The differential diagnosis of syndromes involving hypokalemia, metabolic alkalosis, and hypertension

While there are a number of conditions which can cause the combination of hypokalemia and metabolic alkalosis there are a limited number of disease processes which lead to hypokalemia, metabolic alkalosis, AND hypertension. In order to have hypertension in this setting, the pathological disease process must involve increased sodium (and water) reabsorption which leads to volume expansion and elevated blood pressure. The list of these diseases includes:

1. Liddle's syndrome. Autosomal dominant condition caused by a gain-of-function mutation in the epithelial sodium channel (ENaC) which results in increased Na+ reabsorption.

2. Licorice ingestion and the Syndrome of Apparent Mineralocorticoid Excess (SAME). Ingestion of large amounts of licorice (or licorice-containing tobacco or gun) can lead to inhibition of the enzyme 11-beta-hydroxysteroid dehydrogenase, which converts cortisol into the cortisone in aldosterone target tissues (e.g. collecting ducts). Since cortisol has an equal affinity for the mineralocorticoid receptor compared to aldosterone, it would act as the primary mineralocorticoid if it were not converted into the inactive cortisone. The compound in licorice that is responsible for this enzyme inhibitory activity is glycyrrhetinic acid, which also has some mild mineralocorticoid activity. The mechanism is similar in SAME, in which one has mutations in the 11-beta-hydroxysteroid dehydrogenase enzyme that prevent proper conversion of cortisol into cortisone.

3. Renal artery stenosis and renin secreting tumors. Both of these etiologies are the result of elevated production and secretion of renin leading to hyperaldosteronism.

4. Adrenal hyperfunction. This category includes causes of primary hyperaldosteronism, including adrenal adenoma, adrenal hyperplasis, and adrenal carcinoma.

All of these conditions essentially result in or mimic hyperaldosteronism and can be partly differentiated on the basis of the response of the renin-angiotensin-aldosterone system to the disease processes:

Liddle's -- low renin, low aldo
Licorice and SAME -- low renin, low aldo
Renal artery stenosis and renin-secreting tumors -- high renin, high aldo
Adrenal hyperfunction -- low renin, high aldo

Secondary forms of hypertension

Lisa Cohen recently summarized rare "genetic" forms of hypertension including Liddle's syndrome and PHA type II (Gordon's syndrome).

I want to summarize other causes of "secondary" hypertension which are not inherited (at least not typically in a Mendelian transmission) and which are potentially "fixable".

These phenotypes are distinct from primary hypertension which affects the vast majority of our patients. Secondary forms of hypertension affect typically less then <5% of patients with hypertension.

In order to identify a reversible cause for hypertension following data needs to be obtained:

• HPI
• Family history
• Physical exam
• Initial labs including Chem7, Lipid panel, Urine analysis, EKG
• Indications for further labs include abnormal initial tests (high Ca++ levels, low K+ levels), abrupt onset of hypertension, young age (<30),>50), hypertension resistant or refractory to 3+ medications, worsening hypertension in a previously well controlled patient, BP >180/110 at onset.
  

The most common forms of secondary hypertension are:

1. Renovascular hypertension
2. Coarctation of aorta
3. Cushing’s syndrome
4. Primary Aldosteronism
5. Thyroid/parathyroid disease
6. Pheochromocytoma

Typically others causes such as CKD or sleep apnea are not considered "secondary" forms of hypertension. Physical and laboratory findings can help and guide in ruling out secondary forms of hypertension: If you find this -> think this !!!

1. Truncal obesity and striae -> Cushing's syndrome
2. Labile hypertension -> Pheochromocytoma
3. Abdominal bruits -> renovascular hypertension
4. Decreased BP and Pulse in lower extremities -> Coarctation of aorta
5. Abdominal flank masses -> Polycystic kidney disease
6. Elevated Crea and/or abnormal UA -> parenchymal kidney disease
7. Hypercalcemia -> Hyperparathyrodism
8. Hypokalemia -> Hyperaldosteronism (also Cushing's syndrome and Pheochromocytoma can present with this).

