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culture.

LIVER

Contents

Structure and Function

Enterohepatic Circulation

Nutritional Management of Liver and Biliary Disorders

Structure and Function

D G Cramp, South Wonston, Winchester, UK

This article is reproduced from Encyclopaedia of Food Science,

Gross Structure

0001 The liver is the largest solid organ in the body,

weighing between 1200 and 1500 g. It lies in the

right hypochondrium and is roughly wedge-shaped,

with its apex to the left side and base to the right.

Grossly, it appears to be divided into a larger right

and a smaller left lobe by the falciform ligament.

However, this has no apparent functional signifi-

cance, as the blood supply to the two lobes is almost

equal. This blood supply is derived from two sources:

the hepatic artery, usually a branch of the coeliac

axis, and the portal vein, formed from the mesenteric

vein and the splenic vein.

0002 The total hepatic blood flow is some 1300 ml

min

1

, approximately 25% of the resting cardiac

output, with the hepatic artery supplying about

25–30% of blood by volume and the low-pressure

portal vein the remainder. Both of these vessels run

in the free edge of the lesser omentum to the liver

hilum before dividing into major right and left

branches. Blood leaves the liver through several

hepatic veins that drain directly into the inferior

vena cava, which runs in a groove between the two

lobes. Three such hepatic veins enter just below the

diaphragm, with a number of smaller veins draining

the posterior aspect of the right lobe directly into the

inferior vena cava.

0003The biliary system collects, stores, and concen-

trates bile in the gall bladder, prior to its delivery to

the duodenum as required. The main right and left

hepatic ducts join in the liver hilum to form the

common hepatic duct. The gall bladder itself lies

on the underside of the right lobe of the liver, with

the cystic duct running backwards and upwards in

order to join the hepatic duct; the resulting common

bile duct runs with the hepatic artery and portal vein

and then passes behind the first part of the duodenum

LIVER/Structure and Function 3593

and the head of the pancreas before it enters the

duodenum.

Fine Structure

0004 At the tissue level, the liver is comprised of a large

series of channels lined with endothelial cells, the

sinusoids, which run between layers or plates of hepa-

tocytes. The endothelial cells possess fenestrations,

which allow access of circulating blood to the sinus-

oidal surface of the hepatocytes. Some of the cells

lining the sinusoids, Kuppfer cells, possess phagocytic

activity. The space of Disse, i.e., the space between the

endothelial cells and the hepatocytes, contains inter-

stitial fluid. The membrane transport of nutrients and

waste material between the space of Disse and the

parenchymal cells is facilitated by the numerous

microvilli, which extend the sinusoidal surface of

these cells. From and around the liver branches of

the hepatic artery, portal vein and bile duct are

carried portal tracts, the smallest of which contain

terminal branches supplying groups of sinusoids that

form a functional unit, the acinus. Blood from each

acinus passes into a number of efferent veins. It is

the radially orientated sinusoids centered on these

efferent veins that give the liver its classical lobular

architecture.

0005 Histochemical studies have demonstrated a marked

heterogeneity of hepatocytes, with cells at different

locations differing both structurally and functionally.

This differentiation probably reflects the many spe-

cific metabolic functions that the liver has to meet.

The overall functional capacity of the liver (liver func-

tional mass) is highly dependent on the number and

activity of these hepatocytes and their contact with

circulating blood (effective liver perfusion).

Functions of the Liver

0006 The anatomical site and cellular architecture of the

liver enable it to perform many diverse metabolic

functions that are essential to the body. Its position,

between the digestive tract and the general circula-

tion, ensures that substances ingested orally and

absorbed by the intestine must normally pass to the

liver. As a result, the liver has developed the ability

not only to receive, process, and store these sub-

stances but also to release them or their metabolites

in a highly regulated fashion by monitoring demand

and responding to multiple hormonal and neural

stimuli.

0007 A cardinal role of the liver is to regulate the

supply and utilization of energy-containing substrates

through its participation in the integrated control of

carbohydrate, protein, and lipid metabolism. In the

body, there is a fine balance between anabolic and

catabolic processes, between supply and demand.

This state of metabolic homeostasis is essential for

the maintenance of an adequate and continual supply

of fuel to the tissues, especially cerebral tissue, as the

body adapts to periods of relative plenty alternating

with periods of fasting. This is facilitated by three

processes: providing fuel from ingested food to meet

immediate energy demands; storing fuel reserve as

glycogen in the liver and muscle, at the same time

replenishing tissue protein lost since the last meal;

diverting excess energy-rich substrate into triglycer-

ide for transport to adipose tissue for storage. As for

any tissue, these metabolic processes in the liver are

dependent on several factors, including the circulat-

ing concentration of substrate, blood flow to tissue,

cell permeability, the mechanism of entry to the

metabolic pathways and their hormonal regulation.

(See Amino Acids: Metabolism; Carbohydrates:

Digestion, Absorption and Metabolism; Fatty Acids:

Metabolism; Glycogen.)

