Elsevier

Journal of Hepatology

Volume 67, Issue 5, November 2017, Pages 1062-1073
Journal of Hepatology

Review
Acid-base disorders in liver disease

https://doi.org/10.1016/j.jhep.2017.06.023Get rights and content

Summary

Alongside the kidneys and lungs, the liver has been recognised as an important regulator of acid-base homeostasis. While respiratory alkalosis is the most common acid-base disorder in chronic liver disease, various complex metabolic acid-base disorders may occur with liver dysfunction. While the standard variables of acid-base equilibrium, such as pH and overall base excess, often fail to unmask the underlying cause of acid-base disorders, the physical–chemical acid-base model provides a more in-depth pathophysiological assessment for clinical judgement of acid-base disorders, in patients with liver diseases.

Patients with stable chronic liver disease have several offsetting acidifying and alkalinising metabolic acid-base disorders. Hypoalbuminaemic alkalosis is counteracted by hyperchloraemic and dilutional acidosis, resulting in a normal overall base excess. When patients with liver cirrhosis become critically ill (e.g., because of sepsis or bleeding), this fragile equilibrium often tilts towards metabolic acidosis, which is attributed to lactic acidosis and acidosis due to a rise in unmeasured anions. Interestingly, even though patients with acute liver failure show significantly elevated lactate levels, often, no overt acid-base disorder can be found because of the offsetting hypoalbuminaemic alkalosis.

In conclusion, patients with liver diseases may have multiple co-existing metabolic acid-base abnormalities. Thus, knowledge of the pathophysiological and diagnostic concepts of acid-base disturbances in patients with liver disease is critical for therapeutic decision making.

Introduction

A functioning acid-base balance results in normal blood pH and is critical for regular cellular and organ function.[1], [2] Next to the kidneys and lungs, the liver is now recognised as an important organ of acid-base regulation,3 playing a crucial role in various homeostatic pathways, such as the metabolism of organic acid anions like lactate and certain amino acids.4 Consequently, patients with liver dysfunction often show acid-base disorders. Interestingly, the literature on acid-base disorders in liver disease is very limited. In addition, standard acid-base variables frequently fail to unmask the underlying acid-base disorders in liver disease.[5], [6]

  • Patients with liver disease often have various complex acid-base disorders. Pathophysiological and diagnostic concepts as well as potential therapeutic interventions are reviewed in this article.

In contrast to the traditional model of acid-base equilibrium based on the Henderson-Hasselbalch-formula,[7], [8] the more recent physical-chemical approach (also known as Stewart’s approach)9 provides a better understanding of the underlying mechanisms of acid-base disorders in liver disease. The most common acid-base disturbance in patients with liver disease is respiratory alkalosis; however, various complex metabolic disorders of acid-base equilibrium also occur in patients with both stable and decompensated cirrhosis.10 This review will thus focus on the pathophysiological role of the liver in acid-base disorders that result from liver injury in the setting of cirrhosis, critical illness and acute liver failure; it will also cover diagnostic approaches, as well as specific therapeutic interventions in order to optimise patient management.

Section snippets

Lactate metabolism and the Cori Cycle

Lactic acidosis is the most important type of metabolic acidosis in intensive care patients. It results from tissue hypoxia secondary to circulatory failure,[11], [12] reduced lactate removal due to sympathoadrenal-induced vasoconstriction and reduced blood flow to the liver, kidney and resting muscles.13 Lactate is also produced in the working muscle during anaerobic glucose utilisation. The healthy liver acts as the main consumer of lactate and contributes to 30–70% of lactate metabolism (

The physical-chemical acid-base model

Traditional acid-base analysis according to Siggaard-Andersen acknowledges the influence of PaCO2, as well as organic acids and is based on blood pH.8 However, it neglects the effects of electrolytes and weak acids (albumin and phosphate) on acid-base balance. The more recent physical-chemical acid-base approach according to Stewart integrates all potential modifiers of the acid-base balance.9 While Stewart originally proposed a somewhat complex mathematical model, the simplified model by

Acid-base status in critically ill patients with cirrhosis

Gastrointestinal bleeding, hepatic encephalopathy, acute renal failure, respiratory failure and sepsis are the main reasons patients with cirrhosis are admitted to ICUs, and have high mortality rates.[36], [76] Next to severity of pre-existing liver disease quantified by Child-Pugh-Score,77 for example, development of organ failure resulted in significantly elevated 30-day mortality rates of over 50%.78 From an acid-base point of view, in a study of 181 critically ill patients with cirrhosis,

Acid-base disorders in acute liver failure (ALF)

  • In acute liver failure, pronounced lactic acidosis is counteracted by hypoalbuminaemic alkalosis again resulting in normal pH.