Last but not least, a few more facts on the three most common secondary forms of hypertension:

1. Renovascular hypertension- Renal artery artherosclerosis (males>50, Fibromuscular dysplasia (females<40),Other (rarer) causes include vasculitis, scleroderma, Takayasu arteritis, etc. - Labs show typically hypokalemia and hyper-reninemic hyperaldosteronism - Screening tests recommended are Doppler US, MRA, CT angio, captopril renogram - Gold standard is arteriography which could show “string of beads” vs. single stenosis
2. Hyperaldosteronism: Aldo causes increased Na+ uptake in distal tubule -> increase in intravascular volume
   -Suspect in patients with unexplained low K+
   -Main causes are adrenal adenomas (~ 70%) and b/l adrenal hyperplasia (~ 25%)
   -Screening by checking stimulated PRA or PRC which will be undectable or low
   -Confirm screening tests with salt/fluid loading -> "elevated" Aldo level will NOT be suppressed
3. Pheochromocytoma:
   -Rare tumors arising from chromaffin tissue of the adrenal gland
   -90% occur in the adrenal medulla
   -10% are b/l, 10% are malignant and 10% are familial!
   -Associated with MEN II
   -Remember that 33-50% of patients have sustained hypertension !
   -Suspect it if refractory to treatment
   -Screen for serum or urine metanephrines
   -CT adrenals or/and MIBG scan (meta-iodo-benzyl-guanidine) to detect tumors

Pearls for Boards

1) Topiramate - Watch for non-gap acidosis, nephrolithiasis and hyperammonemia.

2) Jak2 - the intracellular kinase activated by the binding of Epo to the Epo receptor.

3) Live vaccines are contraindicated in kidney transplant recipients – these include MMR, Varicella, Yellow fever and BCG.

4) Liddle's, the opposite of Pseudohypoaldosteronism Type I - Gitelman's, the opposite of Pseudohypoaldosteronism Type II (also known as Gordon's syndrome).

5) Myeloma cast nephropathy - distal intratubular casts, Light Chain Fanconi Syndrome - proximal intracellular crystals.

Guyton was right all along: The primacy of the kidneys (and NaCl) in causing essential hypertension

Dr. Arthur C. Guyton (1919-2003) was one of the greatest physiologists of our time. One of Dr. Guyton’s many seminal contributions to medicine was to establish the role of kidneys in long-term blood pressure regulation via a mechanism known as pressure natriuresis.

Even though essential hypertension is considered a systemic multifactorial disorder associated with complex genetic traits, there is a significant amount of evidence supporting Guyton’s view, i.e. the kidneys play an important role in the genesis of hypertension via extracellular fluid volume (ECF) expansion caused by an intrinsic renal defect in sodium chloride excretion. Multiple observations support this hypothesis:

(1) Essential hypertension is cured when rats and patients receive a kidney transplant. If essential hypertension was a systemic disease that secondarily involved the kidney, then a well-tolerated allograft would not cure that disease. In contrast, hypertension went into remission after kidney transplantation.

(2) Multiple epidemiological observations have clearly shown that essential hypertension is rarer in societies consuming a low salt diet. For instance, the Yanomami Indians, a tribe of the Amazon rainforest that has had very little contact with the Western civilization, have a very low sodium intake as demonstrated by their 24-h urine Na+ excretion of 0.9 mEq. The mean systolic and diastolic blood pressure levels in Yanomami Indians are 95.4 and 61.4 mmHg respectively.

(3) Many mendelian forms of hypertension such as Liddle syndrome , Gordon syndrome , and Activating Mutation of Mineralocorticoid Receptor are associated with mutations in genes that encode renal sodium transporter proteins or related molecules.

(4) Many population studies have identified single nucleotide polymorphisms and haplotypes in genes encoding renal sodium transporter proteins or related molecules such as ENaC or WNK1 that are associated with blood pressure variation, hypertension severity, and response to certain diuretics.

Nephrologists could proudly say now, thanks to Dr. Guyton, that blood pressure “goes with the kidney”.

Classification of Metabolic Alkalosis

Dr John Gennari had another typically excellent review of metabolic alkalosis in AJKD in October. He suggests an alternative means of classifying a metabolic alkalosis according to the etiology of the alkalosis along with the physiological basis for the maintenance of the alkalosis once it has occurred. He also goes into some detail explaining the key role that chloride depletion has in the development and maintenance of a metabolic alkalosis.

