Review

Acid-base disorders in liver disease

Bernhard Scheiner1,2, Gregor Lindner3, Thomas Reiberger1, Bruno Schneeweiss4, Michael Trauner1,
Christian Zauner1, Georg-Christian Funk2,⇑

Keywords: Acid-base disorders; Summary

Liver disease; Cirrhosis; Critically-
ill; Acute liver failure.
Alongside the kidneys and lungs, the liver has been recognised as an important regulator of
Received 27 February 2017; acid-base homeostasis. While respiratory alkalosis is the most common acid-base disorder
received in revised form 21 June in chronic liver disease, various complex metabolic acid-base disorders may occur with liver
2017; accepted 27 June 2017
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
Review

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.
Ó 2017 European Association for the Study of the Liver. Published by Elsevier B.V. All rights
reserved.
1
Division of Gastroenterology and Introduction
Hepatology, Department of Internal
Medicine III, Medical University of
A functioning acid-base balance results in normal however, various complex metabolic disorders of
Vienna, Vienna, Austria;
2
Department of Respiratory and blood pH and is critical for regular cellular and acid-base equilibrium also occur in patients with
Critical Care Medicine, Otto Wagner organ function.1,2 Next to the kidneys and lungs, both stable and decompensated cirrhosis.10 This
Spital, Vienna, Austria; the liver is now recognised as an important organ review will thus focus on the pathophysiological
3
Department of General Internal of acid-base regulation,3 playing a crucial role in role of the liver in acid-base disorders that result
Medicine & Emergency Medicine,
Hirslanden Klinik Im Park, Zurich,
various homeostatic pathways, such as the metabo- from liver injury in the setting of cirrhosis, critical
Switzerland; lism of organic acid anions like lactate and certain illness and acute liver failure; it will also cover diag-
4
Division of Oncology and Hema- amino acids.4 Consequently, patients with liver nostic approaches, as well as specific therapeutic
tology, Department of Internal dysfunction often show acid-base disorders. Inter- interventions in order to optimise patient
Medicine I, Medical University of
estingly, the literature on acid-base disorders in management.
Vienna, Vienna, Austria
liver disease is very limited. In addition, standard
acid-base variables frequently fail to unmask the
Key point underlying acid-base disorders in liver disease.5,6 The physiological role of the healthy liver in
In contrast to the traditional model of acid-base acid-base regulation
Patients with liver disease equilibrium based on the Henderson-Hasselbalch-
often have various complex formula,7,8 the more recent physical-chemical Lactate metabolism and the Cori Cycle
acid-base disorders. Patho- approach (also known as Stewart’s approach)9 pro-
physiological and diagnostic
vides a better understanding of the underlying Lactic acidosis is the most important type of meta-
concepts as well as potential
therapeutic interventions are mechanisms of acid-base disorders in liver disease. bolic acidosis in intensive care patients. It results
reviewed in this article. The most common acid-base disturbance in from tissue hypoxia secondary to circulatory
patients with liver disease is respiratory alkalosis; failure,11,12 reduced lactate removal due to

Journal of Hepatology 2017 vol. 67 j 1062–1073

 JOURNAL OF HEPATOLOGY
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 Ketogenesis Lactate metabolism
healthy liver acts as the main consumer of lactate Controlled by pH-driven Liver metabolizes up
and contributes to 30–70% of lactate metabolism feed-back mechanism to 70% of lactate
(Fig. 1).14,15 Experimental data indicated that liver
lactate consumption is directly related to arterial
lactate concentrations,16 rather than liver blood
flow.17 Even after major hepatectomy with a 50% Albumin synthesis
loss of functional liver tissue, blood lactate concen- Hypoalbuminaemia results
trations remain unchanged, underlining the func- in metabolic alkalosis
tional reserve of a healthy liver to counterbalance
lactic acidosis.18 After hepatic uptake, lactate is first
converted to pyruvate and then retransformed to
glucose in a process called gluconeogenesis.
Together, the release of lactate from the working
muscle and its retransformation to glucose in the
liver is called the Cori Cycle, and it releases
equimolar amounts of HCO 3.
19 Fig. 1. Summary of the physiological role of the healthy liver in maintaining acid-base

Albumin synthesis to urea, which can be excreted via urine. The process
of urea production consumes equal amounts of the
In the physiological range of blood pH, albumin strong base HCO 6
3 . Therefore, urea production is
behaves as a weak acid. Hypoalbuminaemia due not only a detoxification process; it may also play a

Review
to decreased production (e.g., in liver disease or role in acid-base regulation.26 Indeed, early studies
malnutrition) or increased loss (e.g., nephrotic syn- suggested that the liver has a direct acid-base regu-
drome, intestinal loss or large, chronic wounds) lating effect by altering ureagenesis and therefore
results in mild metabolic alkalosis. In contrast, HCO 5,25
3 consumption. However, these results could
hyperalbuminaemia, which can be seen in patients not be reproduced in other studies.27–31 Furthermore,
with severe dehydration but is rarely observed, ureagenesis, an acidifying process, increased rather
contributes to mild metabolic acidosis.20,21 than decreased in experimental human acidosis.32
Boon et al.33,34 showed that the reduction of urea syn-
Ketogenesis and ketoacidosis thesis in acute and chronic acidosis was due to a
marked decrease of hepatic amino acid transport
Keto acids are produced in the mitochondria of the and uptake, rather than a change in the activity of
liver when carbohydrate or fat is incompletely oxi- the ornithine cycle per se. In summary, ureagenesis
dised. The keto acids, 3-hydroxybutyric acid and has no discernible homeostatic effect on acid-base
acetoacetic acid dissociate at physiologic pH, equilibrium in humans.
resulting in increased H+ concentration, and may
ultimately lead to ketoacidosis. Therefore, the net
production of keto acids as well as their urinary The physical-chemical acid-base model
excretion is controlled by a feedback mechanism,
leading to reduced endogenous acid production if Traditional acid-base analysis according to Siggaard-
pH decreases22 and increased keto acid production Andersen acknowledges the influence of PaCO2, as
if pH rises.23 This rapid up- or downregulation well as organic acids and is based on blood pH.8 How-
applies both to hepatic ketogenesis and lactate pro- ever, it neglects the effects of electrolytes and weak
duction. It can be sustained and it reverses com- acids (albumin and phosphate) on acid-base balance.
pletely as an acid-base challenge disappears.24 The more recent physical-chemical acid-base
Hepatic ketogenesis and its regulation are negligi- approach according to Stewart integrates all poten-
ble and do not cause relevant acidosis under nor- tial modifiers of the acid-base balance.9 While Ste-
mal conditions. However, starvation or massive wart originally proposed a somewhat complex
alcohol consumption can cause ketogenesis with mathematical model, the simplified model by Gilfix ⇑ Corresponding author. Address:
substantial metabolic acidosis. et al. describes all possible metabolic acid-base disor- Department of Respiratory and
ders based on base excess (BE) subsets (Fig. 2).20 It Critical Care Medicine, Otto
Urea production includes BE changes explained by variations in the Wagner Spital, Sanatoriumstrasse
2, 1140 Vienna, Austria. Tel.: +43 1
following variables: (i) water (plasma dilution/con- 91060 41008; fax: +43 1 91060
The neurotoxic weak acid NH4 arises during protein centration), (ii) chloride (Cl), (iii) albuminaemia, (iv) 49853.
breakdown, with a daily amount of approximately lactate and (v) unmeasured anions (UMA). Analogous E-mail address: georg-christian.
1 mol NH4 based on an average protein intake of to the regular BE, negative and positive values of BE [email protected] (G.-C.
Funk).
100 g per day.25 In the liver, NH4 is further processed subset indicate acidosis and alkalosis, respectively.