0008The liver is the major site of plasma protein synthe-

sis, including albumin, the a-andb-globulins, clotting

factors, and transport proteins. These proteins have

important roles in body homeostasis: regulation of

blood coagulation and hemostasis; the transport and

optimization of circulating concentrations of calcium

and magnesium ions, bilirubin, fatty acids, and hor-

mones. Also, albumin contributes to the maintenance

of the plasma colloidal oncotic pressure and hence the

control of body fluid distribution. There is a close

relationship between the liver, gut, and muscles with

respect to amino acid metabolism. The average adult

turns over about 2% of total body protein, approxi-

mately 250 g per day, with muscle the major source,

contributing 140 g, and dietary intake accounting for

90 g. After a meal, approximately 25% of the amino

acid nitrogen absorbed into the portal bloodstream

reaches peripheral tissues because the liver has the

ability to regulate the rate of gluconeogenesis and

transamination, thereby modifying the circulating

plasma amino acid composition. The aromatic

amino acids phenyalanine, tyrosine, and methionine

are preferentially metabolized to urea, while the

branched-chain amino acids valine, leucine, and iso-

leucine are selectively able to reach peripheral muscle

for reincorporation into protein. A major synthetic

function of the liver is the formation of bile acids

from cholesterol and their secretion into the intestine,

thereby generating bile flow and facilitating dietary

fat emulsification and absorption. (See Bile.)

0009Substances circulating in the systemic bloodstream

have access to the liver by way of the hepatic artery

and the mesenteric artery. The liver is the main site

of metabolic transformation and detoxification of

3594 LIVER/Structure and Function

endogenous compounds, including bilirubin, ammo-

nia, and thyroid, steroid, and other hormones, as well

as exogenous foreign compounds.

Role of Liver in Postabsorptive Events

0010 Over a 24-h period, a subject of average body mass

utilizes about 7560–8400 kJ (1800–2000 kcal), de-

rived from 75 g of protein (mainly muscle) and some

160 g of triglyceride from adipose tissue. During that

time, the liver releases about 180 g of glucose, 80% of

which is totally oxidized by nervous tissue, mainly the

brain. The rest is metabolized by those tissues for

which glucose is the preferred energy substrate,

namely red blood cells, hemopoietic tissue, and the

renal medulla. The endproducts of this glycolysis,

pyruvate and lactate, are recycled to the liver and

converted to glucose. This carbon shuttle, the Cori

cycle, provides a means of sparing gluconeogenesis

from protein. (See Glucose: Function and Metabol-

ism; Maintenance of Blood Glucose Level.)

0011 Following a large meal with significant carbohydrate

content, the liver takes up glucose in response to in-

creased insulin secretion and suppression of glucagon.

This glucose is converted into glycogen and stored. If

the meal has a relatively low carbohydrate content, the

liver will continue to produce glucose in response to

raised glucagon levels, notwithstanding a normal insu-

lin response to food. Insulin and glucagon regulate the

intracellular concentration of cyclic adenosine mono-

phosphate (cAMP), which in turn initiates complex

enzyme changes that modulate glycogen synthesis and

breakdown as well as gluconeogenesis. In a normal

subject, following the ingestion of a 100-g glucose

load, the liver retains approximately 60–80%, the rest

escaping into the systemic circulation. The liver con-

tains about 10% by weight of glycogen (approximately

150 g), less than the daily body glucose requirement of

some 180–200 g; thus, it is only able to meet short-term

requirements.

0012 The conventional model suggests that glycogeno-

lysis is able to maintain glucose homeostasis for some

18 h into a fast and is then superseded by gluconeo-

genesis. The switch to gluconeogenesis is initiated by

two processes: a raised glucagon: insulin ratio, which

increases the hepatic cAMP concentration, and in-

creased peripheral tissue lipolysis, leading to a higher

intrahepatic concentration of free fatty acids, the oxi-

dation of which yields an increase of gluconeogenic

precursors such as acetylcoenzyme A (acetyl-CoA).

0013 It is the action of insulin and its counter-regulatory

hormones that integrate intermediary metabolism in

both the liver and peripheral tissues. The systemic

regulation of protein and lipid metabolism, through

a variety of actions that affect the flux of protein and

lipid substrates to the liver, complements glucose

regulatory mechanisms.

0014The hepatic actions of insulin lead to fuel conser-

vation, by optimizing glucose availability, reducing

fatty acid oxidation – and thus ketone body produc-

tion – and diverting the fatty acids into triglyceride

for transport to peripheral tissues where they are

stored.

0015In the fasting state, insulin modulates hepatic glu-

cose production by restraining glycogenolysis and

increasing gluconeogenesis. In the fed state, insulin

levels rise, and there is virtually total inhibition of

both these processes so that hepatic glucose produc-

tion drops to zero. This is achieved by inhibition of

phosphorylase and the key gluconeogenic enzymes

pyruvate carboxylase, phosphoenolpyruvate car-

boxykinase and fructose 1,6-diphosphate, proba-

bly through inhibition of cAMP-dependent protein

kinases. Insulin is also essential to the disposition of

incoming glucose through its enhancement of gluco-

kinase activity and glucose phosphorylation. The

glucose 6-phosphate formed can follow several alter-

native metabolic routes:

0016Glycogen formation following the activation of

glycogen synthase: this step is subject to the limi-

tations on the capacity of hepatocytes to store

glycogen. Excess glucose 6-phosphate is converted

to pyruvate, which, through activation of pyruvate

dehydrogenase and acetyl-CoA carboxylase, is

diverted into fatty acid synthesis.