The 3 subtypes that he suggested are:

1. Secondary stimulation of collecting duct ion transport:

This is the commonest type and results largely from a secondary increase in the activity of ENaC in the distal nephron leading to increased sodium reabsorption and hydrogen ion excretion. The commonest causes are chloride depletion syndromes (GI losses, CF) and the use of thiazide and loop diuretics, with congenital disorders such as Bartter and Gitelman syndrome being rarer. Severe potassium depletion can also precipitate a metabolic alkalosis. The mechanism is complicated but it includes increased proximal tubular hydrogen ion secretion, decreased activity of the Na-2K-Cl transporter in the loop of Henle (with increased NH4 transport in this segment also contributing) and subsequent increased activity of ENaC due to the higher distal delivery of sodium. This form of alkalosis is perpetuated by chloride depletion.

2. Primary stimulation of collecting duct ion transport:

This is almost always due to a pathological increase in sodium reabsorption with consequent hypertension and volume expansion. The commonest cause is primary aldosteronism. Other rarer causes include Cushing’s Syndrome, CAH, Liddle’s Syndrome, 11-hydroxysteroid dehydrogenase inhibition (licorice) or deficiency and exogenous mineralocorticoids.

3. Alkali intake or administration:

This is largely an issue of excess alkali administration in patients who are unable to excrete it rapidly – i.e. patients with abnormal renal function

This paper is highly recommended for anyone wanting to understand more about the pathophysiology of metabolic alkalosis

Genetic causes of hypertension

And now for some board review tidbits! Below are some genetic causes of hypertension attributable to specific gene mutations.

1. Glucocorticoid-remediable hyperaldosteronism (GRE)- Autosomal dominant condition caused by uneven crossing over on chromosome 8. A chimeric protein is created in which the ACTH-controlled promoter for 11 beta hydroxylase is joined to the structural gene encoding aldosterone synthase. Aldosterone is overexpressed, leading to a hyporeninemic, salt-sensitive state of volume expansion. Hypokalemia and metabolic alkalosis may be present. Glucocorticoid administration suppresses ACTH and thus also aldosterone synthase production.
2. Apparent mineralocorticoid excess (AME)- Autosomal recessive disorder characterized by deficiency in 11 beta hydroxysteroid dehydrogenase 2. 11 beta dehydrogenase 2 metabolizes cortisol to cortisone. In states of cortisol excess (here caused by decreased metabolism), cortisol binds to and activates type I mineralocorticoid receptors, causing an aldosterone-like effect. Hypokalemia, hypernatremia and hypertension are seen. Treatment is with dexamethasone, which suppresses endogenous cortisol production.
3. Liddle’s syndrome- Autosomal dominant genetic mutation on chromosome 16 that causes defective ENaC ubiquitlyation and endocytosis, leading to increased ENaC cell surface expression and subsequent increased Na reabsorption. Presents in childhood with hypertension, hypokalemia and metabolic alkalosis. ENaC blockade with amiloride or triamterine plus a low Na diet are the usual treatment.
4. Pseudohypoaldosteronism Type II (Gordon’s syndrome)-Not sure what the inheritance pattern is in this condition. A genetic defect in WNK kinases 1 or 4 causes a hyporeninemic, hypertensive state. The mechanism by which these WNK defects may cause high blood pressure is unclear, but the most common explanation is that the mutations lead to an increase in thiazide-sensitive Na-Cl transporter activity. WNK I inhibits ROMK in vitro, so it may cause decreased K secretion in vivo. WNKs may also increase paracellular Cl transport, which would decrease H and K secretion into the lumen. Treatment is with thiazides.
5. Mineralocorticoid recepator activating mutation- please see the excellent post from June 7 from Mike on this condition, which was the answer to a board review question.

Board question: Hypertension-1 answer

The best answer is D.

Lifton et al. described a single gene mutation on the hormone-binding domain of the mineralocorticoid receptor (MCR). Individuals with this missense mutation develop early-onset hypertension with characteristic low renin and aldosterone levels. The mutation causes the MCR to be constitutively active, regardless of aldosterone levels, and transforms the MCR so that steroid hormones that are typically antagonistic become agonistic (in particular, progesterone and cortisone).