Journal of Hepatology 2017 vol. 67 j 1062–1073 1063

 Review
HCO3-
disease can result in a variety of acid-base
Key point disorders.2 Furthermore, extrahepatic organ dysfunc-
43 g/L
tion in liver cirrhosis (e.g., encephalopathy, renal dys-
While respiratory alkalosis Albumin-
is the most common acid-
function) may also cause or aggravate acid-base
24 mEq/L
base disorder in patients disorders.39 However, several studies using standard
with liver disease, a normal Lactate- techniques for determining metabolic or respiratory
pH and base excess do not Na+ acid-base disturbances, including pH-value, HCO 3
exclude underlying meta- (as a marker of plasma
dilution/concentration)
Unmeasured anions- and standard base excess, could not detect significant
bolic acid-base disorders.
metabolic acid-base abnormalities in liver dis-
140 mEq/L ease.30,31,37 In contrast, analyses performed using a
physical-chemical approach (as described earlier)9,38
Cl-
revealed several underlying acidifying and alkalinis-
102 mEq/L ing metabolic acid-base disorders.37 These acidifying
and alkalinising factors will be discussed. While the
treatment of extrahepatic conditions (e.g., hepatore-
nal syndrome) is not a focus of this review, specific
Cations Anions
therapeutic interventions to stabilise acid-base home-
Fig. 2. Gamblegram showing the variables included in the ostasis will be outlined.
physical-chemical acid-base approach as well as normal
values.
Alkalinising factors in patients with liver cirrhosis
(i) Plasma dilution due to an excess of free
water causes dilutional acidosis (Na+ normal
Even though several studies using standard tech-
value: 140 mEq/L): BENa = 0.3  (Na+measured niques for evaluating acid-base equilibrium could
 Na+normal); the multiplicator 0.3 derives from
not find any metabolic acid-base disorders, they
normal strong ion difference ¼ 40 mEq=L
the calculation of: normal Naþ value ¼ 140 mEq=L reported the most well-established acid-base disorder
Review

as any differences from normal strong ion dif- in chronic liver disease, respiratory alkalosis,30,31,40–42
ference result in the respective BE changes. with a more pronounced hypocapnia in patients with
(ii) Loss and retention of HCO 3 followed by severe liver disease or viral hepatitis.37,43,44 While the
changes in serum chloride result in reason for this commonly observed respiratory acid-
hyperchloraemic acidosis and hypochloraemic base disorder is not ultimately clear, there are several
alkalosis, respectively: BE 
Cl = Clnormal  theories and underlying conditions leading to dysp-
(Clobserved  Na +
normal/Na +
observed ). noea and compensatory hyperventilation.45,46 While
(iii) Albumin is a weak, non-volatile acid. Thus, massive ascites and/or hepatic hydrothorax47 cause
hypoalbuminaemia represents a lack hypoxaemia and thus hyperventilation, hyperam-
of acid and results in hypoalbuminaemic alka- monaemia and hepatic encephalopathy48 induce
losis: BEalbuminaemia = (0.148  pH  0.818)  hyperventilation per se. A study by Lustik et al.49
(albuminaemianormal  albuminaemiaobserved). showed a correlation between increased progesterone
(iv) Hyperlactataemia results in lactic acidosis: and oestradiol levels (caused by impaired hepatic
BELactate = lactatenormal  lactatemeasured. metabolism in advanced liver disease) that may
(v) Any change in BE not caused by changes in free directly stimulate ventilation by the activation of pro-
water, chloride, albumin or lactate is attributed gesterone receptors in the central nervous system.
to UMA (e.g. ketone bodies and organic anions): Furthermore, dyspnoea can be aggravated in the case
BEUMA = BE (overall base excess)  of hepatopulmonary syndrome or portopulmonary
(BENa + BECl + BEalbuminaemia + BELactate). hypertension (Fig. 3).46,50,51
Some studies from the 1980s reported overt
In summary, BE is calculated as: BENa + BECl + metabolic alkalosis in patients with stable chronic
BEalbuminaemia + BELactate + BEUMA. Underlying acid- liver disease. It was hypothesised that decreased
base disorders might be overlooked when only hepatic urea cycle enzyme activity would result in
the overall BE is used as BEsubset changes may offset reduced bicarbonate elimination and thus metabolic
each other.20,35–37 alkalosis.5,6,25 However, this theory was challenged
While BENa- and BECl- deviations are clinically as metabolic alkalosis was not actually observed in any
important, changes in the plasma levels of inor- other patient populations with cirrhosis,29–31,37,52
ganic phosphate (Pi), potassium (K), magnesium unless patients were treated with diuretics, had
(Mg) and calcium (Ca) do not play an essential role; taken antacids, or showed secondary hyperaldos-
their serum levels are too low to have a significant teronism or low potassium levels.42,53 Furthermore,
impact on BE.37,38 the decrease in urea cycle enzyme activities seems
to result from reduced hepatic amino acid uptake
Acid-base disorders in liver disease in acute and chronic acidosis rather than from
downregulated enzyme activity.33,34
Considering the various physiologic functions of the A physical-chemical acid-base analysis37
liver, it seems obvious that advanced chronic liver revealed that hypoalbuminaemic alkalosis is the

1064 Journal of Hepatology 2017 vol. 67 j 1062–1073

 JOURNAL OF HEPATOLOGY
main alkalinising metabolic disorder in patients Reasons for hyperventilation
with cirrhosis. As albumin is a weak acid, a
decrease in albumin levels by 1 g/dl is followed
by an approximate base excess increase by I. Hyperammonaemia/hepatic
encephalopathy
3.7 mEq/L,20,54 which explains the fact that BEAlbu-
37
min increases with more severe liver disease. II. Central activation of progesterone/
However, hypoalbuminaemia may already be pre- estradiol receptors
sent in the early stages of liver cirrhosis as a result
of diminished protein intake, increased protein III. Dyspnoea from the following causes:
requirements and altered protein and amino acid
• Hepatopulmonary syndrome
metabolism.55 Therefore, it can be postulated that /portopulmonary hypertension
hypoalbuminaemia represents a major alkalinising
• Hepatic hydrothorax
factor that is present in a large majority of patients
• Elevated diaphragm/Atelectasis due
with cirrhosis;44 hypoalbuminaemia is also a com- to large volume ascites
mon reason for metabolic alkalosis in critically ill
patients.37,56

Acidifying factors in patients with liver cirrhosis

In compensated liver cirrhosis, the aforementioned Fig. 3. Mechanisms of hyperventilation and respiratory alkalosis in liver disease.
alkalinising acid-base disorders are partially bal-
anced by several counteracting acidifying disorders
that are discussed in this section.37
Hyponatraemia is a common finding in cirrho- diuretic-hormone (ADH)-release followed by
sis57,58 and almost 50% of ascites patients present tubular water reabsorption and the activation of

Review
with serum sodium levels below the physiological the sympathetic nervous system.57,58,60,61 This
range.59 Hyponatraemia in cirrhosis is a phe- hypervolemia results in dilutional hyponatraemia.
nomenon caused by portal hypertension-induced Therefore, dilution with free water (pH = 7.00)
systemic, especially splanchnic, vasodilation. This plays a role in hyponatraemia and has an acidifying
results in a relative decrease of effective circulating effect on plasma (pH 7.40).37,44 Furthermore,
blood volume. To compensate for this arterial hyponatraemia is often aggravated by repeated
‘‘underfilling”, water and sodium retention occurs paracentesis (which temporarily activates water-
through activation of the renin-angiotensin- retention mechanisms during post-paracentesis cir-
aldosterone system (RAAS), non-osmotic, anti- culatory dysfunction, when sufficient volume

Hepatic encephalopathy Cholestatic liver disease,

Chronic respiratory Alcohol abuse
+ lactulose therapy
alkalosis Wilson’s disease
(overdose)

↓ Tubular H+ ion secretion Renal tubular acidosis type I:

↓ Acid excretion Diarrhoea Defect in distal tubular
↑ Bicarbonate excretion ↑ Bicarbonate loss H+ secretion causes
↓ Bicarbonate reabsorption high urinary pH

↑ Tubular chloride reabsorption

Hyperchloraemic metabolic acidosis

Renal tubular acidosis type IV:

Hyperkalemia blocks H+ secretion Large volume saline infusion
and therefore NH3-production

Spironolactone treatment for

peripheral oedema/ascites

Fig. 4. Reasons for hyperchloraemic metabolic acidosis in patients with chronic liver disease.

