Symptoms are not specific, and diagnosis can be difficult unless the patient presents with clear indications for arterial blood gas sampling. Symptoms may include chest pain, palpitations, headache, altered mental status such as

severe anxiety due to hypoxia, decreased visual acuity, nausea, vomiting, abdominal pain, altered appetite and weight gain, muscle weakness, bone pain, and joint pain. Those in metabolic acidosis may exhibit deep, rapid breathing called Kussmaul respirations which is classically associated with diabetic ketoacidosis. Rapid deep breaths increase the amount of carbon dioxide exhaled, thus lowering the serum carbon dioxide levels, resulting in some degree of compensation. Overcompensation via respiratory alkalosis to form an alkalemia does not occur.

Extreme acidemia leads to neurological and cardiac complications:

- Neurological: lethargy, stupor, coma, seizures

- Cardiac: arrhythmias (ventricular tachycardia) and decreased response to epinephrine, both leading to hypotension

Physical examination occasionally reveals signs of disease, but is otherwise normal. Cranial nerve abnormalities are reported in ethylene glycol poisoning, and retinal edema can be a sign of methanol intoxication. Longstanding chronic metabolic acidosis leads to osteoporosis and can cause fractures.

When acidosis is present on blood tests, the first step in determining the cause is determining the anion gap. If the anion gap is high (>12 mEq/L), there are several potential causes.

High anion gap metabolic acidosis is a form of metabolic acidosis characterized by a high anion gap (a medical value based on the concentrations of ions in a patient's serum). An anion gap is usually considered to be high if it is over 12 mEq/L.

High anion gap metabolic acidosis is caused generally by acid produced by the body. More rarely, high anion gap metabolic acidosis may be caused by ingesting methanol or overdosing on aspirin. The Delta Ratio is a formula that can be used to assess elevated anion gap metabolic acidosis and to evaluate whether mixed acid base disorder (metabolic acidosis) is present.

The list of agents that cause high anion gap metabolic acidosis is similar to but broader than the list of agents that cause a serum osmolal gap.

Metabolic acidosis is a condition that occurs when the body produces excessive quantities of acid or when the kidneys are not removing enough acid from the body. If unchecked, metabolic acidosis leads to acidemia, i.e., blood pH is low (less than 7.35) due to increased production of hydrogen ions by the body or the inability of the body to form bicarbonate (HCO) in the kidney. Its causes are diverse, and its consequences can be serious, including coma and death. Together with respiratory acidosis, it is one of the two general causes of acidemia.

Terminology :

- Acidosis refers to a process that causes a low pH in blood and tissues.

- Acidemia refers specifically to a low pH in the blood.

In most cases, acidosis occurs first for reasons explained below. Free hydrogen ions then diffuse into the blood, lowering the pH. Arterial blood gas analysis detects acidemia (pH lower than 7.35). When acidemia is present, acidosis is presumed.

Lactic acidosis is commonly found in people who are unwell, such as those with severe heart and/or lung disease, a severe infection with sepsis, the systemic inflammatory response syndrome due to another cause, severe physical trauma, or severe depletion of body fluids. Symptoms in humans include all those of typical metabolic acidosis (nausea, vomiting, generalized muscle weakness, and rapid breathing).

The Cohen-Woods classification categorizes causes of lactic acidosis as:

- Type A: Decreased tissue oxygenation (e.g., from decreased blood flow)

- Type B

- B1: Underlying diseases (sometimes causing type A)

- B2: Medication or intoxication

- B3: Inborn error of metabolism

Causes include:

The newest mnemonic was proposed in "The Lancet" reflecting current causes of anion gap metabolic acidosis:

- G — glycols (ethylene glycol & propylene glycol)

- O — oxoproline, a metabolite of paracetamol

- L — L-lactate, the chemical responsible for lactic acidosis

- D — D-lactate

- M — methanol

- A — aspirin

- R — renal failure

- K — ketoacidosis, ketones generated from starvation, alcohol, and diabetic ketoacidosis

The mnemonic MUDPILES is commonly used to remember the causes of increased anion gap metabolic acidosis.

