22nd June 2023

Disorders of acid-base and electrolytes

Disorders of acid-base

Metabolic acidosis

Metabolic acidosis is defined as a reduced serum pH (<7.35) with a reduced bicarbonate (<22 mmol/L).

In mild to moderate cases, there may be no symptoms of metabolic acidosis itself, but there may be symptoms of its underlying aetiology present, such as dehydration, vomiting or diarrhoea, lethargy or drowsiness in the case of poisoning, or signs of uraemia and fluid overload in the case of renal failure.

In severe cases, there may be evidence of attempted respiratory compensation with Kussmaul breathing (fast, deep breaths to offload CO₂ ), as well as cardiovascular effects such as cardiac arrythmias due to hyperkalaemia, peripheral venoconstriction and reduction in myocardial contractility in turn leading to decreased cardiac output and decrease in systemic blood pressure.

Anion Gap

The anion gap is the difference between the positive and the negative anions found in the body. This is calculated as follows:

Anion Gap (AG) = [Na⁺] – [Cl⁻ + HCO₃⁻]

All units in mmol/L
Normal range = 8-12 mmol/L

Some sources may include potassium in the calculation, but this is not something that has been traditionally included. The role of other anions and cations such as phosphate, sulphate, calcium and magnesium in the deriving of the formula have been left out here as beyond the scope of what is required for MRCP.

Patients who are known to have hypoalbuminaemia may have a falsely lowered anion gap on calculation. However, this can be corrected as follows:

Corrected Anion Gap (cAG) = AG + [0.25 x (40 – measured albumin g/L)]

Normal range = 8-12 mmol/L

Delta ratio

The delta gap can be used in the presence of a high anion gap metabolic acidosis (HAGMA) to assess whether the anion gap is in keeping with pure HAGMA or if there is evidence of co-existing normal anion gap metabolic acidosis or metabolic alkalosis (for example, chronic compensation of COPD).

The delta ratio can be calculated as follows:

Delta ratio =   [AG]-12 / 24-[HCO₃⁻]

Winter’s formula

Winter’s formula can be used in metabolic acidosis to calculate the expected pCO₂ and therefore ascertain if there is also a concurrent respiratory acidosis. If the measured pCO₂ is higher than the calculated pCO₂ , then it suggests that there is also respiratory acidosis present:

Calculated pCO₂ (mmHg) = [1.5 x HCO₃⁻ (mmol/L)] + 8 ± 2

mmHg can be converted to kPa as follows:

kPa = mmHg x 0.1333

The differentials for metabolic acidosis can be broadly separated into two categories: high anion gap and normal anion gap metabolic acidosis.

Metabolic acidosis and the anion gap

High Anion Gap Metabolic Acidosis (HAGMA)

When the corrected anion gap is greater than 12 mmol/L, it is classed as a high anion gap metabolic acidosis. The increase in the anion gap suggests that there are unmeasured anions causing this difference, a suggestion that can be seen in a number of the differential diagnoses associated with high anion gap metabolic acidosis.

A commonly used acronym to remember the causes of high anion gap metabolic acidosis is CAT MUDPILES:

C = Carbon monoxide, cyanide, congenital
A = Aminoglycosides
T = Theophylline, toluene (glue sniffing)

M = Methanol, metformin
U = Uraemia
D = (Diabetic) Ketoacidosis
P = Paraldehyde, paracetamol, propylene glycol
I = Isoniazid, iron
L = Lactic Acidosis
E = Ethanol/Ethylene Glycol
S = Salicylates

It is worth recalling that ketoacidosis is not only seen in diabetic patients on insulin or, more recently, SLGT2 inhibitors but can also be seen as a result of alcohol excess or starvation.

Management of these patients is based around correcting the underlying cause, i.e., treatment of DKA, consideration of dialysis in the uraemic patient, and antidote for poisoning as appropriate. In some cases, there may be a case for alkalisation with agents such as sodium bicarbonate; however, these decisions should generally be led by someone with experience in the use of sodium bicarbonate and is not appropriate in all cases of HAGMA. Before the commencement of sodium bicarbonate, potassium and calcium levels should be available as these can fall with bicarbonate administration.

Normal Anion Gap Metabolic Acidosis (NAGMA)

If the anion gap is within normal range, it is classed as a normal anion gap metabolic acidosis. It is sometimes also referred to as hyperchloremic metabolic acidosis, as in these patients, the body compensates for the loss of bicarbonate by increasing the reabsorption of chloride.

Compared to HAGMA, the list of differentials for NAGMA is much shorter:

C = Chloride excess
A= Addison’s disease, acetazolamide
G = GI causes – including diarrhoea, vomiting and fistulas (pancreatic, biliary, small bowel, ileostomy)
E = Extras – including renal tubular acidosis, spironolactone, hyperalimentation

Traditionally, the urinary anion gap had been used to delineate if the cause of a normal anion gap metabolic acidosis was from a renal or gastrointestinal source, but recent evidence has suggested this is not reliable due to its lack of correlation to urinary ammonium, and wide range of normal values in healthy individuals.

