Excretory functions of the liver

This chapter is relevant to Section N1(i) from the 2023 CICM Primary Syllabus, which expects the trainee to "describe the functions of the liver."  This specific part addresses the excretory function. To be fair, the crossover with the biliary system chapters is substantial, but there is much more to bile than just excretory function, and so the actual physiology of the biliary system is parked elsewhere.

In summary, the excretory functions of the liver are:

Excretion of bile acids

  • Bile acids are actively secreted by hepatocytes
  • 95% of bile acids are reclaimed by enterohepatic recirculation
  • 5% are eliminated in the faeces (some of which, eg. lithocholic acid, are toxic)

Excretion of cholesterol in the bile

  • Cholesterol is secreted in the bile:
    • Esterified cholesterol, at a rate of 800-1200mg/day
    • Converted to bile acids, 200-600mg/day
  • Increased cholesterol levels usually stimulate increased secretion
  • Micellated biliary cholesterol prevents dietary cholesterol absorption by displacing it from micelles, which acts as a regulatory mechanism

Excretion of bilirubin in the bile

  • Bilirubin is a toxic metabolite of haem
  • Approximately 5000 μmol per day is eliminated in the bile
  • It circulates bound to albumin in the blood
  • Hepatocytes acquire it from the sinusoid blood by a high-affinity basal transporter
  • In hepatocytes, it is conjugated with glucouronide, which makes it water soluble 
  • It is actively transported into the bile, where it is trapped by its water solubility

Excretion of ions in the bile

  • Daily biliary flow carries about 100mmol per day of sodium, as well as smaller amounts of other ions
  • This is usually reclaimed in the intestine
  • Situations where biliary drainage is diverted externally (eg. cholecystostomy) can result in hyponatremia.

Excretion of drugs in the bile

  • Some drugs are highly reliant on hepatic biliary clearance for their elimination
  • These are mainly large (>400 Da) molecules which are anionic and polar.
  • Examples include ceftriaxone, rifampicin, digoxin, doxorubicin, apixaban and spironolactone
  • Most of them act as substrates for organic anion transporters on the basal membrane of hepatocytes

Excretion of heavy elements in the bile

  • Some heavy elements are eliminated in the bile mainly as organometallic componds, by unclear active transport mechanisms
  • Examples include lead, mercury, arsenic and cadmium

Biotransformation in the liver

  • Though not excretory per se, biotransformation reactions in the liver prepare xenobiotics for renal excretion by making them more water-soluble and (usually) less toxic

    Bizarrely, the term "excretory function" seems to be an anachronism in liver literature, as most results one comes across are from the 1950s and 1960s. "Excretory function of the liver" seems to have been a common title for an article of that era, dealing with the production of bile and the metabolism of cholesterol. Taking a broader, more modern view, one could interpret "excretion" not as just "extruding waste material from the body" but more as "elimination of unwanted substances", in which case the role expands considerably to cover such functions as the biotransformation of drugs into water-soluble metabolites.

    Excretion of bile 

    Excretion of bile acids

    You can't really call what happens to bile acids "excretion", as most bile acids are very efficiently returned back to the portal blood by enterohepatic recirculation. However a small fraction (~5%) of bile acids are lost in the stool, which is excretion of a sort. Because the gastrointestinal tract goes to such elaborate lengths to reclaim them, and because their continued recirculation is essential for the absorption of dietary fat, we could reasonably regard this as an inadvertent loss rather than as the intentioned elimination of bile salt. The only reason this is mentioned here is because lithocholic acid is, to be fair, somewhat toxic, and to describe it as a "metabolic waste product" would be a believable accusation.

    Enterohepatic recirculation

    "Enterohepatic circulation", "recirculation" or "recycling" is probably worth mentioning here, mainly because there is nowhere else to put it. It does tie in thematically with excretory function, as there are many drugs which undergo enterohepatic recirculation and interrupting this process is an essential part of their toxicology management. What follows is an abbreviated version, and the interested reader is directed to the excellent review articles by Roberts (2002) and Hofmann (2009).