Journal of Hepatology 2017 vol. 67 j 1062–1073 1065

 Review
expansion is not achieved) in patients with decom- Alkalosis Acidosis
pensated cirrhosis.62 A
Hyperchloraemic acidosis is another acidifying BEUMA
disorder that is frequently observed in cirrhosis
and in critically ill patients.63 In general this acid- BEAlbumin BESodium
base disorder is characterised by replacement of
bicarbonate with chloride, owing to various mech- BEChloride
anisms (Fig. 4).64 In stable cirrhosis, hyperchlo-
raemic acidosis might be considered a
compensation for chronic respiratory alkalosis. In
acute respiratory alkalosis, the compensatory
BESo
mechanism is based on alkaline titration of the B dium

body’s non-bicarbonate buffers,65 with plasma pro- BELac

teins and inorganic phosphate (Pi) being the most tate

BEAlb
important ones.38 These mechanisms occur within umin
BEUM
approximately 5–10 minutes, but have limited A

compensatory potential.65 In chronic respiratory BECh

alkalosis, the kidney reacts and reduces acid excre- loride

tion by lowering tubular hydrogen ion secretion,

which can be observed by a reduction in ammo-
nium excretion. Furthermore, bicarbonate excre-
tion is increased and a new steady state develops C
as the kidney chronically suppresses bicarbonate
reabsorption in return for an increased chloride
reabsorption, resulting in hyperchloraemic acidosis BEAlbumin BELactate
Review

(quantified by a negative BEChloride). This adaptation

takes approximately two to three days, but has a
high compensatory potential.65–68
Diarrhoea and the associated gastrointestinal
HCO 
3 loss and Cl retention are another cause of
hyperchloraemic acidosis, especially in patients on
Fig. 5. Acid-base status in patients with chronic liver disease
Key point lactulose therapy (overdose) for hepatic using the physical-chemical approach: (A) Equilibrium of
encephalopathy,69 or in patients with alcoholic acidifying and alkalinising factors in stable cirrhosis; (B) Net
In stable liver cirrhosis, diarrhoea.70 In addition, distal renal tubular acido- metabolic acidosis in critically ill patients with cirrhosis; (C)
hypoalbuminaemic alkalosis Hypoalbuminaemic alkalosis ‘‘neutralises” lactic acidosis in acute
sis (RTA Type I), which is based on a defect in distal
is counteracted by hyper- liver failure. BE:Albumin Base excess due to the alkalinising effect of
chloraemic and dilutional tubular H+ secretion and followed by inadequately hypoalbuminaemia; BEUMA: Base excess due to the acidifying
acidosis resulting in normal high urinary pH ([5.3) during acidosis,63,71 may effect of unmeasured anions (e.g., keto acids); BESodium: Base
pH. occur principally in patients with cholestatic disor- excess due to the acidifying effect of plasma dilution by free
ders, such as primary biliary cholangitis (PBC),72 water; BEChloride: Base excess due to the acidifying effect of
hyperchloraemia; BELactate: Base excess due to the acidifying
Wilson’s disease, amyloidosis and glycogen storage
effect of elevated lactate.
disorders.69 Mild renal acidification defects were
found in patients with various chronic liver dis- important in critically ill patients with cirrhosis37,42
eases and might be explained by the impaired dis- and will be reviewed later.
tal renal Na+ delivery, followed by inadequate Cl
and H+ excretion.73 However, these defects were Balance of acidifying and alkalinising acid-base factors
more common in patients with PBC. In addition, in stable cirrhosis
missing urine acidification is often linked to
spironolactone-treatment, as hypoaldosteronism As shown in Fig.5A, several offsetting acidifying and
is associated with increasing serum potassium alkalinising metabolic factors can be observed in
blocking NH3-production and promoting metabolic stable chronic liver disease, leaving the overall BE
acidosis (known as RTA Type IV).70 Furthermore, and pH unchanged. It is unknown whether this bal-
hyperchloraemic acidosis is a potential limitation ance is a consequence of successful physiologic acid-
for the administration of large volume saline. It is base regulation to avoid overt acidosis and alkalosis,
an ongoing debate whether saline-induced hyper- or if it is a coincidental finding.
chloraemic acidosis also leads to unfavourable clin-
ical outcomes.74,75 Acid-base status in critically ill patients with
In patients with compensated cirrhosis, meta- cirrhosis
bolic acid-base disorders, based on lactate or
UMA, only play a minor role. However, lactate Gastrointestinal bleeding, hepatic encephalopathy,
and UMA, such as ketone bodies, may become acute renal failure, respiratory failure and sepsis

1066 Journal of Hepatology 2017 vol. 67 j 1062–1073

 JOURNAL OF HEPATOLOGY
Table 1. Complications in critically-ill cirrhotic patients with acidosis and comparison of adaptive mechanisms to acidosis in cirrhotic and liver-healthy subjects.

Complications in critically-ill cirrhotic patients with acidosis36,91–95

Complications:
 Development of acute on chronic liver failure (ACLF)
 Increased cardiac output/hyperdynamic circulation
 Lower systemic vascular resistance values
 More pronounced oxygen debt due to decreased oxygen extraction and impaired tissue perfusion
 Blood volume sequestration in the splanchnic venous plexus due to splanchnic vasodilation followed by effective hypovolemia and RAAS activation
leading to renal vasoconstriction and impaired renal function
 More pronounced septic shock-associated hyperlactatemia
 Adrenal insufficiency is common
 Elevated unmeasured anions in patients with liver disease
Adaptive mechanisms in patients with cirrhosis: Adaptive mechanisms in liver-healthy subjects:
 Delayed/missing lactate clearance associated with prolonged acidaemia  More rapid clearance/normalization of hyperlac-
 Susceptibility for extracellular oedema, ascites and pulmonary oedema – compli- tataemia potentially improving lactic acidosis
cating fluid resuscitation and therefore restoring kidney function  More aggressive fluid resuscitation potentially
improving UMA-acidosis

are the main reasons patients with cirrhosis are within the range of normal and lactate levels were
admitted to ICUs, and have high mortality not correlated with Child-Pugh score,37,82 indicating
rates.36,76 Next to severity of pre-existing liver dis- no direct correlation with the severity of compen-
ease quantified by Child-Pugh-Score,77 for example, sated liver disease. Nevertheless, liver function and
development of organ failure resulted in signifi- lactate clearance are further compromised in the
cantly elevated 30-day mortality rates of over presence of acute illness.85,86 A dysfunctional liver
50%.78 From an acid-base point of view, in a study may even become a net lactate producer in sepsis.