- M — Methanol

- U — Uremia (chronic kidney failure)

- D — Diabetic ketoacidosis

- P — Paracetamol, Propylene glycol (used as an inactive stabilizer in many medications; historically, the "P" also stood for Paraldehyde, though this substance is not commonly used today)

- I — Infection, Iron, Isoniazid (which can cause lactic acidosis in overdose), Inborn errors of metabolism (an especially important consideration in pediatric patients)

- L — Lactic acidosis

- E — Ethylene glycol (Note: Ethanol is sometimes included in this mnemonic as well, although the acidosis caused by ethanol is actually primarily due to the increased production of lactic acid found in such intoxication.)

- S — Salicylates

Another frequently used mnemonic is KARMEL.

- K — Ketoacidosis

- A — aspirin

- R — Renal failure

- M — Methanol

- E — Ethylene glycol

- L — Lactic acidosis

Another frequently used mnemonic is KULT.

- K — Ketoacidosis (DKA, AKA)

- U — Uremia

- L — Lactic acidosis

- T — Toxins (Ethylene glycol, methanol, as well as drugs, such as aspirin, Metformin)

The preferred mnemonic of D. Robert Dufour, the chief of the Pathology and Laboratory Medicine Service, Veterans Affairs Medical Center, is DUMPSALE, which omits the I of MUDPILES as the proposed values of *I* are exceedingly rare in clinical practice.

- D — Diabetic ketoacidosis

- U — Uremia

- M — Methanol

- P — Paraldehyde

- S — Salicylates

- A — Alcoholic ketoacidosis

- L — Lactic acidosis

- E — Ethylene Glycol

The mnemonic for the [rare, in comparison] toxins is ACE GIFTs: Aspirin, Cyanide, Ethanolic ketosis, Glycols [ ethylene and propylene ], Isoniazid, Ferrous iron, Toluene. Most of these cause a lactic acidosis.

In general, the cause of a hyperchloremic metabolic acidosis is a "loss of base", either a gastrointestinal loss or a renal loss.

- Gastrointestinal loss of bicarbonate ()

- Severe diarrhea (vomiting will tend to cause hypochloraemic alkalosis)

- Pancreatic fistula with loss of bicarbonate rich pancreatic fluid

- Nasojejunal tube losses in the context of small bowel obstruction and loss of alkaline proximal small bowel secretions

- Chronic laxative abuse

- Renal causes

- Proximal renal tubular acidosis with failure of resorption

- Distal renal tubular acidosis with failure of secretion

- Long-term use of a carbonic anhydrase inhibitor such as acetazolamide

- Other causes

- Ingestion of ammonium chloride, hydrochloric acid, or other acidifying salts

- The treatment and recovery phases of diabetic ketoacidosis

- Volume resuscitation with 0.9% normal saline provides a chloride load, so that infusing more than 3-4L can cause acidosis

- Hyperalimentation ("i.e.", total parenteral nutrition)

The main causes of hypokalemic acidosis are systemic disorders that can be divided into:

- Carbonic anhydrase inhibitors such as acetazolamide

- Dialysis, in the post-treatment

- Diarrhea

- Renal tubular acidosis

- Treated DKA with insulin therapy

- VIPoma

Hypoglycemia is the central clinical problem, the one that is most damaging, and the one that most often prompts the initial diagnosis.

Maternal glucose transferred across the placenta prevents hypoglycemia in a fetus with GSD I, but the liver is enlarged with glycogen at birth. The inability to generate and release glucose soon results in hypoglycemia, and occasionally in lactic acidosis fulminant enough to appear as a primary respiratory problem in the newborn period. Neurological manifestations are less severe than if the hypoglycemia were more acute. The brain's habituation to mild hypoglycemia is at least partly explained by use of alternative fuels, primarily lactate.