    The enterohepatic circulation of bile salts can be thought of as a circuit made up of mechanical and chemical pumps. Mechanical pumps (gallbladder and bile duct) spill the bile all over the duodenum, and chemical pumps patiently clean up the mess, sucking it back up into the portal blood until it collects again in the biliary tree. The main reason for this is the preciousness of bile salt as a digestive reagent. The total pool is about 2-3g, and they are expensive to make (cholesterol being the substrate for this synthesis). It appears that a decent Western meal contains enough fat that at least 9-10 grams of bile salts are required to emulsify it all, which means the total bile salt pool recirculates a few times per meal, and the intestinal tract reabsorbs the same pool of bile salts about ten times during every day. There are two main loops:

    • Enterohepatic circulation:
    • Cholehepatic circulation:
      • Passive reabsorption (mainly of the more lipid-soluble unconjugated primary bile acids) from the bile duct and gallbladder

    Given the liver's unenthusiastic rate of primary bile acid synthesis (200-600mg/day), one can plainly see how the interruption of enterohepatic circulation could rapidly become disastrous, and indeed the bile acid stores of patients with extensive ileal resection (over 100cm) are quickly depleted, leading to fat malabsorption and diarrhoea.

    Excretion of cholesterol

    As virtually every article and textbook chapter seems to constantly remind us, cholesterol is essential for cell membrane structure and function, which means you would probably expect its input and output to be carefully regulated. You've got about 30-60g of cholesterol in a slowly exchangeable tissue pool and about 15-30g in a rapidly exchangeable liver-and-plasma pool, according to Nestel et al (1969). Dietary intake is supposed to be under 300-500mg/day, and endogenous synthesis probably only contributes about 0.7-1.7g/day, which means it should be reasonably difficult for an excess to form. Still, humans are known for nightmarish dietary weirdness and it seems important to have a mechanism (or three) that can help eliminate cholesterol from the body. Of these, the liver is central for two:

    • Elimination of cholesterol in its raw unesterified form, via the bile (800-1200mg/day)
    • Elimination of cholesterol by turning it into bile acids (200-600mg/day)

    The third way is to secrete it via the intestine, where some direct mechanisms allow the direct export of cholesterol into the faeces. This is only 35% of the total daily excretion, and the liver probably still does most of the work.

    Now: the dietary, excreted biliary and excreted intestinal cholesterol are obviously all mingling in the gut lumen, and we know that about 50% of total intestinal cholesterol ends up being absorbed (van der Wulp et al, 2013). So then what's to stop your intestine from idiotically reabsorbing all the cholesterol you have been trying to excrete? Well. It appears the biliary cholesterol has an inhibitory effect on the intestinal absorption of cholesterol, acting as a regulatory mechanism. When Sehayek et al (1998) fed their transgenic mice an excess of cholesterol, the rate of biliary cholesterol secretion was strongly and inversely related to dietary cholesterol absorption. This may be because of the saturation of intestinal micelles with biliary cholesterol: dietary cholesterol, unlike the biliary variety, is nonesterified and mainly dissolved in the lipid content of the chyme, which means it needs to be converted to micelles before it can be an efficient target for pancreatic lipase. Unesterified cholesterol, however, is the main object for intestinal absorption mechanism (whereas the intestine appears to largely ignore esterified cholesterol). Flooding the gut with esterified biliary cholesterol may be an effective way of denying dietary cholesterol the opportunity to be absorbed.

    Excretion of bilirubin

    Bilirubin is important enough that it gets its own chapter in the section dealing with the laboratory tests of liver function. In summary, it is a product of haem metabolism which is left over after iron is liberated from haem. According to Fevery (2008), about 80% of it comes from senescent red cells and about 20% from the catabolism of haem-containing proteins such as myoglobin and CYP450 enzymes. Every day, something like 300mg of unconjugated bilirubin is formed in the adult (about 5000 μmol). All of this material needs to be removed:  it is truly a waste product, with clear evidence of dose-dependent toxicity (the mechanism is thought to be mainly related to the inhibition of peptide phosphorylation). And as the Kupffer cells of the liver are responsible for the bulk of the erythrocyte degradation, it would make sense for the liver to also play a central role in the removal of bilirubin from the organism.

    Unconjugated bilirubin has very poor water solubility and circulates mainly as a complex with albumin. It appears to enter hepatocytes mainly through some combination of passive diffusion and the activity of organic anion transporters, such as OAB 1B1, though exactly how its uptake occurs is not entirely clear. Once inside, it is conjugated with glucuronide, which opens up the molecule and makes it amphipathic (thereby reducing the protein binding and lipid solubility). The resulting conjugated bilirubin is then pumped into the bile against its concentration gradient by multidrug resistance-related protein 2 (MRP2), a membrane transporter so named mainly because it was found to confer chemotherapy resistance in tumour cells. Due to the heroic efforts of this efflux pump, the biliary concentration of bilirubin is about 100 times higher than the plasma concentration, or 1000-2000 μmol/L. Most of this is eliminated via the faeces, and the elimination rate is roughly equal to the rate of production (with a small amount of bilirubin accidentally deconjugated by intestinal bacteria, and reabsorbed).