Review
of 181 critically ill patients with cirrhosis, 39% of While the splanchnic area was reported to be a
patients presented with acidaemia and 27% with major source of lactate production in patients with
alkalaemia at the time of ICU admission. In these sepsis and acute liver dysfunction,87 others could
patients, the overall BE was substantially decreased not confirm these results and reported a net
and the metabolic acid-base disorders due to splanchnic lactate production in only 7% of patients
hypoalbuminaemia, hyperchloraemia, elevated lac- with sepsis.12 However, both studies were not per-
tate and UMA were also profoundly different from formed in a population of patients with cirrho-
those observed in patients with compensated cir- sis.87,88 An experimental study (animal model of
rhosis (Table 1).36,37 Therefore, unlike patients with sepsis) showed that the liver can become a major
compensated cirrhosis, critically ill patients with site of acid production in early sepsis, as measured
cirrhosis showed net metabolic acidosis, owing to by the strong-ion difference.89 Another study sug-
UMA, lactic acidosis and mild dilutional acidosis gested that the elevated lactate levels in patients
compensated by hypoalbuminaemic alkalosis with liver disease are a result of defects in hepatic
(Fig. 5B). Acute renal failure was associated with pyruvate metabolism with a reduction in hepatic
an even more negative BE and BEUMA. Acute renal gluconeogenesis following severe hepatic necrosis.90
failure and the presence of acidaemia and lactic aci- In conclusion, complex disturbances of lactate meta-
dosis were independently associated with bolism can be found in acute and chronic liver dis-
increased ICU mortality.36 ease. More studies directly targeting this question
Lactic acidosis is a common finding in ICU are needed.
patients.79 Considerable progress has been made Dichloroacetate, a drug stimulating the enzyme
in understanding hyperlactataemia in sepsis, which pyruvate dehydrogenase and therefore reducing
is not only driven by overproduction due to tissue pyruvate concentration as a substrate for lactate
hypoxia, dysfunction of the microcirculation80 and production,96 was tested as a treatment for lactic
increased glycolysis,81 but also by underutilisation acidosis.97 This drug was found to be safe in several
caused by impaired mitochondrial oxidation.79 Fur- settings, including patients with sepsis,98 patients
thermore, as 5% of lactate is metabolised by the with end-stage liver disease and patients with cir-
kidney, acute kidney injury (AKI) in the setting of rhosis undergoing orthotopic liver transplanta-
critical illness can worsen hyperlactataemia.82 tion.97,99 While dichloroacetate treatment
While the healthy liver has a huge functional significantly reduced lactate levels,52 no survival
reserve of metabolising lactate,18 this lactate clear- benefit was observed.100
ance is impaired in chronic liver diseases because Metformin-treatment in patients with diabetes
of a decrease in the functional hepatocyte and liver cirrhosis was thought to be associated with
mass.83,84 Accordingly, when compared to liver- an increased incidence of lactic acidosis.101 How-
healthy subjects, fasting lactate levels were signifi- ever, a recent study showed that metformin therapy
cantly elevated in patients with chronic liver dis- was not only safe in patients with cirrhosis, but it
eases.82 However, fasting lactate levels were still also improved survival in patients with diabetes

Journal of Hepatology 2017 vol. 67 j 1062–1073 1067

 Review

Review
1068

Table 2. Summary of specific therapeutic interventions in cirrhotic patients with acid-base balance disorders. PaO2 (mmHg), PaCO2 (mmHg), HCO3 (mEq/L), BE (mEq/L), Na (Sodium, mmol/L), K (Potassium, mmol/L),
Cl (Chloride, mmol/L), Ca (Calcium, mmol/L), Mg (Magnesium, mmol/L), Pi (Phosphate, mmol/L), Alb (Albumin, g/L), Crea (serum creatinine, mg/dL), Lactate (mmol/L), BEsubsets (mEq/L).

Case presentation Acid-base interpretation Clinical interpretation Further diagnostics and

treatment
55-year-old, stable cirrhotic patient (Child-Pugh B); Alkalaemic pH plus hypocapnia indicate respiratory This is the typical acid-base pattern of stable - Find and treat cause of hyper-
Acid-base status: alkalosis. Normal base excess (BE) excludes an cirrhosis (see chapter 3). Potential reasons for ventilation (chest x-ray, CT
pH 7.45; PaO2 55; PaCO2 31; HCO3 21.2; BE -2 overall metabolic acid-base disorder. Underlying hyperventilation are shown in Fig. 1. If severe scan to exclude atelectasis/
Lab: BE subsets show mild disorders offsetting each other. hyperventilation is present, consider: shunt in hypoxaemic patients)
Na 134; K 3.9; Cl 98; Ca 1.22; Mg 0.8; Pi 1.0; - Encephalopathy, - Lab: NH3
Alb 30.0; Crea 0.8; Lactate 1.3 - Ascites, - Echocardiography: systolic
BE subsets: - Dyspnoea/Hypoxaemia (e.g., due to pulmonary artery pressure
BEAlb 4; BENa -3; BECl -2; BEUMA -1; BELactate 0 hepatopulmonary syndrome or (sPAP)
portopulmonary hypertension). - Contrast-echocardiography (in
Journal of Hepatology 2017 vol. 67 j 1062–1073

hypoxaemic patients): intra-

pulmonary shunt?
50-year-old patient with alcoholic liver cirrhosis Acidaemic pH plus high PaCO2 indicate respiratory This acid-base pattern is found in patients with - Find and treat cause of
(Child-Pugh B) and known benzodiazepine abuse. acidosis. Normal BE excludes an overall metabolic alveolar hypoventilation (e.g., due to coma, hypoventilation
Admittance to the emergency department because acid-base disorder. Underlying BE subsets show mild intoxication). - Lab: NH3, ethanol, drug
of somnolence. disorders offsetting each other. screening
Acid-base status: - Consider antidote-treatment
pH 7.24; PaO2 50; PaCO2 65; HCO3 26.9; BE -1 (e.g. flumazenil)
Lab: - Consider mechanical ventila-
Na 133; K 3.9; Cl 97; Ca 1.22; Mg 0.8; Pi 1.0; Alb 29.0; tion (non-invasive ventilation)
Crea 0.7; Lactate 1.5
BE subsets:
BEAlb 3; BENa -3; BECl -1; BEUMA 0; BELactate –1
47-year-old patient with posthepatitic cirrhosis Acidaemic pH plus negative BE indicate metabolic This acid-base pattern is frequently found in - Find and treat cause of lactic
(Child-Pugh B) and large oesophageal varices. acidosis. Calculation of BE subsets reveals patients with shock (e.g. haemorrhagic, septic) acidosis
Admittance to the emergency department because lactic acidosis. but might also be drug-induced (e.g., metformin, - Assess haemodynamic
of severe variceal bleeding. betamimetics – compare chapter 4). situation
Acid-base status: - Consider ICU admission
pH 7.28; PaO2 85; PaCO2 32; HCO3 14.6; BE -11
Lab:
Na 130; K 4.1; Cl 95; Ca 1.22; Mg 0.85; Pi 1.05; Alb 30.0;
Crea 1; Lactate 7.3
BE subsets:
BEAlb 3; BENa -4; BECl -2; BEUMA -2; BELactate -6
46-year-old cirrhotic patient (Child-Pugh B) with Acidaemic pH plus negative BE indicate This acid-base pattern is found in cases of - Find and treat cause
sepsis due to spontaneous bacterial peritonitis. metabolic acidosis. Calculation of BE subsets reveals chloride-rich infusions (e.g., normal saline), - Measure glomerular filtration
Patient is treated at a normal ward and hyperchloraemic acidosis due to chloride-rich but also in patients with diarrhoea or rate
received 4 l NaCl 0.9% because of hypotension. infusions. renal-tubular acidosis (compare chapter 3). - Calculate urine anion gap
Acid-base status: - Measure urine pH
pH 7.31; PaO2 70; PaCO2 29; HCO3 14.2; BE -11
Lab:
Na 133; K 3.7; Cl 105; Ca 1.22; Mg 0.87; Pi 1.1; Alb 28.0;
Crea 0.9; Lactate 1.4
BE subsets:
BEAlb 4; BENa -3; BECl -10; BEUMA -1; BELactate -0
 40-year-old cirrhotic patient (Child-Pugh C) Acidaemic pH plus negative BE indicate metabolic This acid-base pattern is found in patients - Find and treat cause
undergoing large volume ascites paracentesis (10 l) acidosis. Calculation of BE subsets reveals acidosis with acidosis due to unmeasured anions - Test for urinary ketones
with state-of-the-art albumin substitution three due to unmeasured anions because of (e.g., ketoacidosis, uremic acidosis due to - Measure glomerular filtration
days before admittance. Patient is now presenting paracentesis-induced circulatory and acute renal failure, intoxications). rate
with somnolence at the emergency department. renal failure and uremic acidosis. - Correct hypovolemia (fluid
Acid-base status: challenge)
pH 7.26; PaO2 65; PaCO2 36; HCO3 15.6; BE -10 - Consider renal replacement
Lab: therapy
Na 129; K 7; Cl 95; Ca 1.22; Mg 1; Pi 1.3; Alb 25.0;
Crea 5.4; Lactate 2.3
BE subsets:
BEAlb 4; BENa -4; BECl -2; BEUMA -7; BELactate -1
60-year-old cirrhotic patient (Child-Pugh A) with Alkalaemic pH plus positive BE indicate metabolic This acid-base pattern is found in patients with - Find and treat cause
diuretically controlled ascites. Diuretic dose was alkalosis. Calculation of BE subsets reveals alkalosis due to hypochloraemia (e.g., vomiting, - Reconsider diuretic choice and
adjusted by the general practitioner one week ago hypochloraemic alkalosis caused by diuretics, gastric drainage, hypovolaemia). dose (e.g. consider acetazo-
because of lower leg oedema. diuretic overdose. lamide- treatment)
Acid-base status: - Consider potassium
pH 7.50; PaO2 70; PaCO2 37; HCO3 28.6; BE 6 replacement
Journal of Hepatology 2017 vol. 67 j 1062–1073