Most patients with acute liver failure (ALF) have substantially elevated lactate levels. However, these changes were observed without acidaemia.[35], [42], [103] This counterintuitive phenomenon was described as “stress hyperlactataemia”, resulting from a massive increase in glycolysis caused by catecholamine- and other cytokine-mediated increases in cellular glucose

Therapeutic implications

The monitoring of acid-base status using the simplified physical-chemical model in patients with cirrhosis has several potential therapeutic consequences and is summarised in Table 2.

While specific treatment of the underlying disease is the only intervention with a proven benefit on mortality (e.g., bleeding control, antibiotic treatment in the setting of sepsis), several supportive therapies have the potential to improve patient management.[11], [116], [117] In mechanically ventilated patients

Conclusions and outlook

  • When patients with liver cirrhosis get critically ill, the acid-base equilibrium often tilts towards metabolic acidosis due to lactic acidosis and unmeasured anions.

  • The physical-chemical acid-base model should be applied to diagnose and properly manage underlying disorders of acid-base homeostasis in patients with acute and chronic liver disease.

In healthy individuals, the most important hepatic contributions to a stable acid-base state are lactate clearance and albumin production, while

Financial support

The authors received no financial support in relation to the production of the manuscript.

Conflict of interest

B.S. received travel support from Gilead. G.L., Br.S., C.Z. and G.-C.F. have nothing to declare. T.R. received travel support from Boehringer-Ingelheim, Gore, Gilead, Roche and MSD; grant support from Abbvie, Boehringer-Ingelheim; served on Advisory boards for Abbvie; and received lecture fees from Boehringer-Ingelheim, Gore, MSD and Roche. M.T. serves as a consultant for Albireo, Falk, Genfit, Gilead, Intercept, MSD, Novartis and Phenex and is a member of the speakers' bureau of Falk, Gilead,

Authors’ contributions

Study conception and design: B.S., G.-C.F.; Selection of appropriate literature: B.S., G.-C.F.; Drafting of the manuscript: B.S., T.R., M.T., G.-C.F.; Critical revision of the manuscript for important intellectual content: G.L., T.R., Br.S., M.T., C.Z., G.-C.F.

References (118)

  • T.H. Casey et al.

    Body and serum potassium in liver disease. II. Relationships to arterial ammonia, blood Ph, and hepatic coma

    Gastroenterology

    (1965)
  • J.J. McAuliffe et al.

    Hypoproteinemic alkalosis

    Am J Med

    (1986)
  • V.K. Sinha et al.

    Hyponatremia in cirrhosis-pathogenesis, treatment, and prognostic significance

    Adv Chronic Kidney Dis

    (2015)
  • S.N. Ahya et al.

    Acid-base and potassium disorders in liver disease

    Semin Nephrol

    (2006)
  • C.M. Pastor et al.

    Liver injury during sepsis

    J Crit Care

    (1995)
  • D. Bihari et al.

    Lactic acidosis in fulminant hepatic failure. Some aspects of pathogenesis and prognosis

    J Hepatol

    (1985)
  • J.A. Kellum et al.

    Strong ion gap: a methodology for exploring unexplained anions

    J Crit Care

    (1995)
  • M.K. Nadim et al.

    Management of the critically ill patient with cirrhosis: A multidisciplinary perspective

    J Hepatol

    (2016)
  • R.E. Shangraw et al.

    Mechanism of dichloroacetate-induced hypolactatemia in humans with or without cirrhosis

    Metabolism

    (2004)
  • G.S. Sacks

    The ABC’s of acid-base balance

    J Pediatr Pharmacol Ther

    (2004)
  • M. Bernardi et al.

    Disturbances of acid-base balance in cirrhosis: a neglected issue warranting further insights

    Liver Int

    (2005)
  • D. Haussinger et al.

    Metabolic alkalosis as driving force for urea synthesis in liver disease: pathogenetic model and therapeutic implications

    Clin Invest

    (1992)
  • D. Haussinger et al.

    Ammonium and bicarbonate homeostasis in chronic liver disease

    Klin Wochenschr

    (1990)
  • Henderson LJ. Das Gleichgewicht der Säuren und Basen im tierischen Organismus. Ergebnisse der Physiologie, biologischen...
  • W.B. Schwartz et al.

    A critique of the parameters used in the evaluation of acid-base disorders. “Whole-blood buffer base” and “standard bicarbonate” compared with blood pH and plasma bicarbonate concentration

    N Engl J Med

    (1963)
  • P.A. Stewart

    Modern quantitative acid-base chemistry

    Can J Physiol Pharmacol

    (1983)
  • T. Naka et al.

    Acid-base balance in combined severe hepatic and renal failure: a quantitative analysis

    Int J Artif Organs

    (2008)
  • H.J. Adrogue et al.

    Management of life-threatening acid-base disorders. First of two parts

    N Engl J Med

    (1998)
  • D. De Backer et al.