During pregnancy, when progesterone levels increase 100-fold, the MCR becomes hyperactive and leads to sodium reabsorption and potassium secretion via the principal cell of the distal collecting tubule (Figure above). The avid sodium retention and volume expansion appropriately suppress renin and aldosterone levels. This condition is not associated with proteinuria, edema, or neurologic changes, which distinguishes it from pre-eclampsia.

Given the low levels of aldosterone, this condition is refractory to standard medical therapy aimed at reducing aldosterone levels through RAAS blockade. In fact, mineralocorticoid receptor antagonists can actually exacerbate hypertension in this condition! Delivery of the fetus may be necessary to treat severe, refractory hypertension during pregnancy.

Essential hypertension results from a complex interplay of both genetic and environmental influences. Uncommonly, an isolated genetic mutation can engender hypertension, like in this case. These monogenic forms of hypertension affect either electrolyte transport in the distal nephron, or the synthesis and/or activity of mineralocorticoids, leading to a common final pathway of increased distal tubular reabsorption of sodium and chloride, volume expansion, and hypertension.

Other low renin, monogenic forms of hypertension include:

• Familial Hyperaldosteronism Type 1 (aka, glucocorticoid-remediable aldosteronism)
• Familial Hyperaldosteronism Type II
• Syndrome of apparent mineralocorticoid excess
• Liddle syndrome
• Pseudohypoaldosteronism type II (aka, Gordon syndrome)
• Congenital Adrenal Hyperplasia

They provide excellent fodder for any number of board-style questions!

Michael Lattanzio DO

A unified view of abnormal sodium regulation in the nephron

Summer has come to the northern hemisphere and it is time to praise our kidneys for all the hard work of preserving the intravascular volume. Although only 30% of Na reabsorption takes place in the distal nephron, this is the place for most common genetic diseases causing abnormal sodium handling:

What are the responsible proteins for these diseases?

1. Bartter syndrome: Na reabsorption decreases via NKCC2 due to defects in NKCC2, ROMK and basolateral Cl channels or from an overactive basolateral CaSR.

2. Gitelman syndrome: Na reabsorption decreases due to a reduced number of NCCs on the luminal membrane.

3. Pseudohypoaldosteronism type 1: Na reabsorption decreases due to the defects in ENaC or mineralocorticoid receptor.

4. Liddle syndrome: Na reabsorption increases due to a higher number of ENaCs on the luminal membrane (they are spared from ubiquitination).

5. Gordon syndrome: Na reabsorption increases due to a higher concentration of NCCs on the luminal membrane (defects in WNK4 or overactive WNK1). More recently, mutations were discovered in the genes encoding KLHL3 and CUL3 proteins.

CUL3 is a component of ubiquitin ligase and KLHL3 is its partner (expressed in the DCT). It is speculated that the defects in these proteins may change the distribution of NCC.

Is this clinically relevant?

In Gordon syndrome, these mutations can occur de novo and are encountered more frequently (47% for KLHL3 and 32% for CUL3) than those involving the WNK kinases (13%). It appears that they are under-diagnosed and some of the cases of RTA type 4 with hypertension could be caused by them!

50 years after Bartter syndrome was described, the work on mechanisms responsible for abnormal Na regulation in the nephron continues…

Posted by Tomoki Tsukahara MD 

 

ENAC Mutations

The ENAC channel in the distal tubule is responsible for sodium reabsorption. It is comprised of 2 alpha, 1 beta, and 1 gamma subunit with each encoded by a separate gene. Interestingly, mutations in ENAC can lead to two different and largely opposite phenotypes.

Gain-of-function mutations in the ENAC result in Liddle's syndrome, which is not surprisingly characterized by metabolic alkalosis, hypertension, hypokalemia. Despite behaving physiologically like patients with hyperaldosteronism, their aldosterone levels are suppressed. This condition can generally be treated with amiloride or triamterene (which inhibit the Enac channel some) and a Na restricted diet.

In contrast, loss-of-function mutations--usually in either the alpha or beta subunits--can result in type I pseudohypoaldosteronism. This is often (but not always) autosomal dominant in nature and causes severe salt-wasting in children which is unresponsive to mineralocorticoid treatment. It can be treated with a high Na diet.