Lab:
Na 131; K 3.5; Cl 88; Ca 1.18; Mg 0.8; Pi 0.95; Alb 35.0;
Crea 0.9; Lactate 1.3
BE subsets:
BEAlb 2; BENa -3; BECl 7; BEUMA 0; BELactate 0
54-year-old non-cirrhotic patient presenting with Normal pH-value indicates no acid-base disorder. This acid-base pattern is typically found in - Find and treat cause
fulminant Hepatitis B after starting of anti-TNF-a- However, calculation of BE subsets reveals offsetting patients with acute liver failure (compare - Test for proteinuria
treatment for severe rheumatoid arthritis. Patient hypoalbuminaemic alkalosis and lactic acidosis. chapter 5). Hypoalbuminaemic alkalosis may - Consider careful albumin sub-
presents at the emergency department because of Furthermore, mild respiratory alkalosis is present. also be attributed to malnutrition or stitution in order to improve
progressive jaundice. nephrotic syndrome. anasarca and maintain ade-
Acid-base status: quate perfusion pressure
pH 7.41; PaO2 75; PaCO2 30; HCO3 18.6; BE -5
Lab:
Na 133; K 4; Cl 96; Ca 1.25; Mg 0.9; Pi 1; Alb 20.0; Crea
1.3; Lactate 6.5
BE subsets:

JOURNAL OF HEPATOLOGY
BEAlb 6; BENa -3; BECl 0; BEUMA -2; BELactate -6
IPS: intrapulmonary shunt; Hb: Haemoglobin; ICU: intensive care unit.
1069

Review
 Review
and cirrhosis due to non-alcohol-steatohepatitis was statistically significant, but still very small
(NASH). However, this study mainly included due to the buffered drug formulation.115 Therefore,
patients with Child-Pugh A liver disease. Metformin the finding that albumin infusion induced net
should be used with caution in patients with Child- metabolic acidaemia, as described earlier, might
Pugh B and C cirrhosis.102 also be explained by an increase in UMA due to
the high prevalence of coexisting renal failure in
this group.10
Acid-base disorders in acute liver failure (ALF)

Most patients with acute liver failure (ALF) have

Therapeutic implications
substantially elevated lactate levels. However,
these changes were observed without aci-
The monitoring of acid-base status using the simpli-
daemia.35,42,103 This counterintuitive phenomenon
fied physical-chemical model in patients with cir-
was described as ‘‘stress hyperlactataemia”,
rhosis has several potential therapeutic
resulting from a massive increase in glycolysis
consequences and is summarised in Table 2.
caused by catecholamine- and other cytokine-
While specific treatment of the underlying dis-
mediated increases in cellular glucose uptake
ease is the only intervention with a proven benefit
without hypoxia,104,105 as well as a reduction in
on mortality (e.g., bleeding control, antibiotic treat-
total body clearance.106 In accordance, net local
ment in the setting of sepsis), several supportive
production of lactate in the absence of hypoxia
therapies have the potential to improve patient
was observed in the splanchnic area107,108 and
management.11,116,117 In mechanically ventilated
the lungs, in the setting of ALF,109 after large
patients with cirrhosis and acidaemia due to meta-
burns,110 in pulmonary injury111 and in sepsis.112
bolic acidosis, hyperventilation mitigates the sever-
However, at physiological pH, lactic acid is almost
ity of acidaemia. Based on physiologic
completely dissociated into lactate and H+ and
considerations the targeted decrease in paCO2 from
should therefore cause metabolic acidosis.113,114
Review

40 mmHg (DpaCO2) should equal the observed

Accordingly, a study using the physical-chemical
decrease in standard base excess (DSBE).118 For
acid-base model9 revealed offsetting metabolic
example, in a patient with an SBE of 10 mmol/L
acid-base disorders (Fig. 5C). Lactic acidosis was
the target paCO2 is 30 mmHg (subtracting 10 from
compensated by pronounced hypoalbuminaemic
the normal paCO2 of 40 mmHg).
alkalosis in patients with non-paracetamol-
induced ALF, resulting in net respiratory alka-
laemia due to hyperventilation.35,103 Another
study reported an additional alkalinising effect Conclusions and outlook
Key point of hypochloraemia in patients with combined
severe hepatic and renal failure.10 While overt In healthy individuals, the most important hepatic
In acute liver failure, pro- metabolic acidosis seems to be rare in non- contributions to a stable acid-base state are lactate
nounced lactic acidosis is clearance and albumin production, while hepatic
paracetamol-induced ALF, there is conflicting data
counteracted by hypoalbu- ureagenesis does not represent a relevant acid-
minaemic alkalosis again
on patients with paracetamol-induced ALF.
Record et al. published a report on three patients base regulating mechanism. Patients with stable
resulting in normal pH.
with severe acidosis presenting at 48 hours after liver cirrhosis show an equilibrium between acidify-
paracetamol intoxication with high lactate levels; ing and alkalinising metabolic acid-base disorders,
the patients presented without clinical signs of resulting in a normal overall BE and pH. However,
liver failure, but with an obvious failure of gluco- during hepatic decompensation or critical illness,
neogenesis.103 Importantly, most patients with this equilibrium may be rapidly destabilised, most
ALF present with a stable overall acid-base state. often resulting in overt metabolic acidosis. Impor-
Whether the presence of these offsetting acid- tantly, a normal pH and BE do not exclude underly-
base disorders is a coincidence, or if the hypoal- ing metabolic acid-base disorders in patients with
buminaemia is a result of hyperlactatemia liver disease. Therefore, the physical-chemical
remains unclear.35 However, we believe that model of acid-base evaluation, which considers the
these beneficial disorders – in terms of acid- acid-base effects of albumin and electrolytes, should
base balance – are a result of ALF and do not rep- be applied to understand and properly treat the
resent a regulatory mechanism. It is of clinical underlying disorders in patients with acute and
importance to consider that correction of hypoal- chronic liver disease.
buminaemia by exogenous albumin infusions
might lead to net metabolic acidaemia, as
Financial support
observed in severely sick patients with hepatic
and renal failure.10 However, the acidifying effect
The authors received no financial support in relation
of 20% albumin solution (1 g/kg of bodyweight)
to the production of the manuscript.
infused in patients with intact liver function

