State of knowledge on ammonia handling by the kidney.

The disposal of ammonia, the main proton buffer in the urine, is important for acid-base homeostasis. Renal ammonia excretion is the predominant contributor to renal net acid excretion, both under basal condition and in response to acidosis. New insights into the mechanisms of renal ammonia production and transport have been gained in the past decades. Ammonia is the only urinary solute known to be produced in the kidney and selectively transported through the different parts of the nephron. Both molecular forms of total ammonia, NH3 and NH4+, are transported by specific proteins. Proximal tubular ammoniagenesis and the activity of these transport processes determine the eventual fate of total ammonia produced and excreted by the kidney. In this review, we summarized the state of the art of ammonia handling by the kidney and highlighted the newest processes described in the last decade.

The Role of the Endocrine System in the Regulation of Acid-Base Balance by the Kidney and the Progression of Chronic Kidney Disease.

Systemic acid-base status is primarily determined by the interplay of net acid production (NEAP) arising from metabolism of ingested food stuffs, buffering of NEAP in tissues, generation of bicarbonate by the kidney, and capture of any bicarbonate filtered by the kidney. In chronic kidney disease (CKD), acid retention may occur when dietary acid production is not balanced by bicarbonate generation by the diseased kidney. Hormones including aldosterone, angiotensin II, endothelin, PTH, glucocorticoids, insulin, thyroid hormone, and growth hormone can affect acid-base balance in different ways. The levels of some hormones such as aldosterone, angiotensin II and endothelin are increased with acid accumulation and contribute to an adaptive increase in renal acid excretion and bicarbonate generation. However, the persistent elevated levels of these hormones can damage the kidney and accelerate progression of CKD. Measures to slow the progression of CKD have included administration of medications which inhibit the production or action of deleterious hormones. However, since metabolic acidosis accompanying CKD stimulates the secretion of several of these hormones, treatment of CKD should also include administration of base to correct the metabolic acidosis.

The physiological consequences of a very large natural meal in a voracious marine fish, the staghorn sculpin (Leptocottus armatus).

Little information exists on physiological consequences when wild fish eat natural food. Staghorn sculpins at 10-13°C voluntarily consumed 15.8% of their body mass in anchovies. Gastric clearance was slow with >60% of the meal retained in the stomach at 48 h, and was not complete until 84 h. At 14-24 h post-feeding, pH was depressed by 3 units and Cl- concentration was elevated 2-fold in gastric chyme, reflecting HCl secretion, while in all sections of the intestine, pH declined by 1 pH unit but Cl- concentration remained unchanged. PCO2 and total ammonia concentration were greatly elevated throughout the tract, whereas PNH3 and HCO3- concentration were depressed. Intestinal HCO3- secretion rates, measured in gut sacs in vitro, were also lower in fed fish. Whole-animal O2 consumption rate was elevated approximately 2-fold for 72 h post-feeding, reflecting 'specific dynamic action', whereas ammonia and urea-N excretion rates were elevated about 5-fold. Arterial blood exhibited a modest 'alkaline tide' for about 48 h, but there was negligible excretion of metabolic base to the external seawater. PaCO2 and PaO2 remained unchanged. Plasma total amino acid concentration and total lipid concentration were elevated about 1.5-fold for at least 48 h, whereas small increases in plasma total ammonia concentration, PNH3 and urea-N concentration were quickly attenuated. Plasma glucose concentration remained unchanged. We conclude that despite the very large meal, slow processing with high efficiency minimizes internal physiological disturbances. This differs greatly from the picture provided by previous studies on aquacultured species using synthetic diets and/or force-feeding. Questions remain about the role of the gastro-intestinal microbiome in nitrogen and acid-base metabolism.

The AE4 transporter mediates kidney acid-base sensing.

The kidney plays a key role in the correction of systemic acid-base imbalances. Central for this regulation are the intercalated cells in the distal nephron, which secrete acid or base into the urine. How these cells sense acid-base disturbances is a long-standing question. Intercalated cells exclusively express the Na+-dependent Cl-/HCO3- exchanger AE4 (Slc4a9). Here we show that AE4-deficient mice exhibit a major dysregulation of acid-base balance. By combining molecular, imaging, biochemical and integrative approaches, we demonstrate that AE4-deficient mice are unable to sense and appropriately correct metabolic alkalosis and acidosis. Mechanistically, a lack of adaptive base secretion via the Cl-/HCO3- exchanger pendrin (Slc26a4) is the key cellular cause of this derailment. Our findings identify AE4 as an essential part of the renal sensing mechanism for changes in acid-base status.