    The hepatosplanchnic area is not a common source of lactate in patients with severe sepsis

    Crit Care Med

    (2001)
  • O.B. Nielsen et al.

    The Na+/K(+)-pump protects muscle excitability and contractility during exercise

    Exerc Sport Sci Rev

    (2000)
  • L.B. Rowell et al.

    Splanchnic removal of lactate and pyruvate during prolonged exercise in man

    J Appl Physiol

    (1966)
  • R.D. Cohen

    Some acid problems

    J R Coll Physicians Lond

    (1982)
  • R.W. Samsel et al.

    Hepatic oxygen and lactate extraction during stagnant hypoxia

    J Appl Physiol

    (1991)
  • P.J. Goldstein et al.

    Effect of acid-base alterations on hepatic lactate utilization

    J Physiol

    (1972)
  • R. Chiolero et al.

    Effect of major hepatectomy on glucose and lactate metabolism

    Ann Surg

    (1999)
  • Nöldge-Schomburg G, Armbruster K, Geiger K, Zander R. Experimentelle Untersuchungen zum Säure-Basen-Haushalt und...
  • G.C. Funk

    Stewart's acid-base approach

    Wien Klin Wochenschr

    (2007)
  • B.J. Stinbaugh et al.

    Mechanism for the paradoxical aciduria following alkali administration to prolonged-fasted patients

    Metabolism

    (1975)
  • S.R. Lipsky et al.

    The effects of alkalosis upon ketone body production and carbohydrate metabolism in man

    J Clin Invest

    (1954)
  • B.M. LaGrange et al.

    Ketoacid production in acute respiratory and metabolic acidosis and alkalosis in rats

    Am J Physiol

    (1989)
  • D. Haussinger et al.

    Hepatic urea synthesis and pH regulation. Role of CO2, HCO3-, pH and the activity of carbonic anhydrase

    Eur J Biochem

    (1985)
  • M.L. Halperin et al.

    Is urea formation regulated primarily by acid-base balance in vivo?

    Am J Physiol

    (1986)
  • S. Cheema-Dhadli et al.

    Regulation of urea synthesis by acid-base balance in vivo: role of NH3 concentration

    Am J Physiol

    (1987)
  • H. Prytz et al.

    Acid-base status in liver cirrhosis. Disturbances in stable, terminal and portal-caval shunted patients

    Scand J Gastroenterol

    (1976)
  • R. Moreau et al.

    Arterial and mixed venous acid-base status in patients with cirrhosis. Influence of liver failure

    Liver

    (1993)
  • R.E. Shangraw et al.

    Effect of liver disease and transplantation on urea synthesis in humans: relationship to acid-base status

    Am J Physiol

    (1999)
  • M. Hosch et al.

    Ureagenesis: evidence for a lack of hepatic regulation of acid-base equilibrium in humans

    Am J Physiol Renal Physiol

    (2004)
  • L. Boon et al.

    Acute acidosis inhibits liver amino acid transport: no primary role for the urea cycle in acid-base balance

    Am J Physiol

    (1994)
  • L. Boon et al.

    Response of hepatic amino acid consumption to chronic metabolic acidosis

    Am J Physiol

    (1996)
  • G.C. Funk et al.

    Acid-base disturbances in critically ill patients with cirrhosis

    Liver Int

    (2007)
  • Cited by (67)

    • Acid-base abnormalities and liver dysfunction

      2022, Annals of Hepatology
      Citation Excerpt :

      This increase in lactic acid, on the one hand, is due to increased production (>1500mmol/day) (tissue hypotension-hypoxia, suppression of cellular metabolism due to sepsis, hypercatabolic syndrome) and on the other hand, reduced breakdown in the liver (liver function loss, sepsis) [50–52]. In these patients total BE remains reduced with a predominance of MAc due to an increase in lactic acid, an increase in UMA in contrast to stabilized patients with liver cirrhosis (Fig. 4) [9,10]. These patients have increased mortality due to complications in the function of other organs (multiorgan failure).

    • Preventive and therapeutic role of betaine in liver disease: A review on molecular mechanisms

      2021, European Journal of Pharmacology
      Citation Excerpt :

      However, due to constant changes of people's living environment and irregular living habits, the number of patients with liver disease in the world has been increasing year by year in recent years. There are many factors that may cause liver disease, such as chemical drugs or poisons, virus infection, excessive drinking, malnutrition, acid-base disorders and so on (Bajaj, 2019; Fisher et al., 2015; Liang, 2009; Mandato et al., 2017; Scheiner et al., 2017). At present, the liver disease has become one of the most common diseases in the world, mainly including drug-induced acute/chronic liver injury, nonalcoholic fatty liver disease (NAFLD), alcoholic fatty liver disease (AFLD), viral hepatitis, liver fibrosis, cirrhosis and even liver cancer (Asrani et al., 2019; Xiao et al., 2019).

    View all citing articles on Scopus
    View full text