1070 Journal of Hepatology 2017 vol. 67 j 1062–1073

 JOURNAL OF HEPATOLOGY
Conflict of interest Authors’ contributions
Key point
B.S. received travel support from Gilead. G.L., Br.S., Study conception and design: B.S., G.-C.F.; Selection
C.Z. and G.-C.F. have nothing to declare. T.R. of appropriate literature: B.S., G.-C.F.; Drafting of the When patients with liver cir-
rhosis get critically ill, the
received travel support from Boehringer- manuscript: B.S., T.R., M.T., G.-C.F.; Critical revision
acid-base equilibrium often
Ingelheim, Gore, Gilead, Roche and MSD; grant sup- of the manuscript for important intellectual con- tilts towards metabolic aci-
port from Abbvie, Boehringer-Ingelheim; served on tent: G.L., T.R., Br.S., M.T., C.Z., G.-C.F. dosis due to lactic acidosis
Advisory boards for Abbvie; and received lecture and unmeasured anions.
fees from Boehringer-Ingelheim, Gore, MSD and
Roche. M.T. serves as a consultant for Albireo, Falk, Supplementary data
Genfit, Gilead, Intercept, MSD, Novartis and Phenex
and is a member of the speakers’ bureau of Falk, Key point
Supplementary data associated with this article can
Gilead, MSD and Roche; received travel grants from be found, in the online version, at http://dx.doi.org/ The physical-chemical acid-
Falk, Roche and Gilead and unrestricted research 10.1016/j.jhep.2017.06.023. base model should be
grants from Albireo, Falk, Intercept, MSD and applied to diagnose and
Takeda and is also co-inventor of a patent on the properly manage underlying
medical use of norUDCA. disorders of acid-base home-
Please refer to the accompanying ICMJE disclo- ostasis in patients with acute
sure forms for further details. and chronic liver disease.

References [20] Gilfix BM, Bique M, Magder S. A physical chemical approach to the analysis of
acid-base balance in the clinical setting. J Crit Care 1993;8:187–197.
[1] Sacks GS. The ABC’s of acid-base balance. J Pediatr Pharmacol Ther [21] Funk GC. Stewart’s acid-base approach. Wien Klin Wochenschr
2004;9:235–242. 2007;119:390–403.

Review
[2] Bernardi M, Predieri S. Disturbances of acid-base balance in cirrhosis: a [22] Stinbaugh BJ, Marliss EB, Goldstein MB, Fox IH, Schloeder FX, Halperin ML.
neglected issue warranting further insights. Liver Int 2005;25:463–466. Mechanism for the paradoxical aciduria following alkali administration to
[3] Cohen RD. Roles of the liver and kidney in acid-base regulation and its prolonged-fasted patients. Metabolism 1975;24:915–922.
disorders. Br J Anaesth 1991;67:154–164. [23] Lipsky SR, Apler BJ, Rubini ME, Van Eck WF, Gordon ME. The effects of
[4] Halperin ML, Jungas RL. Metabolic production and renal disposal of hydrogen alkalosis upon ketone body production and carbohydrate metabolism in
ions. Kidney Int 1983;24:709–713. man. J Clin Invest 1954;33:1269–1276.
[5] Haussinger D, Steeb R, Gerok W. Metabolic alkalosis as driving force for urea [24] LaGrange BM, Hood VL. Ketoacid production in acute respiratory and
synthesis in liver disease: pathogenetic model and therapeutic implications. metabolic acidosis and alkalosis in rats. Am J Physiol 1989;256:F437–445.
Clin Invest 1992;70:411–415. [25] Haussinger D, Gerok W. Hepatic urea synthesis and pH regulation. Role of
[6] Haussinger D, Steeb R, Gerok W. Ammonium and bicarbonate homeostasis in CO2, HCO3-, pH and the activity of carbonic anhydrase. Eur J Biochem
chronic liver disease. Klin Wochenschr 1990;68:175–182. 1985;152:381–386.
[7] Henderson LJ. Das Gleichgewicht der Säuren und Basen im tierischen [26] Atkinson DE, Camien MN. The role or urea synthesis in the removal of
Organismus. Ergebnisse der Physiologie, biologischen Chemie und experimentel- metabolic bicarbonate and the regulation of blood pH. Curr Top Cell Regul
len Pharmakologie. 1909;8:254–325. 1982;21:261–302.
[8] Schwartz WB, Relman AS. A critique of the parameters used in the evaluation [27] Halperin ML, Chen CB, Cheema-Dhadli S, West ML, Jungas RL. Is urea
of acid-base disorders. ‘‘Whole-blood buffer base” and ‘‘standard bicarbon- formation regulated primarily by acid-base balance in vivo? Am J Physiol
ate” compared with blood pH and plasma bicarbonate concentration. N Engl J 1986;250:F605–612.
Med 1963;268:1382–1388. [28] Cheema-Dhadli S, Jungas RL, Halperin ML. Regulation of urea synthesis by
[9] Stewart PA. Modern quantitative acid-base chemistry. Can J Physiol Phar- acid-base balance in vivo: role of NH3 concentration. Am J Physiol 1987;252:
macol 1983;61:1444–1461. F221–225.
[10] Naka T, Bellomo R, Morimatsu H, et al. Acid-base balance in combined severe [29] Prytz H, Thomsen AC. Acid-base status in liver cirrhosis. Disturbances in
hepatic and renal failure: a quantitative analysis. Int J Artif Organs stable, terminal and portal-caval shunted patients. Scand J Gastroenterol
2008;31:288–294. 1976;11:249–256.
[11] Adrogue HJ, Madias NE. Management of life-threatening acid-base disorders. [30] Moreau R, Hadengue A, Soupison T, et al. Arterial and mixed venous acid-
First of two parts. N Engl J Med 1998;338:26–34. base status in patients with cirrhosis. Influence of liver failure. Liver
[12] De Backer D, Creteur J, Silva E, Vincent JL. The hepatosplanchnic area is not a 1993;13:20–24.
common source of lactate in patients with severe sepsis. Crit Care Med [31] Shangraw RE, Jahoor F. Effect of liver disease and transplantation on urea
2001;29:256–261. synthesis in humans: relationship to acid-base status. Am J Physiol
[13] Nielsen OB, Clausen T. The Na+/K(+)-pump protects muscle excitability and 1999;276:G1145–1152.
contractility during exercise. Exerc Sport Sci Rev 2000;28:159–164. [32] Hosch M, Muser J, Hulter HN, Krapf R. Ureagenesis: evidence for a lack of
[14] Rowell LB, Kraning 2nd KK, Evans TO, Kennedy JW, Blackmon JR, Kusumi F. hepatic regulation of acid-base equilibrium in humans. Am J Physiol Renal
Splanchnic removal of lactate and pyruvate during prolonged exercise in Physiol 2004;286:F94–99.
man. J Appl Physiol 1966;21:1773–1783. [33] Boon L, Blommaart PJ, Meijer AJ, Lamers WH, Schoolwerth AC. Acute acidosis
[15] Cohen RD. Some acid problems. J R Coll Physicians Lond 1982;16:69–79. inhibits liver amino acid transport: no primary role for the urea cycle in acid-
[16] Samsel RW, Cherqui D, Pietrabissa A, et al. Hepatic oxygen and lactate base balance. Am J Physiol 1994;267:F1015–1020.
extraction during stagnant hypoxia. J Appl Physiol 1991;70:186–193. [34] Boon L, Blommaart PJ, Meijer AJ, Lamers WH, Schoolwerth AC. Response of
[17] Goldstein PJ, Simmons DH, Tashkin DP. Effect of acid-base alterations on hepatic amino acid consumption to chronic metabolic acidosis. Am J Physiol
hepatic lactate utilization. J Physiol 1972;223:261–278. 1996;271:F198–202.
[18] Chiolero R, Tappy L, Gillet M, et al. Effect of major hepatectomy on glucose [35] Funk GC, Doberer D, Fuhrmann V, et al. The acidifying effect of lactate is
and lactate metabolism. Ann Surg 1999;229:505–513. neutralized by the alkalinizing effect of hypoalbuminemia in non-paraceta-
[19] Nöldge-Schomburg G, Armbruster K, Geiger K, Zander R. Experimentelle mol-induced acute liver failure. J Hepatol 2006;45:387–392.
Untersuchungen zum Säure-Basen-Haushalt und Laktatmetabolismus der [36] Funk GC, Doberer D, Kneidinger N, Lindner G, Holzinger U, Schneeweiss B.
Leber. Anästhesiol. Intensivmed. Notfallmed. Schmerzther. 1995;Sonderheft Acid-base disturbances in critically ill patients with cirrhosis. Liver Int
1(30):43–47. 2007;27:901–909.