Strong ions and charge-balance.

It has been shown that the ability to predict the pH in any chemically characterized fluid, together with its buffer-capacity and acid content can be based on the requirement of electroneutrality, conservation of mass, and rules of dissociation as provided by physical chemistry. More is not required, and less is not enough. The charge in most biological fluids is dominated by the constant charge on the completely dissociated strong ions but, nonetheless, a persistent narrative in physiology has problematized the notion that these have any role at all in acid-base homeostasis. While skepticism is always to be welcomed, some common arguments against the importance of strong ions are examined and refuted here. We find that the rejection of the importance of strong ions comes with the prize that even very simple systems such as fluids containing nothing else, or solutions of sodium bicarbonate in equilibrium with known tensions of CO2 become incomprehensible. Importantly, there is nothing fundamentally wrong with the Henderson-Hasselbalch equation but the idea that it is sufficient to understand even simple systems is unfounded. What it lacks for a complete description is a statement of charge-balance including strong ions, total buffer concentrations, and water dissociation.

A Randomized Study on the Effect of Dried Fruit on Acid-Base Balance, Diet Quality, and Markers of Musculoskeletal Health in Community Dwelling Adults.

OBJECTIVES: We tested whether 100 g/day of dried fruit (vs. no supplemental fruit control) for 6 months alters 24-hr urinary net acid excretion (NAE), bone resorption, weight, body composition, muscle performance, and diet quality. We explored consistency of self-selected dietary composition and potential renal acid load (PRAL). METHODS: This randomized, single-blind, 2-armed study included 83 normal- and over-weight men and postmenopausal women (age ≥50 years) on self-reported low fruit diets. Endpoints included group differences in NAE (primary), 24-hr urinary N-telopeptide (NTX), weight, body composition, muscle performance, and diet quality. RESULTS: At baseline, mean (±SD) age was 69 ± 8 years; 86% were Caucasian; body mass index was 24.5 ± 2.8 kg/m2; 46% female, and NAE was 32.4 ± 23.1 mmol with no significant baseline group differences. No significant group differences were noted in NAE (primary), NTX, weight, body composition, muscle performance or diet quality at 6 months. In the cohort as a whole, 6-month change in NAE was positively associated with change in NTX, but no significant associations were noted in other outcomes. PRAL on the day of the urine collection was positively associated with NAE. Comparison of two consecutive baseline 24-hr diet recalls revealed wide intra-individual variability in PRAL in self-selected diets in our participants. CONCLUSION: In this field study of older adults consuming self-selected diets, making one change to the diet by adding 100 g/day of dried fruit (equivalent to 4 servings per day) had no significant impact on NAE when compared to a no supplemental fruit control. This null finding may be attributable to the high day-to-day variability in consumption of foods affecting NAE. Added fruit also had no significant effect on weight, fat, muscle, or bone outcomes over a 6-month period.

Acid-base and hematological regulation in chicken embryos during internal progressive hypercapnic hypoxia.

Development of the capacity to mitigate potential disturbances to blood physiology in bird embryos is incompletely understood. We investigated regulation of acid-base and hematology in day 15 chicken embryos exposed to graded intrinsic hypercapnic hypoxia created by varying degrees of water submersion. Metabolic acidosis with additional respiratory or metabolic acidosis occurred at 2 h according to magnitude of submersion. Acid-base disturbance was partially compensated by metabolic alkalosis at 6 h, but compensatory metabolic alkalosis was absent at 24 h. Following submersion with only air cell exposed to air, both hypercapnic respiratory acidosis and metabolic acidosis occurred within 10 min. Subsequently, both forms of acidosis created lethal levels of [HCO3-] at ∼120 min. Blood hematology showed small but significant effects associated with induced acid-base disturbance. Increased Hct occurring during partial egg submersion lasting 24 h was attributed to an increase in MCV. By day 15 of development chicken embryos are able to partially compensate for and withstand all but severe induced internal hypoxic hypercapnia.

Acid content and buffer-capacity: a charge-balance perspective.