0017Increased flux of glucose 6-phosphate into the

pentose phosphate shunt increases the availability

of the reduced form of nicotinamide adenine

dinucleotide phosphate for fatty acid synthesis.

The fatty acids are esterified with glycerol 3-phos-

phate also formed during glycolysis. The resulting

triglycerides are incorporated into very-low-dens-

ity lipoproteins (VLDLs) and secreted by the liver

to extrahepatic sites for storage. (See Lipoproteins.)

0018As fatty acid synthesis is accelerated, fatty acid

oxidation and ketogenesis are inhibited. The first

committed step of fatty acid synthesis is malonyl-

CoA formation. Increased levels inhibit the

enzyme carnitine acyltransferase I, which facili-

tates the transport of fatty acids, as fatty acyl-

CoA, into mitochondria for oxidation. If fatty

acids cannot be oxidized, they become available

for esterification; furthermore, the blocking of

fatty acid oxidation also prevents ketogenesis,

owing to the lack of precursor acetyl-CoA.

Glucose Homeostasis

0019During a brief fast, a precipitate fall in the blood

glucose concentration is avoided by drawing upon

LIVER/Structure and Function 3595

hepatic glycogen stores. During long-term fasting,

i.e., starvation, gluconeogenesis plays the most sig-

nificant role in maintaining blood glucose concentra-

tions. If the pathways activated during a brief fast

persisted through a period of prolonged food depriv-

ation, the loss of body protein to provide glucose

would be extremely rapid. However, with prolonged

starvation the brain is progressively able to adapt to

utilizing lipid-derived ketone bodies as a substitute

for glucose. The reduction in protein breakdown, as

reflected by a fall in urinary nitrogen, and the con-

comitant decreased gluconeogenesis result from the

increased utilization of ketone bodies. They not only

decrease the requirement of the brain for glucose

derived from protein but also have a direct effect on

reducing peripheral tissue glucose utilization and the

flux of alanine from muscle.

Cholesterol and Bile Acid Metabolism

0020 The liver has a primary role in cholesterol metabolism

within the body because it is the site of most of the

endogenous cholesterol synthesis, it handles exogen-

ous cholesterol from the diet and extrahepatic tissues

received by way of plasma lipoproteins, and it is the

only organ with the capacity to excrete cholesterol

from the body.

0021 Hepatocytes have the capacity both to synthesize

and to take up cholesterol from lipoprotein remnants.

Negative feedback control of the cholesterol synthesis

pathway and control of the cell surface receptor

population ensure that intracellular accumulation of

cholesterol does not occur. Some cholesterol may be

secreted from hepatic cells in VLDL, the vehicle

for triglyceride transport to adipose tissue. On

removal of triglyceride, the lipoproteins become

smaller, cholesterol-rich particles, low-density lipo-

proteins (LDLs), which are recognized by LDL re-

ceptors on hepatocytes. Following internalization,

cholesterol is released from the disrupted lipoprotein.

0022 The dietary cholesterol intake is about 600–800 mg

daily and is mainly derived from dairy products, eggs,

and meat. Cholesterol derived from dietary fat, to-

gether with that from the bile, is taken up by mucosal

cells of the intestinal wall with about 30–60% of the

total presented being absorbed or reabsorbed. The

efficiency of absorption increases with the saturated

fat content of the diet. Absorbed cholesterol reaches

the liver in chylomicron remnants and is taken up by

chylomicron receptors.

0023 The primary bile acids, cholic and chenodeoxy-

cholic acid, are synthesized in the liver from

cholesterol, conjugated with the amino acids taurine

or glycine to form bile salts, and then excreted by an

active transport mechanism into the bile canaliculi

and, eventually, into the duodenum. In the distal

ileum, there is an active reverse transport mechanism,

whereby bile salts are conserved by reabsorption after

fulfilling their digestive function. The enterohepatic

circulation is extremely efficient: the entire body pool

of bile salts is cycled through the gut roughly twice

during the course of a meal, with so little being lost

that only about 5% needs replacement by de-novo

synthesis. The small amount that reaches the stools

(about 4%) is acted upon by bacteria in the gut lumen

to yield, by 7-a hydroxylation, the secondary bile

acids deoxycholic and lithocholic acids. All bile salts

are powerful detergents, solubilizing lipids by enclos-

ing them in bile salt aggregates to form micelles.

These are structured so that hydrophobic groups are

orientated towards the lipid-rich interior of the mi-

celle, while the hydrophilic hydroxyl (OH) and carb-

oxyl (COOH) groups are on the outside.

0024Cholesterol and lecithin are excreted into the bile,

but if their concentration is too high, relative to that

of bile salts, the bile becomes supersaturated, and

precipitation of cholesterol occurs, particularly if a

nidus for crystal formation is present. This is the

pathophysiological basis of gallstone formation. The

active transport of bile salts is the main driver of bile

formation and secretion. Failure leads to intrahepatic

cholestasis. A bile-salt-independent contribution to

bile secretion is the result of active sodium transport

in the distal canaliculus, with bicarbonate being

secreted into the small bile ductules under the stimu-

lus of the hormone secretin. Cholecystokinin stimu-

lates gall bladder contraction.