Journal of Hepatology 2017 vol. 67 j 1062–1073 1071

 Review
[37] Funk GC, Doberer D, Osterreicher C, Peck-Radosavljevic M, Schmid M, is not geared to the defense of extracellular (H+). J Clin Invest
Schneeweiss B. Equilibrium of acidifying and alkalinizing metabolic acid- 1976;57:1483–1489.
base disorders in cirrhosis. Liver Int 2005;25:505–512. [68] Madias NE. Renal acidification responses to respiratory acid-base disorders. J
[38] Fencl V, Jabor A, Kazda A, Figge J. Diagnosis of metabolic acid-base Nephrol 2010;23:S85–91.
disturbances in critically ill patients. Am J Respir Crit Care Med [69] Ahya SN, Jose Soler M, Levitsky J, Batlle D. Acid-base and potassium disorders
2000;162:2246–2251. in liver disease. Semin Nephrol 2006;26:466–470.
[39] Peck-Radosavljevic M, Angeli P, Cordoba J, Farges O, Valla D. Managing [70] Gabow PA, Moore S, Schrier RW. Spironolactone-induced hyperchloremic
complications in cirrhotic patients. United European Gastroenterol J acidosis in cirrhosis. Ann Intern Med 1979;90:338–340.
2015;3:80–94. [71] Kocyigit I, Unal A, Kavuncuoglu F, et al. Renal tubular acidosis in renal
[40] Karetzky MS, Mithoefer JC. The cause of hyperventilation and arterial transplantation recipients. Ren Fail 2010;32:687–690.
hypoxia in patients with cirrhosis of the liver. Am J Med Sci [72] Golding PL, Mason AS. Renal tubular acidosis and autoimmune liver disease.
1967;254:797–804. Gut 1971;12:153–157.
[41] Mulhausen R, Eichenholz A, Blumentals A. Acid-base disturbances in patients [73] Batlle DC, Hizon M, Cohen E, Gutterman C, Gupta R. The use of the urinary
with cirrhosis of the liver. Medicine 1967;46:185–189. anion gap in the diagnosis of hyperchloremic metabolic acidosis. N Engl J
[42] Oster JR, Perez GO. Acid-base disturbances in liver disease. J Hepatol Med 1988;318:594–599.
1986;2:299–306. [74] Yunos NM, Bellomo R, Hegarty C, Story D, Ho L, Bailey M. Association
[43] Kaltsakas G, Antoniou E, Palamidas AF, et al. Dyspnea and respiratory muscle between a chloride-liberal vs. chloride-restrictive intravenous fluid admin-
strength in end-stage liver disease. World J Hepatol 2013;5:56–63. istration strategy and kidney injury in critically ill adults. JAMA
[44] Henriksen JH, Bendtsen F, Moller S. Acid-base disturbance in patients with 2012;308:1566–1572.
cirrhosis: relation to hemodynamic dysfunction. Eur J Gastroenterol Hepatol [75] Young P, Bailey M, Beasley R, et al. Effect of a buffered crystalloid solution vs.
2015;27:920–927. saline on acute kidney injury among patients in the intensive care unit: the
[45] Halank M, Strassburg CP, Hoeper MM. Pulmonary complications of liver SPLIT randomized clinical trial. JAMA 2015;314:1701–1710.
cirrhosis: hepatopulmonary syndrome, portopulmonary hypertension and [76] Thomson SJ, Moran C, Cowan ML, et al. Outcomes of critically ill patients
hepatic hydrothorax. Internist 2010;51:255–263. with cirrhosis admitted to intensive care: an important perspective from the
[46] Hoeper MM, Krowka MJ, Strassburg CP. Portopulmonary hypertension and non-transplant setting. Aliment Pharmacol Ther 2010;32:233–243.
hepatopulmonary syndrome. Lancet 2004;363:1461–1468. [77] Ho YP, Chen YC, Yang C, et al. Outcome prediction for critically ill cirrhotic
[47] Kiafar C, Gilani N. Hepatic hydrothorax: current concepts of pathophysiology patients: a comparison of APACHE II and Child-Pugh scoring systems. J
and treatment options. Ann Hepatol 2008;7:313–320. Intensive Care Med 2004;19:105–110.
[48] Heinemann HO. Respiration and circulation in patients with portal cirrhosis [78] Jalan R, Stadlbauer V, Sen S, Cheshire L, Chang YM, Mookerjee RP. Role of
of the liver. Circulation 1960;22:154–159. predisposition, injury, response and organ failure in the prognosis of patients
[49] Lustik SJ, Chhibber AK, Kolano JW, et al. The hyperventilation of cirrhosis: with acute-on-chronic liver failure: a prospective cohort study. Crit Care
Review

progesterone and estradiol effects. Hepatology 1997;25:55–58. 2012;16:R227.