Like high anion gap metabolic acidosis, the management depends on the underlying aetiology. In the next section, we will cover renal tubular acidosis in more detail, including management where appropriate.

Renal Tubular Acidosis (RTA)

Type 1 Renal Tubular Acidosis

Type 1 RTA, also known as distal RTA, is caused by the failure of acid secretion of the alpha intercalated cells in the distal tubule. As a result, patients will have a urine pH >5.5, an inappropriate finding considering there is usually evidence of acidosis systemically with bicarbonate levels usually <15 mmol/L. Biochemistry will also show evidence of hypokalaemia, hypercalciuria and decreased citrate excretion with a normal anion gap metabolic acidosis. Hypokalaemia in these patients is driven by secondary hyperaldosteronism.

In a subset of patients with distal RTA, the inability to acidify urine is present without evidence of systemic acidosis. This is termed incomplete distal RTA.

Patients with distal RTA – due to alkalised urine, hypercalciuria and low urinary citrate – are prone to urinary stone formation and nephrocalcinosis, which in itself can cause distal RTA. They also undergo bone demineralisation causing rickets in children and osteomalacia in adults.

Causes for distal RTA include:

• Autoimmune disease – classically Sjogren’s syndrome but can also be seen with hypergammaglobulinemia or SLE.
• Chronic obstructive uropathy
• Cirrhosis
• Drugs – commonly associated medications include amphotericin B, ifosfamide and lithium.
• Hereditary – mutation of kidney band 3 anion transport protein is associated with distal RTA. It can be transmitted in both autosomal dominant and recessive fashions.
• Renal transplantation
• Sickle cell anaemia

Treatment of distal RTA is with sodium bicarbonate supplementation. The repletion of bicarbonate and sodium will lead to a reversal of secondary hyperaldosteronism and the resolution of hypokalaemia. In some cases, potassium citrate can be given to increase potassium levels, as well as reduce the risk of exacerbating stone disease (which can be an associated risk of using sodium bicarbonate or sodium citrate).

Type 2 Renal Tubular Acidosis

Whilst distal RTA is due to an inability to clear hydrogen ions, proximal RTA (otherwise known as Type 2 RTA) derives from a failure in reabsorbing bicarbonate, leading to bicarbonate wasting in urine and subsequent systemic acidaemia. As the distal intercalated cells are still functioning, the urine is still able to acidify, meaning the same levels of urine alkalisation are not seen in proximal RTA that are seen in distal RTA.
Causes of proximal RTA include primary causes such as Fanconi’s syndrome or Lowe syndrome, familial causes such as cystinosis (abnormal accumulation of cystine crystals throughout the body) or Wilson’s disease, or acquired disorders such as amyloidosis, multiple myeloma, and exposures to heavy metals, ifosfamide or acetazolamide.

Fanconi’s syndrome refers to a generalised dysfunction of the proximal tubules, leading to inadequate reabsorption of multiple electrolytes, including glucose, phosphate, and bicarbonate. Due to the loss of phosphate, patients with Fanconi’s are at high risk of bone demineralisation causing osteomalacia in adults and rickets in children.

Causes of Fanconi’s syndrome can be inherited (either as a primary idiopathic cause or secondary to another process such as cystinosis, tyrosinaemia or Wilson’s disease), or acquired from intrinsic renal diseases such as interstitial nephritis, acute tubular nephrosis, Sjogren’s syndrome, myeloma, or amyloidosis. Drugs such as cisplatin, ifosfamide, sodium valproate, tenofovir and aminoglycoside antibiotics such as gentamicin can also cause Fanconi’s syndrome.

Management in Fanconi’s syndrome involves treatment of the metabolic acidosis with alkali such as bicarbonate or citrate, replacement of lost electrolytes and treatment of underlying cause if present.

Type 4 Renal Tubular Acidosis

Type 4 Renal Tubular Acidosis is noteworthy as the only RTA which causes a high rather than a low potassium. Type 4 RTA results from either a deficiency or lack of response to aldosterone on the distal tubule. As a result of the reduced excretion of potassium and hydrogen ions from this disturbance in aldosterone, a hyperkalaemic, normal anion gap metabolic acidosis can be seen. The hyperkalaemia also feeds back to affect the proximal tubule by reducing the amount of ammonia (NH₃) synthesised, leading to a further inability to excrete acid.