More commonly, infants with GSD I tolerate without obvious symptoms a chronic, mild hypoglycemia, and compensated lactic acidosis between feedings. Blood glucose levels are typically 25 to 50 mg/dl (1.4–2.8 mM). These infants continue to need oral carbohydrates every few hours. Many never sleep through the night even in the second year of life. They may be pale, clammy, and irritable a few hours after a meal. Developmental delay is not an intrinsic or inevitable effect of glucose-6-phosphatase deficiency but is common if the diagnosis is not made in early infancy.

Although mild hypoglycemia for much of the day may go unsuspected, the metabolic adaptations described above make severe hypoglycemic episodes, with unconsciousness or seizure, uncommon before treatment. Episodes which occur are likely to happen in the morning before breakfast. GSD I is therefore a potential cause of ketotic hypoglycemia in young children.

Once the diagnosis has been made, the principal goal of treatment is to maintain an adequate glucose level and prevent hypoglycemia.

Hyperchloremic acidosis is a form of metabolic acidosis associated with a normal anion gap, a decrease in plasma bicarbonate concentration, and an increase in plasma chloride concentration (see anion gap for a fuller explanation). Although plasma anion gap is normal, this condition is often associated with an "increased" urine anion gap, due to the kidney's inability to secrete ammonia.

Intestinal involvement can cause mild malabsorption with steatorrhea, greasy stools, but usually requires no treatment.

Hypokalemic acidosis is a normal anion gap metabolic acidosis that has various direct and associated symptoms. Symptoms are associated with hypokalemia instead of hyperkalemia.

Nervous system involvement may be seen with acidosis and occurs more often with respiratory acidosis than with metabolic acidosis. Signs and symptoms that may be seen in acidosis include headaches, confusion, feeling tired, tremors, sleepiness, flapping tremor, and dysfunction of the cerebrum of the brain which may progress to coma if there is no intervention.

The differential diagnosis of normal anion gap acidosis is relatively short (when compared to the differential diagnosis of "acidosis"):

- Hyperalimentation

- Acetazolamide and other carbonic anhydrase inhibitors

- Renal tubular acidosis

- Diarrhea: due to a loss of bicarbonate. This is compensated by an increase in chloride concentration, thus leading to a normal anion gap, or hyperchloremic, metabolic acidosis. The pathophysiology of increased chloride concentration is the following: fluid secreted into the gut lumen contains higher amounts of Na than Cl; large losses of these fluids, particularly if volume is replaced with fluids containing equal amounts of Na and Cl, results in a decrease in the plasma Na concentration relative to the Clconcentration. This scenario can be avoided if formulations such as lactated Ringer’s solution are used instead of normal saline to replace GI losses.

- Ureteroenteric fistula - an abnormal connection (fistula) between a ureter and the gastrointestinal tract

- Pancreaticoduodenal fistula - an abnormal connection between the pancreas and duodenum

- Spironolactone

As opposed to high anion gap acidosis (which involves increased organic acid production), normal anion gap acidosis involves either increased production of chloride (hyperchloremic acidosis) or increased excretion of bicarbonate.

The most common clinical history in patients with glycogen-storage disease type 0 (GSD-0) is that of an infant or child with symptomatic hypoglycemia or seizures that occur before breakfast or after an inadvertent fast. In affected infants, this event typically begins after they outgrow their nighttime feeds. In children, this event may occur during acute GI illness or periods of poor enteral intake.

Mild hypoglycemic episodes may be clinically unrecognized, or they may cause symptoms such as drowsiness, sweating, lack of attention, or pallor. Uncoordinated eye movements, disorientation, seizures, and coma may accompany severe episodes.