[50] Rodriguez-Roisin R, Krowka MJ, Herve P, Fallon MB. Committee ERSTFP- [79] Kraut JA, Madias NE. Lactic acidosis. N Engl J Med 2014;371:2309–2319.
HVDS. Pulmonary-Hepatic vascular Disorders (PHD). Eur Respir J [80] Ince C. The microcirculation is the motor of sepsis. Crit Care 2005;9:
2004;24:861–880. S13–19.
[51] Krowka MJ. Portopulmonary hypertension: diagnostic advances and caveats. [81] Taylor DJ, Faragher EB, Evanson JM. Inflammatory cytokines stimulate
Liver Transpl 2003;9:1336–1337. glucose uptake and glycolysis but reduce glucose oxidation in human dermal
[52] Shangraw RE, Winter R, Hromco J, Robinson ST, Gallaher EJ. Amelioration of fibroblasts in vitro. Circ Shock 1992;37:105–110.
lactic acidosis with dichloroacetate during liver transplantation in humans. [82] Jeppesen JB, Mortensen C, Bendtsen F, Moller S. Lactate metabolism in
Anesthesiology 1994;81:1127–1138. chronic liver disease. Scand J Clin Lab Invest 2013;73:293–299.
[53] Casey TH, Summerskill WH, Bickford RG, Rosevear JW. Body and serum [83] Almenoff PL, Leavy J, Weil MH, Goldberg NB, Vega D, Rackow EC. Prolon-
potassium in liver disease. II. Relationships to arterial ammonia, blood Ph, gation of the half-life of lactate after maximal exercise in patients with
and hepatic coma. Gastroenterology 1965;48:208–215. hepatic dysfunction. Crit Care Med 1989;17:870–873.
[54] McAuliffe JJ, Lind LJ, Leith DE, Fencl V. Hypoproteinemic alkalosis. Am J Med [84] Woll PJ, Record CO. Lactate elimination in man: effects of lactate concen-
1986;81:86–90. tration and hepatic dysfunction. Eur J Clin Invest 1979;9:397–404.
[55] Kawaguchi T, Izumi N, Charlton MR, Sata M. Branched-chain amino acids as [85] Pastor CM, Billiar TR, Losser MR, Payen DM. Liver injury during sepsis. J Crit
pharmacological nutrients in chronic liver disease. Hepatology Care 1995;10:183–197.
2011;54:1063–1070. [86] Levraut J, Ciebiera JP, Chave S, et al. Mild hyperlactatemia in stable septic
[56] Story DA, Poustie S, Bellomo R. Quantitative physical chemistry analysis of patients is due to impaired lactate clearance rather than overproduction. Am
acid-base disorders in critically ill patients. Anaesthesia 2001;56:530–533. J Respir Crit Care Med 1998;157:1021–1026.
[57] Gines P, Berl T, Bernardi M, et al. Hyponatremia in cirrhosis: from [87] Douzinas EE, Tsidemiadou PD, Pitaridis MT, et al. The regional production of
pathogenesis to treatment. Hepatology 1998;28:851–864. cytokines and lactate in sepsis-related multiple organ failure. Am J Respir
[58] Sinha VK, Ko B. Hyponatremia in cirrhosis-pathogenesis, treatment, and Crit Care Med 1997;155:53–59.
prognostic significance. Adv Chronic Kidney Dis 2015;22:361–367. [88] Bakker J, Nijsten MW, Jansen TC. Clinical use of lactate monitoring in
[59] Angeli P, Wong F, Watson H, Gines P, Investigators C. Hyponatremia in cirrhosis: critically ill patients. Ann Intensive Care 2013;3:12.
Results of a patient population survey. Hepatology 2006;44:1535–1542. [89] Kellum JA, Bellomo R, Kramer DJ, Pinsky MR. Hepatic anion flux during acute
[60] John S, Thuluvath PJ. Hyponatremia in cirrhosis: pathophysiology and endotoxemia. J Appl Physiol 1995;78:2212–2217.
management. World J Gastroenterol 2015;21:3197–3205. [90] Bihari D, Gimson AE, Lindridge J, Williams R. Lactic acidosis in fulminant
[61] Bichet D, Szatalowicz V, Chaimovitz C, Schrier RW. Role of vasopressin in hepatic failure. Some aspects of pathogenesis and prognosis. J Hepatol
abnormal water excretion in cirrhotic patients. Ann Intern Med 1985;1:405–416.
1982;96:413–417. [91] Moreau R, Hadengue A, Soupison T, et al. Septic shock in patients with
[62] Doberer D, Funk GC, Schneeweiss B. Dilutional acidosis: an endless story of cirrhosis: hemodynamic and metabolic characteristics and intensive care
confusion. Crit Care Med 2003;31:337–338, [Author reply 338]. unit outcome. Crit Care Med 1992;20:746–750.
[63] Brunner R, Drolz A, Scherzer TM, et al. Renal tubular acidosis is highly [92] Kellum JA, Kramer DJ, Pinsky MR. Strong ion gap: a methodology for
prevalent in critically ill patients. Crit Care 2015;19:148. exploring unexplained anions. J Crit Care 1995;10:51–55.
[64] Koch SM, Taylor RW. Chloride ion in intensive care medicine. Crit Care Med [93] Sterling SA, Puskarich MA, Jones AE. The effect of liver disease on lactate
1992;20:227–240. normalization in severe sepsis and septic shock: a cohort study. Clin Exp
[65] Madias NE, Adrogue HJ. Cross-talk between two organs: how the kidney Emerg Med 2015;2:197–202.
responds to disruption of acid-base balance by the lung. Nephron Physiol [94] Nadim MK, Durand F, Kellum JA, et al. Management of the critically ill
2003;93:p61–66. patient with cirrhosis: A multidisciplinary perspective. J Hepatol
[66] Gennari FJ, Goldstein MB, Schwartz WB. The nature of the renal adaptation to 2016;64:717–735.
chronic hypocapnia. J Clin Invest 1972;51:1722–1730. [95] Myc LA, Stine JG, Chakrapani R, Kadl A, Argo CK. Vasopressin use in critically
[67] Cohen JJ, Madias NE, Wolf CJ, Schwartz WB. Regulation of acid-base ill cirrhosis patients with catecholamine-resistant septic shock: The CVICU
equilibrium in chronic hypocapnia. Evidence that the response of the kidney cohort. World J Hepatol 2017;9:106–113.

1072 Journal of Hepatology 2017 vol. 67 j 1062–1073

 JOURNAL OF HEPATOLOGY
[96] Shangraw RE, Jahoor F. Mechanism of dichloroacetate-induced hypolac- [108] Murphy ND, Kodakat SK, Wendon JA, et al. Liver and intestinal lactate
tatemia in humans with or without cirrhosis. Metabolism metabolism in patients with acute hepatic failure undergoing liver trans-
2004;53:1087–1094. plantation. Crit Care Med 2001;29:2111–2118.
[97] Stacpoole PW, Nagaraja NV, Hutson AD. Efficacy of dichloroacetate as a [109] Walsh TS, McLellan S, Mackenzie SJ, Lee A. Hyperlactatemia and pulmonary
lactate-lowering drug. J Clin Pharmacol 2003;43:683–691. lactate production in patients with fulminant hepatic failure. Chest
[98] Shangraw RE, Jahoor F, Wolfe RR, Lang CH. Pyruvate dehydrogenase 1999;116:471–476.
inactivity is not responsible for sepsis-induced insulin resistance. Crit Care [110] Wilmore DW, Aulick LH, Mason AD, Pruitt Jr BA. Influence of the burn
Med 1996;24:566–574. wound on local and systemic responses to injury. Ann Surg
[99] Shangraw RE, Rabkin JM, Lopaschuk GD. Hepatic pyruvate dehydrogenase 1977;186:444–458.
activity in humans: effect of cirrhosis, transplantation, and dichloroacetate. [111] Routsi C, Bardouniotou H, Delivoria-Ioannidou V, Kazi D, Roussos C,
Am J Physiol 1998;274:G569–577. Zakynthinos S. Pulmonary lactate release in patients with acute lung
[100] Stacpoole PW, Kerr DS, Barnes C, et al. Controlled clinical trial of injury is not attributable to lung tissue hypoxia. Crit Care Med
dichloroacetate for treatment of congenital lactic acidosis in children. 1999;27:2469–2473.
Pediatrics 2006;117:1519–1531. [112] Gore DC, Jahoor F, Hibbert JM, DeMaria EJ. Lactic acidosis during sepsis is
[101] Brackett CC. Clarifying metformin’s role and risks in liver dysfunction. J Am related to increased pyruvate production, not deficits in tissue oxygen
Pharm Assoc 2010;50:407–410. availability. Ann Surg 1996;224:97–102.
[102] Zhang X, Harmsen WS, Mettler TA, et al. Continuation of metformin use after [113] Sahlin K, Harris RC, Nylind B, Hultman E. Lactate content and pH in muscle
a diagnosis of cirrhosis significantly improves survival of patients with obtained after dynamic exercise. Pflugers Arch 1976;367:143–149.
diabetes. Hepatology 2014;60:2008–2016. [114] Gladden LB. Lactate metabolism: a new paradigm for the third millennium. J
[103] Record CO, Iles RA, Cohen RD, Williams R. Acid-base and metabolic Physiol 2004;558:5–30.
disturbances in fulminant hepatic failure. Gut 1975;16:144–149. [115] Bruegger D, Jacob M, Scheingraber S, et al. Changes in acid-base balance
[104] Mizock BA. Significance of hyperlactatemia without acidosis during hyper- following bolus infusion of 20% albumin solution in humans. Intensive Care
metabolic stress. Crit Care Med 1997;25:1780–1781. Med 2005;31:1123–1127.
[105] Mizock BA. Alterations in carbohydrate metabolism during stress: a review [116] Adrogue HJ, Madias NE. Management of life-threatening acid-base disorders.
of the literature. Am J Med 1995;98:75–84. Second of two parts. N Engl J Med 1998;338:107–111.
[106] Record CO, Chase RA, Williams R, Appleton D. Disturbances of lactate [117] Cabrera JL, Pinsky MR. Management of septic shock: a protocol-less
metabolism in patients with liver damage due to paracetamol overdose. approach. Crit Care 2015;19:260.
Metabolism 1981;30:638–643. [118] Schlichtig R, Grogono AW, Severinghaus JW. Human PaCO2 and standard
[107] Clemmesen JO, Hoy CE, Kondrup J, Ott P. Splanchnic metabolism of fuel base excess compensation for acid-base imbalance. Crit Care Med
substrates in acute liver failure. J Hepatol 2000;33:941–948. 1998;26:1173–1179.

Review

Journal of Hepatology 2017 vol. 67 j 1062–1073 1073