Type 4 RTA can be picked up on routine testing in patients with hyperkalaemia
Causes include:

• Medication – e.g. NSAIDs, ACE inhibitors and ARBs, ciclosporin and potassium sparing diuretics such as spironolactone and eplerenone.
• Primary hypoaldosteronism – commonly primary adrenal insufficiency but also includes congenital adrenal hyperplasia.
• Secondary hypoaldosteronism – stemming from diseases of the pituitary and hypothalamus, likely also affecting the adrenals.
• Hyporeninaemic hypoaldosteronism – commonly caused by diabetic nephropathy or chronic interstitial nephritis.
• Pseudohypoaldosteronism – genetic resistance to aldosterone that mimics hypoaldosteronism.

Management of Type 4 RTA involves treatment of the hyperkalaemia with dietary restriction and diuresis as required. If the underlying cause can be treated (such as primary adrenal insufficiency), this should be done. Some patients may also benefit from mineralocorticoid replacement, with careful monitoring for exacerbation of hypertension or oedema.

Type 3 Renal Tubular Acidosis

Amongst a series of rare disorders, type 3 renal tubular acidosis is rarer still. This is a mixed renal tubular acidosis involving the proximal and distal tubule and can be associated with congenital type II carbonic anhydrase deficiency. Information on type 3 renal tubular acidosis is limited to case reports and is highly unlikely to come up in an MRCP examination.

Disorders of electrolytes

Abnormalities of potassium balance

Liddle’s Syndrome

Liddle’s syndrome is a rare autosomal dominant disorder causing higher than normal activity of the epithelial sodium channel (ENaC). It is commonly asymptomatic and picked up on investigation of hypertension in a young person, but patients can also present with symptoms of hypokalaemia such as weakness, fatigue or palpitations.

Biochemically, these patients tend to have a metabolic alkalosis with high sodium and low potassium, similar to hyperaldosteronism. However, patients with Liddle’s syndrome tend to have low to normal aldosterone levels. The diagnosis is then made with genetic testing looking for a mutation in the associated gene (SCNN1A, SCNN1B or SCNN1G).

The first line of treatment for Liddle’s syndrome is amiloride, which blocks ENaC in the kidney. The use of other potassium sparing medications, such as spironolactone, tend to be ineffective in these patients as they act on aldosterone, which is already low in these patients. Patients are also advised to follow a low sodium diet.

Bartter Syndrome

Another rare cause of metabolic alkalosis with hypokalaemia is Bartter syndrome, an autosomal recessive disorder. Unlike the other causes discussed in this section, Bartter syndrome is generally diagnosed in neonates or those in the early years of life.

There are five subtypes of Bartter syndrome; three of the five subtypes (types 1, 2 and 4) are found neonatally, with some signs presenting in the antenatal period (such as polyhydramnios and prematurity of birth). After birth, these infants may present with polyuria and polydipsia, as well as lethargy and a failure to gain weight. If not recognised early and hydrated appropriately, these symptoms can be life threatening. Types 1 and 2 can cause hypercalciuria, and as a result, these patients may have nephrocalcinosis. Type 4 is associated with irreversible sensorineural deafness. The remaining subtypes (Type 3 and 5) generally present later, sometimes within the first two years of life but usually when school aged. Patients tend to present with symptoms of hypokalaemia, as well polydipsia, polyuria and salt craving.

Whilst simple biochemical findings such as potassium and bicarbonate are similar to Gitelman syndrome (see below), Bartter syndrome differentiates itself by high levels of renin and aldosterone, compared to Gitelman syndrome, in which these levels tend to be low.

Management of all subtypes involves adequate hydration, replacement of potassium and sodium through diet and supplementation, a potassium-sparing diuretic such as spironolactone, and NSAIDs such as indomethacin.

Gitelman Syndrome

In 1966, a physician by the name of Hillel Gitelman described in his paper “A new familial disorder characterised by hypokalaemia and hypomagnesemia” a pair of sisters with characteristics in keeping with Bartter’s syndrome but differing through also having hypomagnesaemia. This was later to be known as Gitelman syndrome.

Gitelman syndrome is an autosomal recessive disease affecting approximately 1 in 40000 of the Caucasian population. The clinical markers that would suggest this diagnosis are a metabolic acidosis with low levels of serum potassium, magnesium, chloride and sodium, and high levels of renin and aldosterone. Urinary biochemistry shows low levels of calcium as well as inappropriately high levels of potassium (considering serum hypokalaemia). Urinary chloride levels can also be useful as low urinary chloride would suggest gastrointestinal losses and point towards an alternative diagnosis such as bulimia or chronic diarrhoea.

Symptoms and severity can vary from person to person and tend to stem from the electrolyte abnormalities. These include muscle weakness, spasms, cramping, fatigue and paraesthesia. Some affected adults may also experience salt craving, polydipsia with polyuria, as well as chondrocalcinosis (accumulation of calcium in joints). QTc prolongation may also be seen on ECG and, in some cases, may lead to a fatal arrythmia. Blood pressure tends to be low.
The mainstay of treatment is supplementation of potassium and magnesium. Potassium-sparing diuretics may also be used.