Glycogen-storage disease type 0 affects only the liver. Growth delay may be evident with height and weight percentiles below average. Abdominal examination findings may be normal or reveal only mild hepatomegaly.Signs of acute hypoglycemia may be present, including the following:

Ketoacidosis is a metabolic state associated with high concentrations of ketone bodies, formed by the breakdown of fatty acids and the deamination of amino acids. The two common ketones produced in humans are acetoacetic acid and β-hydroxybutyrate.

Ketoacidosis is a pathological metabolic state marked by extreme and uncontrolled ketosis. In ketoacidosis, the body fails to adequately regulate ketone production causing such a severe accumulation of keto acids that the pH of the blood is substantially decreased. In extreme cases ketoacidosis can be fatal.

Ketoacidosis is most common in untreated type 1 diabetes mellitus, when the liver breaks down fat and proteins in response to a perceived need for respiratory substrate. Prolonged alcoholism may lead to alcoholic ketoacidosis.

Ketoacidosis can be smelled on a person's breath. This is due to acetone, a direct by-product of the spontaneous decomposition of acetoacetic acid. It is often described as smelling like fruit or nail polish remover. Ketosis may also give off an odor, but the odor is usually more subtle due to lower concentrations of acetone.

Treatment consists most simply of correcting blood sugar and insulin levels, which will halt ketone production. If the severity of the case warrants more aggressive measures, intravenous sodium bicarbonate infusion can be given to raise blood pH back to an acceptable range. However, serious caution must be exercised with IV sodium bicarbonate to avoid the risk of equally life-threatening hypernatremia.

In fructose bisphosphatase deficiency, there is not enough fructose bisphosphatase for gluconeogenesis to occur correctly. Glycolysis (the breakdown of glucose) will still work, as it does not use this enzyme.

Symptoms of high blood sugar including increased thirst (polydipsia), increased volume of urination (polyurea), and increase hunger (polyphagia).

Symptoms of HHS include:

- Altered level of consciousness

- Neurologic signs including: blurred vision, headaches, focal seizures, myoclonic jerking, reversible paralysis

- Motor abnormalities including flaccidity, depressed reflexes, tremors or fasiciculations

- Hyperviscosity and increased risk of blood clot formation

- Dehydration

- Weight loss

- Nausea, vomiting, and abdominal pain

- Weakness

- Low blood pressure with standing

In renal physiology, normal anion gap acidosis, and less precisely non-anion gap acidosis, is an acidosis that is "not" accompanied by an abnormally increased anion gap.

The most common cause of normal anion gap acidosis is diarrhea with a renal tubular acidosis being a distant second.

Without effective gluconeogenesis (GNG), hypoglycaemia will set in after about 12 hours of fasting. This is the time when liver glycogen stores have been exhausted, and the body has to rely on GNG. When given a dose of glucagon (which would normally increase blood glucose) nothing will happen, as stores are depleted and GNG doesn't work. (In fact, the patient would already have high glucagon levels.)

There is no problem with the metabolism of glucose or galactose, but fructose and glycerol cannot be used by the liver to maintain blood glucose levels. If fructose or glycerol are given, there will be a buildup of phosphorylated three-carbon sugars. This leads to phosphate depletion within the cells, and also in the blood. Without phosphate, ATP cannot be made, and many cell processes cannot occur.

High levels of glucagon will tend to release fatty acids from adipose tissue, and this will combine with glycerol that cannot be used in the liver, to make triacylglycerides causing a fatty liver.

As three carbon molecules cannot be used to make glucose, they will instead be made into pyruvate and lactate. These acids cause a drop in the pH of the blood (a metabolic acidosis). Acetyl CoA (acetyl co-enzyme A) will also build up, leading to the creation of ketone bodies.

In the fetus, the normal range differs based on which umbilical vessel is sampled (umbilical vein pH is normally 7.25 to 7.45; umbilical artery pH is normally 7.18 to 7.38). Fetal metabolic acidemia is defined as an umbilical vessel pH of less than 7.20 and a base excess of less than −8.