See also: Amino Acids: Metabolism; Bile;

Carbohydrates: Digestion, Absorption, and Metabolism;

Fatty Acids: Metabolism; Glucose: Function and

Metabolism; Maintenance of Blood Glucose Level;

Glycogen; Lipoproteins

Further Reading

Arias IM, Popper H, Schachter D and Shafritz DA (eds)

(1982) The Liver Biology and Pathobiology. New York:

Raven Press.

Cramp DG (ed.) (1982) Quantitative Approaches to

Metabolism. Chichester, UK: John Wiley.

Cramp DG and Carson ER (eds) (1990) Liver Function.

London: Chapman & Hall.

3596 LIVER/Structure and Function

Enterohepatic Circulation

A Lanzini, University of Brescia, Brescia, Italy

Definition

0001 The enterohepatic circulation is an anatomical and

physiological entity, only part of which is vascular.

It involves passage of substances that have been

absorbed from the intestine via the portal vein to the

liver, and their subsequent passage via the biliary

system back into the intestine. Bile acid molecules

are unique in that they are restricted to the entero-

hepatic circulation (Figure 1). They are secreted in

bile as glycine and taurine conjugates, and are mainly

absorbed by active transport in the distal ileum.

Many other endogenous and exogenous compounds

undergo some degree of enterohepatic circulation, but

this usually represents a minor component of their

tissue distribution. By contrast with bile acids, these

substances are excreted in bile as glucuronate or

sulfate conjugates, and deconjugation by colonic

bacteria is essential for these molecules to reenter

the enterohepatic circulation by passive colonic ab-

sorption following biliary excretion.

Bile Acids

0002The driving force for the enterohepatic circulation of

bile acids comprises chemical and mechanical pumps,

both affecting bile acid kinetics to a different extent.

Kinetics

0003All aspects of bile acid kinetics are measurable under

physiological conditions in humans using the isotope

dilution technique developed by Lindstedt. According

to this technique, bile acid pool size is the mass of bile

acid that dilutes a trace amount of an isotopically

labeled bile acid. The fractional turnover rate is the

fraction of the pool lost from the enterohepatic circu-

lation and replaced by de novo bile acid synthesis

each day. Chenodeoxycholic acid and cholic acid are

the only two bile acids synthesized by the human liver,

and are thus called ‘primary’ bile acids (See Bile.)

These two bile acids are biotransformed in the intes-

tine to form ‘secondary’ bile acids, lithocholic and

deoxycholic acid. Further intestinal and hepatic bio-

transformation of primary bile acids results in the

formation of ‘tertiary’ bile acids (ursodeoxycholic

acid and ursocholic acid). Input rate is the amount

of bile acid entering the pool each day, and represents

synthesis in the case of the primary bile acids.

0004According to the Lindstedt’s technique, the specific

activity (SA ¼ disintegrations per minute/bile acid

mass) of the radiolabeled bile acid injected intra-

venously is measured in gallbladder bile samples

collected on 4–5 successive days by nasoduodenal

intubation during intravenous infusion of cholecysto-

kinin to contract the gallbladder. The reduction of

the SA over time is exponential (Figure 2) because a

constant fraction rather than a constant amount of

the pool is lost each day (first-order kinetics). This

exponential decrease of SA is described by the

following equation:

¼ SA

Kt

were SA

and SA

are the SAs at times t and zero

respectively. The extrapolated value for SA

on loga-

rithmic scale gives the specific activity of the pool

assuming instantaneous mixing of the injected tracer

with the pool, and the slope of the line (K) gives the

turnover rate. Total bile acid pool size is derived by

the following formula:

Bile acid pool ¼ SA

inj

=SA

Fecal excretion

(= biosynthesis)

Active transport

by ileocytes

Transit to

ileum by

intestinal

propulsion

Transit to liver

by portal

blood flow

Biosyn-

thesis

hepato-

cytes

Storage and

emptying by

gallbladder

Sphincter

of Oddi

Active transport

by hepatocytes

Spillover into

systemic circulation

Passive

transport by

colonocytes

Transit to liver

by mesenteric

and hepatic

arterial blood

flow

fig0001 Figure 1 Schematic representation of the enterohepatic

circulation of bile acids: see text for details. Reproduced from

Hofmann AF (1992) Bile acids in liver and biliary disease. In:

Millward-Sadler GH, Wright R, and Arthur MJP (eds) Wright’s

Liver and Biliary Disease, 3rd edn, pp. 289–316. London, UK: WB

Saunders, with permission.

LIVER/Enterohepatic Circulation 3597

where SA

inj

is the specific activity of the injected

tracer. Daily synthesis rate is derived by the following

formula:

Synthesis rate ¼ pool size K

If bile acid secretion rate is measured by means of

duodenal perfusion techniques simultaneously with

bile acid pool size, the recycling frequency of the

pool can be derived from the following formula:

Recycling frequency ¼ 24-h bile acid secretion=bile

acid pool size

The kinetics of the enterohepatic circulation vary for

individual bile acids, and values for each individual

bile acid are reported in Table 1. Given a secretion

rate of 11–40 g day

1

and a pool size of 1.3–4.0 g, the

recycling frequency of the pool varies between 4 and

15 per day in humans.