Rational treatment and thorough diagnostic classification of acid-base disorders requires quantitative understanding of the mechanisms that generate and dissipate loads of acid and base. A natural precondition for this tallying is the ability to quantify the acid content in any specified fluid. Physical chemistry defines the pH-dependent charge on any buffer species, and also on strong ions on which, by definition, the charge is pH-invariant. Based, then, on the requirement of electroneutrality and conservation of mass, it was shown in 1914 that pH can be calculated and understood on the basis of the chemical composition of any fluid. Herein we first show that this specification for [H+] of the charge-balance model directly delivers the pH-dependent buffer-capacity as defined in the literature. Next, we show how the notion of acid transport as proposed in experimental physiology can be understood as a change in strong ion difference, ΔSID. Finally, based on Brønsted-Lowry theory we demonstrate that by defining the acid content as titratable acidity, this is equal to SIDref - SID, where SIDref is SID at pH 7.4. Thereby, any chemical situation is represented as a curve in a novel diagram with titratable acidity = SIDref - SID as a function of pH. For any specification of buffer chemistry, therefore, the change in acid content in the fluid is path invariant. Since constituents of SID and titratable acidity are additive, we thereby, based on first principles, have defined a new framework for modeling acid balance across a cell, a whole organ, or the whole-body.

Acid-base disorders: A primer for clinicians.

An understanding of acid-base physiology is necessary for clinicians to recognize and correct problems that may negatively affect provision of nutrition support and drug therapy. An overview of acid-base physiology, the different acid-base disorders encountered in practice, a stepwise approach to evaluate arterial blood gases, and other key diagnostic tools helpful in formulating a safe and effective medical and nutrition plan are covered in this acid-base primer. Case scenarios are also provided for the application of principles and the development of clinical skills.

Kidney metabolism and acid-base control: back to the basics.

Kidneys are central in the regulation of multiple physiological functions, such as removal of metabolic wastes and toxins, maintenance of electrolyte and fluid balance, and control of pH homeostasis. In addition, kidneys participate in systemic gluconeogenesis and in the production or activation of hormones. Acid-base conditions influence all these functions concomitantly. Healthy kidneys properly coordinate a series of physiological responses in the face of acute and chronic acid-base disorders. However, injured kidneys have a reduced capacity to adapt to such challenges. Chronic kidney disease patients are an example of individuals typically exposed to chronic and progressive metabolic acidosis. Their organisms undergo a series of alterations that brake large detrimental changes in the homeostasis of several parameters, but these alterations may also operate as further drivers of kidney damage. Acid-base disorders lead not only to changes in mechanisms involved in acid-base balance maintenance, but they also affect multiple other mechanisms tightly wired to it. In this review article, we explore the basic renal activities involved in the maintenance of acid-base balance and show how they are interconnected to cell energy metabolism and other important intracellular activities. These intertwined relationships have been investigated for more than a century, but a modern conceptual organization of these events is lacking. We propose that pH homeostasis indissociably interacts with central pathways that drive progression of chronic kidney disease, such as inflammation and metabolism, independent of etiology.

Alkalosis-induced hypoventilation in cystic fibrosis: The importance of efficient renal adaptation.

The lungs and kidneys are pivotal organs in the regulation of body acid-base homeostasis. In cystic fibrosis (CF), the impaired renal ability to excrete an excess amount of HCO3- into the urine leads to metabolic alkalosis [P. Berg et al., J. Am. Soc. Nephrol. 31, 1711-1727 (2020); F. Al-Ghimlas, M. E. Faughnan, E. Tullis, Open Respir. Med. J. 6, 59-62 (2012)]. This is caused by defective HCO3- secretion in the ß-intercalated cells of the collecting duct that requires both the cystic fibrosis transmembrane conductance regulator (CFTR) and pendrin for normal function [P. Berg et al., J. Am. Soc. Nephrol. 31, 1711-1727 (2020)]. We studied the ventilatory consequences of acute oral base loading in normal, pendrin knockout (KO), and CFTR KO mice. In wild-type mice, oral base loading induced a dose-dependent metabolic alkalosis, fast urinary removal of base, and a moderate base load did not perturb ventilation. In contrast, CFTR and pendrin KO mice, which are unable to rapidly excrete excess base into the urine, developed a marked and transient depression of ventilation when subjected to the same base load. Therefore, swift renal base elimination in response to an acute oral base load is a necessary physiological function to avoid ventilatory depression. The transient urinary alkalization in the postprandial state is suggested to have evolved for proactive avoidance of hypoventilation. In CF, metabolic alkalosis may contribute to the commonly reduced lung function via a suppression of ventilatory drive.