The major differential diagnosis is diabetic ketoacidosis (DKA). In contrast to DKA, serum glucose levels in HHS are extremely high, usually greater than 40-50 mmol/L (600 mg/dL). Metabolic acidosis is absent or mild. A temporary state of confusion (delirium) is also more common in HHS than DKA. HHS also tends to affect older people more. DKA may have fruity breath, and rapid and deep breathing.

DKA often has serum glucose level greater than 300 mg/dL (HHS is >600 mg/dL). DKA usually occurs in type 1 diabetics whereas HHS is more common in type 2 diabetics. DKA is characterized by a rapid onset, and HHS occurs gradually over a few days. DKA also is characterized by ketosis due to the breakdown of fat for energy.

Both DKA and HHS may show symptoms of dehydration, increased thirst, increased urination, increased hunger, weight loss, nausea, vomiting, abdominal pain, blurred vision, headaches, weakness, and low blood pressure with standing.

Because renal excretion is the primary means of eliminating acid from the body, there is consequently a tendency towards acidemia.

This leads to the clinical features of dRTA:

- Normal anion gap metabolic acidosis/acidemia

- Hypokalemia

- Urinary stone formation (related to alkaline urine, hypercalciuria, and low urinary citrate).

- Nephrocalcinosis (deposition of calcium in the substance of the kidney)

- Bone demineralisation (causing rickets in children and osteomalacia in adults)

The symptoms and sequelae of dRTA are variable and range from being completely asymptomatic, to loin pain and hematuria from kidney stones, to failure to thrive and severe rickets in childhood forms as well as possible renal failure and even death.

dRTA commonly leads to sodium loss and volume contraction, which causes a compensatory increase in blood levels of aldosterone. Aldosterone causes increased resorption of sodium and loss of potassium in the collecting duct of the kidney, so these increased aldosterone levels cause the hypokalemia which is a common symptom of dRTA.

Proximal RTA (pRTA) is caused by a failure of the proximal tubular cells to reabsorb filtered bicarbonate from the urine, leading to urinary bicarbonate wasting and subsequent acidemia. The distal intercalated cells function normally, so the acidemia is less severe than dRTA and the alpha intercalated cells can produce H to acidify the urine to a pH of less than 5.3. pRTA also has several causes, and may occasionally be present as a solitary defect, but is usually associated with a more generalized dysfunction of the proximal tubular cells called Fanconi syndrome, in which there is also phosphaturia, glycosuria, aminoaciduria, uricosuria, and tubular proteinuria.

The principle feature of Fanconi syndrome is bone demineralization (osteomalacia or rickets) due to phosphate wasting.

Distal RTA (dRTA) is the classical form of RTA, being the first described. Distal RTA is characterized by a failure of H+ secretion into lumen of nephron by the alpha intercalated cells of the medullary collecting duct of the distal nephron.

This failure of acid secretion may be due to a number of causes, and it leads to an inability to acidify the urine to a pH of less than 5.3. Because renal excretion is the primary means of eliminating from the body, there is consequently a tendency towards acidemia. There is an inability to excrete H while cannot be reclaimed by the cell, leading to acidemia (as builds up in the body) and hypokalemia (as cannot be reabsorbed by the alpha cell).

This leads to the clinical features of dRTA; In other words, the intercalated cells' apical H+/K+ antiporter is non-functional, resulting in proton retention and potassium excretion. Since calcium phosphate stones demonstrate a proclivity for deposition at higher pHs (alkaline), the substance of the kidney develops stones bilaterally; this does not occur in the other RTA types.

- Normal anion gap metabolic acidosis/acidemia

- Hypokalemia, Hypocalcemia, Hyperchloremia

- Urinary stone formation (related to alkaline urine, hypercalciuria, and low urinary citrate).

- Nephrocalcinosis (deposition of calcium in the substance of the kidney)

- Bone demineralisation (causing rickets in children and osteomalacia in adults)

- Sjogren's syndrome