Chemical Pumps

0005Intestinal absorption Two chemical pumps are

involved in the enterohepatic circulation, intestinal

absorption and hepatic uptake. The mechanisms

involved in intestinal bile acid absorption vary with

the anatomical site and consist of passive nonionic

diffusion in the whole intestine, and of active absorp-

tion in the distal ileum.

0006The ileal transport system satisfies the criteria for

active and saturable transport, and the rate of active

ileal bile acid transport is described in terms of max-

imal transport velocity (V

max

) and Michaelis–Menten

constant (K

). In humans, V

max

is higher for tauro-

cholic acid than for chenodeoxycholic and glycoche-

nodeoxycholic acid by a factor of 4:2:1 respectively.

Values for K

are similar for conjugated and uncon-

jugated bile acids. It appears, therefore, that active

ileal transport is best suited for taurine-conjugated

bile acids, i.e., for bile acids with negligible passive

absorption in the proximal small intestine.

0007The active uptake of bile acid on the enterocyte

apical membrane is mediated by the ileal Na

-taur-

ocholate cotransporter (iNTCP), a glycoprotein con-

taining 348 aminoacids with predicted molecular

mass of 38 kDa. This glycoprotein presumably con-

tains seven transmembrane domains and belongs to a

superfamily of Na

-solute transporters. The expres-

sion of the sodium-bile acid cotransporter is inducible

by taurocholate, suggesting that this mechanism

may protect against ileal bile acid loss and subsequent

formation of excess secondary bile acids in the colon.

This uptake mechanism is absent in the duodenum

and jejunum.

0008During transmembrane transport, bile acid orien-

tation is though to be ‘head ahead,’ i.e., with the

steroid nucleus ‘head’ crossing first the apical mem-

brane followed by the side-chain ‘tail.’ Bile acid

molecules are transported within the ileocyte by a

cytosolic bile acid-binding protein constituted of

128 amino acids and with putative molecular weight

of 14 kDa. Following intracellular translocation, bile

acids leaves the ileocyte by a sodium-independent

anion exchange mechanism. The overall efficiency

of the ileal transport system in humans is very high,

in the region of 90% per meal, or 70–80% per day.

0009By contrast with the distal ileum, bile acid absorp-

tion in the jejunum and in the colon occurs by passive

nonionic diffusion alone. At the physiological pH

of the upper small intestinal content (pH 5.5–6.5),

about 50% of unconjugated bile acids is undisso-

ciated by comparison with only about 25% of glycine

conjugates. At this pH no taurine-conjugated bile

acid is protonated. These observations suggest that,

on a purely physicochemical basis, passive diffusion

tbl0001 Table 1 Kinetics of individual bile acids in humans

Bile acids Pool size FTR Synthesis Input

(g) (days

1

) (g) (q)

Cholic 0.5–1.5 0.2–0.5 0.2–0.4

Deoxycholic 0.2–1.0 0.2–0.3 0.04–0.2

Chenodeoxycholic 0.5–1.4 0.2–0.3 0.1–0.25

Lithocholic 0.05–0.1 1.0 0.04–1.0

Total 1.3–4.0 0.28–0.61 0.08–0.3

FTR, fractional turnover rate.

From Carey MC and Duane WC (1994) Enterohepatic circulation. In: Arias

IM, Boyer JL, Fausto N, Jakoby WB, Schachter D and Shafritz DA (eds) The

Liver: Biology and Pathobiology, 3rd edn, pp. 769–786. New York: Raven

Press, with permission.

0.0

0.1

1.0 2.0 3.0 4.0 5.0

Time (days)

Chenodeoxycholic

Ursodeoxycholic

Lithocholic

Mole ratio (x 10

)

fig0002 Figure 2 Decline of specific activity of a ‘primary’ bile acid

(chenodeoxycholic) and input of ‘secondary’ (lithocholic acid)

and ‘tertiary’ (ursodeoxycholic acid) bile acids in gallbladder

bile samples collected over a 5-day period. Reproduced from

Hofmann AF (1989) Enterohepatic circulation of bile acids. In:

Handbook of Physiology, section 6, vol. III, pp. 567–596. American

Physiological Society, with permission.

3598 LIVER/Enterohepatic Circulation

in the proximal small intestine is best suited for

glycine-conjugated bile acids, i.e., for bile acids less

efficiently absorbed by the active ileal transport

system. At the slightly acidic pH of colonic content

unconjugated bile acids resulting from bacterial

deconjugation of bile acids escaping ileal absorption

are also absorbed by passive nonionic diffusion.

0010 Hepatic uptake Following absorption, bile acids are

transported to the liver in the portal blood, and to a

negligible extent in the lymph. In blood, bile acids are

strongly bound to albumin, a phenomenon prevent-

ing dispersion of bile acids outside the enterohepatic

circulation. The binding affinity of bile acids for

serum albumin is greater for unconjugated than for

conjugated bile acids, and for mono- than for di- and

trihydroxylated bile acids.