    Excretion of ions

    Though biliary excretion might not be regarded as normal way to regulate your electrolytes, bile sure is an aqueous solution that contains them, and so the 600-800ml of daily bile flow results in the movement of ions out through the liver.  As one might recall, there's a nontrivial amount of them in there, and a day's worth of bile might represent a loss of about 100 mmol of sodium. Fortunately bile empties into the intestine, a structure well suited to reclaiming stray electrolytes, which means that they should not be lost forever. Therefore, only in scenarios where the bile empties into something other than the small bowel (eg. where the patient has had a cholecystostomy) do you tend to get electrolyte loss by this mechanism. Hyponatremia is usually the derangement that results, as other ions (eg. potassium) are relatively underrepresented in the bile, and the human body is well capable of compensating for biliary loss by increasing intestinal uptake and decreasing renal excretion. It also must be said that this sort of scenario is rare enough to merit a case report each time it happens, because the usually unflappable sodium defence mechanisms are never overwhelmed by merely normal biliary output, and only a truly vast bile leak (in the order of litres) would be required to fully whelm them.

    Drugs cleared by biliary excretion

    Now we get to the figurative money. Having a fat-rich effluent makes for a convenient mechanism for the exit of fat-soluble xenobiotics from the body. This seems more convenient than metabolising them into a water-soluble product. To say that some drugs rely on this route would imply that they are intentionally eliminated like that for some sort of toxicological purpose, but in reality it is usually a happy accident where they end up being trapped in the lipid partition, sequestered from metabolic enzymes. 

    Which drugs are these? Reader, we know everyone loves lists, and certainly no one loves them more than the CICM examiners, considering how easily they form into exam questions. To ask "list drugs which are excreted by the biliary route" would not be unexpected from these people. However, memorising lists is painful, and the pointlessness of the exercise will soon loom heavily over any owner of a smartphone , to which such memory tasks are these days outsourced. 

    Now, one could counter that it should not be necessary to commit long lists to memory, as it is often possible to predict which drugs will enjoy a high degree of biliary excretion. This is because the mechanism of their excretion is usually dependent on acting as a substrate for transporters such as the OATP, an organic anion transporter on the sinusoidal (basal) surface of hepatocytes. In order for these transporters to be interested in you, you would usually need to be at least 400-475 Da in mass, anionic, with a large polar surface area, having multiple rotatable bonds, and poor lipophilicity (Varma et al, 2012; Rollins & Klaassen, 1979). Simply apply this principle to drugs you already know the properties of, you should be confidently able to predict the vast majority of drugs which depend on the biliary route for their clearance. 

    Unfortunately, the vast majority of us are unable to recall the molecular weight of any of the drugs we routinely use, let alone their number of chiral carbons or pKa value. So, here's a list to memorise:

    Drugs which are Excreted in Bile
    Drug % excreted in bile
    Antibiotics  

    Rifampicin

    25%

    Metronidazole

    24%

    Ceftriaxone

    11%
    Cardiovascular agents

    Digoxin

    8-30%

    Spironolactone

    5-33%

    Aliskiren (a renin antagonist)

    Almost 100%

    Apixaban

    33%
    Central nervous system agents and analgesics

    Diazepam

    15%

    Indomethacin

    15%

    Diclofenac

    30%
    Antineoplastic agents

    Doxorubicin

    42%

    Vincristine

    21%
    Endocrine agents

    Oestradiol

    52%

    Biliary excretion of heavy metals 

    Hepatic elimination, and specifically the biliary route, is for whatever reason quantitatively more important for some metals, and specifically for heavy exotic elements. Substances that appear to rely on biliary elimination, according to Klaasen (1976) include:

    • Copper
    • Lead
    • Arsenic
    • Manganese
    • Mercury
    • Cadmium
    • Chromium

    It appears that nobody has a very clear idea of how these are eliminated, other than to point to some active process, and to confirm that many of these substances are eliminated as organometallic compounds rather than raw cations. Many of these elements appear in the bile in extremely high concentrations, pointing to the need for a transport mechanism that works against a concentration gradient (Cikrt, 1981). Additionally, some may bind to some of the high-molecular-weight components of bile and therefore become "chelated" and trapped in the faeces, and others may become deconjugated and experience recirculation.

    Hepatic metabolism as a step to excretion

    It is probably worth mentioning this, because even though it is not an "excretory" function per se, it is certainly central to excretion, insofar as the elimination of xenobiotics just would not work unless the liver modifies them. Very few drugs are eliminated unchanged in the bile or urine; the vast majority require some sort of biotransformation for them to become susceptible to elimination mechanisms, and the liver does most of this work. The details of hepatic biotransformation are discussed elsewhere.

    References

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