Intestinal ion regulation exhibits a daily rhythm in Gymnocypris przewalskii exposed to high saline and alkaline water.

Naked carp (Gymnocypris przewalskii), endemic to the saline-alkaline Lake Qinghai, have the capacity to tolerate combinations of high salinity and alkalinity, but migrate to spawn in freshwater rivers each year. In this study, we measured the drinking rate over a 24 h period for naked carp exposed to saline-alkaline lake waters with salinities of 15 (L15) and 17 (L17). We also assessed the daily feed intakes of naked carp exposed to L15 and fresh water (FW). Additionally, we studied the daily expression of acid-base regulation and osmoregulation related genes and proteins in the intestine of naked carp exposed to saline-alkaline lake waters. Our results revealed that the drinking rate at night was significantly higher than in daytime when exposed to either L15 or L17, while feed intakes in daytime were significantly higher than at night. The relative expression of Na+/K+-ATPase α (NKA-α), solute carrier family members 26A6 (SLC26A6) and 4A4 (SLC4A4) in the intestine of naked carp exposed to L17 at night was higher than in daytime. Specifically, NKA-α mRNA expression at 4:00 was 7.22-fold and 5.63-fold higher than that at 10:00 and 16:00, respectively, and the expression at 22:00 was 11.29-fold and 8.80-fold higher than that at 10:00 and 16:00, respectively. Similarly, SLC26A6 mRNA expression was greatest at 22:00, exceeding that observed at 4:00, 10:00 and 16:00 by 3.59, 4.44 and 11.14-fold, respectively. Finally, the expression of NKA-α and SLC26A6 protein at the single cell level was also higher at night than during the day, which was 1.65-fold and 1.37-fold higher at 22:00 respectively compared to 16:00. Overall, the present findings revealed that naked carp drinks at night and feeds during the day, demonstrating that intestinal ion regulation exhibits a daily rhythm when exposed to high saline and alkaline lake water.

Trans-cerebral HCO3- and PCO2 exchange during acute respiratory acidosis and exercise-induced metabolic acidosis in humans.

This study investigated trans-cerebral internal jugular venous-arterial bicarbonate ([HCO3-]) and carbon dioxide tension (PCO2) exchange utilizing two separate interventions to induce acidosis: 1) acute respiratory acidosis via elevations in arterial PCO2 (PaCO2) (n = 39); and 2) metabolic acidosis via incremental cycling exercise to exhaustion (n = 24). During respiratory acidosis, arterial [HCO3-] increased by 0.15 ± 0.05 mmol ⋅ l-1 per mmHg elevation in PaCO2 across a wide physiological range (35 to 60 mmHg PaCO2; P < 0.001). The narrowing of the venous-arterial [HCO3-] and PCO2 differences with respiratory acidosis were both related to the hypercapnia-induced elevations in cerebral blood flow (CBF) (both P < 0.001; subset n = 27); thus, trans-cerebral [HCO3-] exchange (CBF × venous-arterial [HCO3-] difference) was reduced indicating a shift from net release toward net uptake of [HCO3-] (P = 0.004). Arterial [HCO3-] was reduced by -0.48 ± 0.15 mmol ⋅ l-1 per nmol ⋅ l-1 increase in arterial [H+] with exercise-induced acidosis (P < 0.001). There was no relationship between the venous-arterial [HCO3-] difference and arterial [H+] with exercise-induced acidosis or CBF; therefore, trans-cerebral [HCO3-] exchange was unaltered throughout exercise when indexed against arterial [H+] or pH (P = 0.933 and P = 0.896, respectively). These results indicate that increases and decreases in systemic [HCO3-] - during acute respiratory/exercise-induced metabolic acidosis, respectively - differentially affect cerebrovascular acid-base balance (via trans-cerebral [HCO3-] exchange).

[Acid-base balance and Stewart concept : Guide to routine daily use]. / Säure-Basen-Haushalt und Stewart-Konzept : Anleitung zum täglichen Gebrauch.

In 1981 the Canadian Peter Stewart presented a new concept for the interpretation of the acid-base balance. Rehm et al. published the first German language article on this topic. In 2007 the works of Deetjen and Lichtwarck-Aschoff as well as Funk presented both the physiological and clinical foundations of the Stewart concept as well as algorithms to interpret the acid-base status more precisely. Furthermore, since 2004 many other publications on the Stewart concept have been published, which have sometimes been controversially discussed and has not yet found its way into the everyday interpretation of blood gas analysis. This gap is intended to be filled by this work. It introduces a simple, practical algorithm and provides an approach to understanding the acid-base balance and the Stewart concept, which assumes that the plasma ions determine the pH value and the base excess (BE) in the plasma.