0011 Given a portal blood flow of 500 ml min

1

and

a bile acid concentration of 20 mmol l

1

, about

600 mmol h

1

bile acid reaches the liver by the portal

system. The process of hepatic uptake is extremely

efficient, and consists of a saturable carrier-mediated

process involving a 54-kDa carrier protein. Hepatic

first-pass clearance of bile acids depends upon both

portal blood flow and hepatic first-pass extraction of

bile acids. This latter is relatively independent of flow

within the physiological range of portal flows, and is

mainly influenced by bile acid structure. First-pass

extraction of total (conjugated plus unconjugated)

bile acids ranges between 80% and 90% for cholic

acid, and is about 70% for both chenodeoxycholic

and deoxycholic acid.

0012The transport system responsible for hepatic bile

acid uptake is located on the sinusoidal membrane

of the hepatocyte and consists of the liver NTCP

(Figure 3), a glycoprotein with 40% structural

identity to the ileal iNTCP described above. Other

transport systems for bile acids have been described

in addition to NTCP. In particular an organic

anion-transporting polypetide has been cloned

from rat (oatp) and human (OATP) liver. OATP is a

polyspecific Na

-independent transport system

involved in the hepatic uptake of a large number

of structurally unrelated anphipatic compounds,

including bromosulfophthalein, bile acids, and

steroids (See Bile.)

0013Portal bile acids escaping first-pass hepatic

extraction account for the 1–5 mmol l

1

bile acid

concentration in peripheral blood. Intravenous

administration of radiolabeled bile acids is followed

within a few minutes by clearance of radioactivity

from plasma, suggesting that bile acids in peripheral

blood are rapidly taken up by the liver, thus reenter-

ing the enterohepatic circulation.

Inside

Outside

fig0003 Figure 3 Model of the hepatic Na

-taurocholate cotransporter. Reproduced from Mejer PJ, Hagenbuch B, and Stieger B (1994)

Properties of two-cloned basolateral bile acid uptake proteins of rat and human liver. In: Hofmann AF, Paumgartner G and Stiehl A

(eds) Bile Acids in Gastroenterology, Basic and Clinical Advances, pp. 139–146. Lancaster, UK: Kluwer Academic Publishers, with

permission.

LIVER/Enterohepatic Circulation 3599

Mechanical Pumps

0014 Gallbladder and intestinal motility provide the main

propulsive forces for bile acids to reach the site of

intestinal absorption, thus acting as mechanical

pumps for the enterohepatic circulation. By contrast

with the very rapidly acting chemical pumps, mech-

anical pumps have storage capacity for the bile acid

pool and therefore comprise the slow limb of the

enterohepatic circulation (Figure 4).

0015 There is a striking inverse relationship between the

recycling frequency of the bile acid pool and bile acid

pool size (Figure 5). If one assumes that bile acid pool

size is the dependent variable and that the chemical

pumps are not saturated under physiological condi-

tions, then gallbladder and small intestinal motor

function represent the main factors affecting the kin-

etics of the enterohepatic circulation. Two main lines

of evidence support this concept. First, bile acid pool

size has been reported to vary inversely with gallblad-

der emptying rate in healthy male subjects. Further-

more, the smaller pool size in subjects with a faster

gallbladder emptying rate is associated with a greater

fractional turnover rate for primary bile acids, and

with no change in their synthesis rate. These observa-

tions indirectly suggest an effect of gallbladder

emptying on the recycling frequency of the bile acid

pool.

0016 There is also a negative relationship between small

intestinal transit rate and total bile acid pool size.

By contrast with gallbladder emptying, it is synthesis

rate for both primary bile acids, and not their frac-

tional turnover rate, that is significant associated with

small intestinal transit rate. Taken together, these

observations suggest that, whereas gallbladder

emptying is an important factor in affecting the recyc-

ling frequency of the pool, small intestinal transit rate

may be more important as a regulating factor for bile

acid synthesis, probably by affecting the rate of bile

acid return to the liver. This hypothesis is supported

by the finding that hepatic microsomal cholesterol

7a-hydroxylase, the rate-limiting enzyme of a major

synthetic bile acid pathway, is subject to feedback

repression by hydrophobic bile acids returning to

the liver via the enterohepatic circulation.

0017A second line of evidence supporting a role for the

mechanical pumps as regulatory factors in bile acid

kinetics is provided by studies involving manipulation

of gallbladder emptying and small intestinal transit

rate. Reduction in postprandial gallbladder emptying

by means of dietary measures (sugar diet) results in

increased bile acid pool size. This effect is accompan-

ied by a decreased fractional turnover rate for the

primary bile acids, with no change in synthesis rate.

Similar results are achieved by prolonging small

intestinal transit time by chronic administration of

anticholinergic drugs. Opposite effects occur with

chronic reduction in small intestinal transit time

with sorbitol administration, or with regular injec-

tions of cholecystokinin octapeptide.

Bile Acid Biotransformation

0018Bile acid biotransformation occurs at two sites in the

enterohepatic circulation – the intestine and the liver.

During enterohepatic cycling, bile acids are exposed

Liver

Bile

Ileum

Ileal NTCP

Portal

vein

Hepatic

NTCP

fig0004 Figure 4 Schematic illustration of the main mechanical (GB,

gallbladder, and ileum) and chemical pumps (ileal and hepatic

-taurocholate cotransporter (NTCP)) of the enterohepatic

circulation.

