disposal, lactate does not accumulate unless a stable cirrhotic patient develops sudden deterioration in liver disease (acute-on-chronic liver failure), sepsis (systemic or spontaneous bacterial peritonitis), and shock due to gastrointestinal bleeding, alcoholic ketoacidosis, or metformin use. Under these conditions, lactic acid accumulates with resultant high AG metabolic acidosis. In a prospective study of 181 patients with cirrhosis, high AG metabolic acidosis developed due to sepsis, gastrointestinal bleeding, acute kidney injury, and hepatic encephalopathy. Lactic acid and unmeasured anions accounted for metabolic acidosis. Mortality was high in these patients with pH<7.06.

The low incidence of metabolic acidosis in cirrhotic patients is partly attributed to the failure to recognize its presence when physiologic approach for acid-base analysis was followed. This was emphasized in a study by Funk et al. [1]. These investigators evaluated acid-base status in 50 stable cirrhotic patients and 10 healthy controls and analyzed acid-base status by physicochemical method of Stewart (Chap. 3). Pertinent labs in control and cirrhotic (Child-Pugh B and C) patients:

Labs	Control	Patient
Na⁺ (mEq/L)	140	133
Cl⁻ (mEq/L)	102	105
HCO₃ ⁻ (mEq/L)	23.5	22.2
Albumin (g/dL)	4.43	2.79
pH	7.42	7.45
pCO₂	37.1	31.9
AG	14.5	9.9 (corrected for albumin of 4.43 g/dL)
Base excess (BE, mEq/L)	1.1	−1.0
BE_Alb	0.1	4.6
BE_Na	0.0	−2.1
BE_Cl	0.8	−2.3
BE_UMA	−0.1	−0.7