Effect of Waters Enriched in O2 by Injection or Electrolysis on Performance and the Cardiopulmonary and Acid-Base Response to High Intensity Exercise.

Several brands of water enriched with O2 (O2-waters) are commercially available and are advertised as wellness and fitness waters with claims of physiological and psychological benefits, including improvement in exercise performance. However, these claims are based, at best, on anecdotal evidence or on a limited number of unreliable studies. The purpose of this double-blind randomized study was to compare the effect of two O2-waters (~110 mg O2·L-1) and a placebo (10 mg O2·L-1, i.e., close to the value at sea level, 9-12 mg O2·L-1) on the cardiopulmonary responses and on performance during high-intensity exercise. One of the two O2-waters and the placebo were prepared by injection of O2. The other O2-water was enriched by an electrolytic process. Twenty male subjects were randomly allocated to drink one of the three waters in a crossover study (2 L·day-1 × 2 days and 15 mL·kg-1 90 min before exercise). During each exercise trial, the subjects exercised at 95.9 ± 4.7% of maximal workload to volitional fatigue. Exercise time to exhaustion and the cardiopulmonary responses, arterial lactate concentration and pH were measured. Oxidative damage to proteins, lipids and DNA in blood was assessed at rest before exercise. Time to exhaustion (one-way ANOVA) and the responses to exercise (two-way ANOVA [Time; Waters] with repeated measurements) were not significantly different among the three waters. There was only a trend (p = 0.060) for a reduction in the time constant of the rapid component of VO2 kinetics with the water enriched in O2 by electrolysis. No difference in oxidative damage in blood was observed between the three waters. These results suggest that O2-water does not speed up cardiopulmonary response to exercise, does not increase performance and does not trigger oxidative stress measured at rest.

Beyond the Plateau: pL Dependence of Proton Inventories as a Tool for Studying Ribozyme and Ribonuclease Catalysis.

Acid/base catalysis is an important catalytic strategy used by ribonucleases and ribozymes; however, understanding the number and identity of functional groups involved in proton transfer remains challenging. The proton inventory (PI) technique analyzes the dependence of the enzyme reaction rate on the ratio of D2O to H2O and can provide information about the number of exchangeable sites that produce isotope effects and their magnitude. The Gross-Butler (GB) equation is used to evaluate H/D fractionation factors from PI data typically collected under conditions (i.e., a "plateau" in the pH-rate profile) assuming minimal change in active site residue ionization. However, restricting PI analysis to these conditions is problematic for many ribonucleases, ribozymes, and their variants due to ambiguity in the roles of active site residues, the lack of a plateau within the accessible pL range, or cooperative interactions between active site functional groups undergoing ionization. Here, we extend the integration of species distributions for alternative enzyme states in noncooperative models of acid/base catalysis into the GB equation, first used by Bevilacqua and colleagues for the HDV ribozyme, to develop a general population-weighted GB equation that allows simulation and global fitting of the three-dimensional relationship of the D2O ratio (n) versus pL versus kn/k0. Simulations using the GPW-GB equation of PI results for RNase A, HDVrz, and VSrz illustrate that data obtained at multiple selected pL values across the pL-rate profile can assist in the planning and interpreting of solvent isotope effect experiments to distinguish alternative mechanistic models.

Approach to Patients With High Anion Gap Metabolic Acidosis: Core Curriculum 2021.

The anion gap (AG) is a mathematical construct that compares the blood sodium concentration with the sum of the chloride and bicarbonate concentrations. It is a helpful calculation that divides the metabolic acidoses into 2 categories: high AG metabolic acidosis (HAGMA) and hyperchloremic metabolic acidosis-and thereby delimits the potential etiologies of the disorder. When the [AG] is compared with changes in the bicarbonate concentration, other occult acid-base disorders can be identified. Furthermore, finding that the AG is very small or negative can suggest several occult clinical disorders or raise the possibility of electrolyte measurement artifacts. In this installment of AJKD's Core Curriculum in Nephrology, we discuss cases that represent several very common and several rare causes of HAGMA. These case scenarios highlight how the AG can provide vital clues that direct the clinician toward the correct diagnosis. We also show how to calculate and, if necessary, correct the AG for hypoalbuminemia and severe hyperglycemia. Plasma osmolality and osmolal gap calculations are described and when used together with the AG guide appropriate clinical decision making.