Normals

Obesity

Type II

Type IV

hyperlipidemia

Gallstones

Bile salt therapy

}

Total bile salt pool (mg per 70 kg)

1750 3500 5250 7000

0 50 100 150 200 250

Recycling frequency (days

−1

)

Bile salt pool (µmol kg

−1

)

fig0005Figure 5 Inverse relationship between bile acid pool size and

recycling frequency of the pool in various pathophysiological

conditions. Reproduced from Carey MC and Duane WC (1994)

Enterohepatic circulation. In: Arias IM, Boyer JL, Fausto N,

Jakoby WB, Schachter D and Shafritz DA (eds) The Liver: Biology

and Pathobiology, 3rd edn, pp. 769–786. New York: Raven Press,

with permission.

3600 LIVER/Enterohepatic Circulation

to an increasing concentration of anaerobic bacteria

from the mid-ileum down to the rectum. These bac-

teria are capable of a variety of metabolic biotrans-

formations of bile acids, and the three most important

are deconjugation, 7-dehydroxylation, and 3- (or 7)-

oxidation. A small proportion of conjugated bile

acids is deconjugated in the mid-ileum and absorbed

by passive nonironic diffusion. Bile acids reaching the

distal ileum after each meal are absorbed by active

transport. Only about 10% of conjugated bile acids

reaching the distal ileum after each meal escape ab-

sorption and are deconjugated in the colon by cholyl-

glycine hydrolase, an enzyme produced by a great

variety of bacterial species. The two primary bile

acids, cholic and chenodeoxycholic acid, undergo

further biotransformation by bacterial 7-alpha dehy-

droxylase with formation of deoxycholic and

lithocholic acid respectively. By contrast with decon-

jugation, dehydroxylation of bile acids at C-7 is

mediated solely by a relatively small number of

anaerobic bacterial species. A total of 20–50% of

the secondary bile acids is reabsorbed by the colonic

mucosa, returned back to the liver, conjugated with

glycine or taurine and secreted in bile as secondary

bile acids. The human liver has the capacity further to

conjugate glyco- and taurolithocholic acid with a

sulfate group, a phenomenon favoring fecal excretion

of this potentially toxic bile acid. As a result of effi-

cient fecal excretion lithocholic acid is less than 5% of

total bile acid pool in all species examined. By con-

trast, the proportion of deoxycholic acid varies be-

tween 0 and 60% in humans in health and in disease

depending on variable input of newly formed deoxy-

cholic acid from the colon.

0019 As a result of bacterial dehydrogenase activity,

3- and 7-oxo bile acids are formed in the intestine.

These compounds are absorbed in the colon and re-

duced stereospecifically in the liver. About 20% of the

7-oxo bile acids are reduced in the liver with forma-

tion of the beta-epymers and are called ‘tertiary’

bile acids. This mechanism accounts for the small

proportion of ursodeoxycholic acid and ursocholic

acid, the 7-beta-epymer of chenodeoxycholic and of

cholic acid respectively, present in human bile.

Physiological Effects

0020 The distribution of the bile acid pool changes during

the day, as illustrated by the diurnal variation of bile

acid concentration in blood, bile, and intestine. These

two latter phenomena have important effects on the

physicochemical state of bile and on the digestion and

absorption of dietary lipids.

0021 Hepatic bile acid secretion rate declines progres-

sively in humans from 10 to 30 mmol kg

1

during

the first hour following an evening meal, to less

than 5 mmol kg

1

before the following breakfast.

These changes are accompanied by about 50% net

storage in the gallbladder of the hepatic bile during

nocturnal fasting, indicating 50% interruption of the

enterohepatic circulation. These diurnal changes in

bile acid secretion rate are accompanied by changes

in the relative proportion of cholesterol and phospho-

lipid in hepatic bile, especially at low bile acid secre-

tion rates. This phenomenon is accounted for by the

hyperbolic relationships between bile acid and chol-

esterol secretion and between bile acid and phospho-

lipid secretion (Figure 6). These relationships explain

why the cholesterol/phospholipid ratio is relatively

constant in all animal species at high bile acid secre-

tion rate, and why it sharply increases at bile acid

secretion lower than about 12 mmol kg

1

min

1

This phenomenon also explains why hepatic bile is

supersaturated with cholesterol at bile acid secretion

rates < 20 mmol kg

1

in healthy subjects.

0022The diurnal variation in cholesterol saturation of

hepatic bile which accompanies the diurnal fasting–

eating pattern is mirrored by a similar but smaller

diurnal variation in cholesterol saturation of gall-

bladder bile. The diurnal variation in bile acid

concentration entering the intestinal limb of the enter-

ohepatic circulation also has important physiological

effects on the digestion and solubilization of dietary

lipids. As a result of dietary stimuli to gallbladder

contraction, intraduodenal bile acid concentration

increases above the critical value of 4–8 mmol re-

quired for normal lipid digestion and absorption.

Disease conditions causing detective bile acid

secretion secondary to cholestasis or to interrupted

enterohepatic circulation (ileal diseases or resection)

result in lipid malabsorption and steatorrhea.

500

400

300

200

100

500 100 1500

2000

Lecithin

Cholesterol

Bile salt secretion (µmol h

−1

)

Lipid secretion (µmol h

−1

)

fig0006Figure 6 Relationship between bile acid and cholesterol, and

between bile acid and phospholipid hepatic secretion rate. Re-

produced from Carey MC and Duane WC (1994) Enterohepatic

circulation. In: Arias IM, Boyer JL, Fausto N, Jakoby WB, Schach-

ter D and Shafritz DA (eds) The Liver: Biology and Pathobiology, 3rd

edn, pp. 769–786. New York: Raven Press, with permission.

LIVER/Enterohepatic Circulation 3601

Other Endogenous Compounds

0023 Apart from bile acids, no other major organic com-

pounds excreted in bile undergo an enterohepatic

circulation. Although both biliary cholesterol and

phospholipids are absorbed in the small intestine to-

gether with their dietary sources, their biliary secre-

tion originates from a preformed hepatic pool.

Daily bilirubin secretion equals its daily production,

a phenomenon indicating no enterohepatic recir-

culation for this pigment under physiological

conditions. This is because mono- and diglucuro-

nated bilirubin molecules are too large and polar

to be absorbed in the small intestine. In the colon,

bacterial b-glucuronidase hydrolyzes bilirubin conju-

gates and unconjugated bilirubin either precipitates

as an insoluble calcium salt or is further catabolized

to urobilinogen. This latter may be partly absorbed

in the colon and undergo a limited enterohepatic

circulation.

0024 Studies in rodents suggest that bilirubin absorption

may occur under conditions of increased bile acid

concentration in the colon resulting from ileal bile

acid malabsorption. Under these circumstances

excess colonic bile acid concentration may solubilize

unconjugated bilirubin, thus favoring passive intes-

tinal absorption and reentry in the enterohepatic cir-

culation of this pigment. This phenomenon may

explain the incidence of pigment gallstones in patients

with ileal disease and the phenomenon of acquired

gallstone calcification in a minority of patients with

cholesterol gallstones treated with ursodeoxycholic

acid, a bile acid causing malabsorption of endogen-

ous bile acid.

0025 Other endogenous compounds present in very low

concentrations in human bile undergo an enterohepa-

tic circulation. This is the case for some vitamins,

such as 25-hydroxyvitamin D

, 1,25-dihydroxyvita-

min D

, vitamin B

, and folic acid. Enterohepatic

circulation has also been reported to contribute to

the conservation of several hormones, such as corti-

costerone, hydrocortisone, androsterone, estrone,

and thyroid hormones. These endogenous com-

pounds are mainly excreted in bile as their glucuro-

nide or sulfate conjugates, and deconjugation by

colonic bacteria is essential for them to be passively

reabsorbed by the colonic mucosa.

Exogenous Compounds

0026 Many environmental pollutors, toxins, and drugs

undergo an enterohepatic circulation. For the major-

ity of these substances the evidence supporting

an enterohepatic circulation is based on animal stud-

ies, and the large interspecies variation in biliary

excretion of xenobiotics indicates that extrapolation

of results to humans must be taken with caution.

0027Among environmental pollutants, heavy metals

such as mercury, arsenic, manganese, and copper

undergo an enterohepatic circulation. Methylmer-

cury poisoning has been reported to occur in Iraqi

and Japanese populations exposed to this pollutant.

Oral administration of a polythiol-binding resin inter-

rupts the enterohepatic circulation of methylmercury,

and has been reported to benefit exposed popula-

tions. An enterohepatic circulation has been reported

for many insecticides and for polycyclic aromatic

hydrocarbons. Mutagenic metabolites of benzo-[a]-

pyrene, an environmental carcinogen, are excreted

in rat and rabbit bile and undergo an enterohepatic

circulation, 1-nitropyrene, a combustion product of

diesel engines, is also a potent mutagenic substance

which is mainly excreted in bile and reabsorbed in the

gut in rat.

0028Certain fungal toxins exert their effect by accumu-

lating in the body via the enterohepatic circulation.

This is the case for ochratoxin, a mycotoxin that may

contaminate food, and for a-amanitin, a toxin pro-

duced by mushrooms of the Amanita phalloides

species. Amanita poisoning in humans is due to enter-

ohepatic recirculation of a-amanitin for up to 48

following ingestion of Amanita mushrooms. This

toxin is harmless in some herbivorous animals lacking

an enterohepatic circulation of a-amanitin.

0029Many drugs undergo enterohepatic circulation,

including the following examples:

0030Demeclocycline

0031Rifampicin

0032Digoxin

0033Digitoxin

0034Imipramine

0035Sulindac

0036Eterophine hydrocloride

0037Estradiol

0038Mycophenolate mofetil

0039Verapamil

0040Colchicine

0041Oxazepam

0042Phenytoin

0043Spironolactone

0044Indometacin

0045Diclofenac

0046Valproic acid

0047Morphine

0048Warfarin

0049Lormetazepam

0050Adriamycin

For some of these drugs, conservation via the entero-

hepatic circulation is beneficial because it prolongs

3602 LIVER/Enterohepatic Circulation