Acid-base transporters and pH dynamics in human breast carcinomas predict proliferative activity, metastasis, and survival.

Breast cancer heterogeneity in histology and molecular subtype influences metabolic and proliferative activity and hence the acid load on cancer cells. We hypothesized that acid-base transporters and intracellular pH (pHi) dynamics contribute inter-individual variability in breast cancer aggressiveness and prognosis. We show that Na+,HCO3- cotransport and Na+/H+ exchange dominate cellular net acid extrusion in human breast carcinomas. Na+/H+ exchange elevates pHi preferentially in estrogen receptor-negative breast carcinomas, whereas Na+,HCO3- cotransport raises pHi more in invasive lobular than ductal breast carcinomas and in higher malignancy grade breast cancer. HER2-positive breast carcinomas have elevated protein expression of Na+/H+ exchanger NHE1/SLC9A1 and Na+,HCO3- cotransporter NBCn1/SLC4A7. Increased dependency on Na+,HCO3- cotransport associates with severe breast cancer: enlarged CO2/HCO3--dependent rises in pHi predict accelerated cell proliferation, whereas enhanced CO2/HCO3--dependent net acid extrusion, elevated NBCn1 protein expression, and reduced NHE1 protein expression predict lymph node metastasis. Accordingly, we observe reduced survival for patients suffering from luminal A or basal-like/triple-negative breast cancer with high SLC4A7 and/or low SLC9A1 mRNA expression. We conclude that the molecular mechanisms of acid-base regulation depend on clinicopathological characteristics of breast cancer patients. NBCn1 expression and dependency on Na+,HCO3- cotransport for pHi regulation, measured in biopsies of human primary breast carcinomas, independently predict proliferative activity, lymph node metastasis, and patient survival.

The time to peak blood bicarbonate (HCO3-), pH, and the strong ion difference (SID) following sodium bicarbonate (NaHCO3) ingestion in highly trained adolescent swimmers.

The timing of sodium bicarbonate (NaHCO3) supplementation has been suggested to be most optimal when coincided with a personal time that bicarbonate (HCO3-) or pH peaks in the blood following ingestion. However, the ergogenic mechanisms supporting this ingestion strategy are strongly contested. It is therefore plausible that NaHCO3 may be ergogenic by causing beneficial shifts in the strong ion difference (SID), though the time course of this blood acid base balance variable is yet to be investigated. Twelve highly trained, adolescent swimmers (age: 15.9 ± 1.0 years, body mass: 65.3 ± 9.6 kg) consumed their typical pre-competition nutrition 1-3 hours before ingesting 0.3 g∙kg BM-1 NaHCO3 in gelatine capsules. Capillary blood samples were then taken during seated rest on nine occasions (0, 60, 75, 90, 105, 120, 135, 150, 165 min post-ingestion) to identify the time course changes in HCO3-, pH, and the SID. No significant differences were found in the time to peak of each blood measure (HCO3-: 130 ± 35 min, pH: 120 ± 38 min, SID: 98 ± 37 min; p = 0.08); however, a large effect size was calculated between time to peak HCO3- and the SID (g = 0.88). Considering that a difference between time to peak blood HCO3- and the SID was identified in adolescents, future research should compare the ergogenic effects of these two individualized NaHCO3 ingestion strategies compared to a traditional, standardized approach.

Alkalemia and Hepatic Encephalopathy in a Chronic Dialysis Patient.

Hepatic encephalopathy (HE) includes cognitive, psychiatric and neuromotor abnormalities observed from brain dysfunction secondary to liver disease and/or porto-systemic shunting. HE can have a wide range of clinical manifestations ranging from trivial lack of awareness, decreased attention span, personality changes to confusion, seizures, coma, and death. The onset of HE in cirrhosis is a poor prognostic factor. While HE has a complex pathogenesis which is not completely understood, hyperammonemia plays an important role in neurotoxicity and brain dysfunction. Alkalemia facilitates the conversion of NH4+ to NH3, which is free to cross the blood-brain barrier exacerbating HE. Prompt recognition and correction of underlying risk factors is central to the management of HE.