This chapter tries to reapproximate the edges of Section N1(i) from the 2017 CICM Primary Syllabus, which expects nothing less than the trainee "describe the storage, synthetic, metabolic, immunological and excretory functions of the liver." The objective commanded by this imperative statement is so vast that to address it in a single page would be overambitious even for the notoriously immoderate writer of Deranged Physiology (where "summary" chapters routinely run to 9,000 words). This section of the CICM syllabus really deserves to be split into several smaller sections to make it manageable, and to make it easier for the reader to ignore the parts they view as boring or irrelevant; and of these latter attributes, this functional anatomy section surely is the epitome.
The main reason for having it here is the dim and distant possibility that some day somebody may ask about it in a written exam question of cross-table viva. For many of the other organ systems (notably, the kidney) examiners have either approached the question directly, or had implied the expectation of it in their comments. Certainly, the liver is an attractive candidate for an "outline the functional anatomy" sort of question. For instance, the eye-pleasing hexagonal regularity of the hepatic microcirculatory unit just begs for an SAQ involving a labelled diagram; and the dual blood supply of the liver is sufficiently unique and interesting that it has already been exploited in several past paper questions (covered in the separate section dealing with hepatic blood flow).
Gross structure of the liver
- Highly vascular 1500-1800g organ with a dual blood supply
- Consists of hepatocytes (70%), cholangiocytes (15%) and Kupffer cells (15%)
- Separated functionally (by blood supply) into four lobes and eight sectors
Fine structure of the liver
- Separated functionally into 1-2mm units (hepatic lobules)
- Each lobule has a central hepatic vein and peripheral portal tracts (portal vein, biliary ductule, hepatic arteriole), connected by hepatic sinusoids.
- Low resistance fenestrated vessels with very low pressure (2-4 mmHg), surrounded by the space of Disse and containing specialised cell populations:
- Sinusoid endothelial cells are highly permeable and extensively fenestrated vascular endothelial cells with mainly transport functions
- Kupffer cells, monocytes that are part of the reticuloendothelial system and which play a phagocytic/metabolic role (eg. in the reclamation of iron from haem and senescent RBCs)
- Hepatic stellate cells, pericytes performing regulatory (blood flow) and storage functions (store Vit A)
- Hepatocytes, highly metabolically active specialised transport cells with numerous microvilli
- Cholangiocytes, specialised cuboidal/columnar epithelial cells which secrete and concentrate bile
- Space of Disse is the narrow (500-1000nm) space that contains hepatocyte microvilli, hepatocyte precursor stem cells and hepatic stellate cells.
- From the space of Disse, filtered blood plasma flows through interstitial lymphatic channels into the thoracic duct, where hepatic lymph contributes ~50% of the total flow
Anatomy of the hepatic circulation, briefly
- Total blood flow = 25% of the total cardiac output
- Dual blood supply, from the hepatic artery (30%) and portal vein (70%)
- "Hepatic arterial buffer response" autoregulates arterial supply to compensate for changes in portal venous flow
- Anastomosis of portal venules and hepatic arterioles form the hepatic sinusoids
- Sinusoids drain into the hepatic vein, which returns to the IVC
Anatomy of the biliary circulation
- Bile is secreted initially by hepatocytes, into biliary canaliculi (fine canals between adjacent hepatocyte walls)
- Canaliculi drain into canals of Hering, then interlobular ducts, terminal cholangioles, interlobular ducts, septal ducts, area ducts, segmental ducts and finally into hepatic ducts, which are a part of the extrahepatic biliary tree
The best peer-reviewed reference for this material has to be this textbook chapter by Nagy et al (2020), best mainly because it is free online somehow. For the reader whose time is as limitless as their interest in liver physiology, the rest of that textbook (The Liver, Irwin et al, 2020) is also a solid recommendation. On the other hand, for those who have only enough time to skim two pages of quick notes, Mitra & Metcalf (2009) are literally that.
If you had to describe the liver in a single catchy headline phrase, like the opening line of a dating app profile, you'd be forced to blather something like this:
The liver is the largest gland in the body, a 1.8kg wedge-shaped intraperitoneal organ occupying most of the right hypochondrium and extending across the epigastrium into the left hypochondrium.
This is a paraphrase of the opening words from Mitra & Metcalf, intended to borrow and harness some of the mindboggling absurdity of such statements. It is absolutely remarkable that, for articles where an international authority on hepatology is invited to write a paper on liver physiology for an international liver journal or liver textbook with a predominantly specialist physician readership, inevitably the opening paragraph introduces the liver to the reader as if they were aliens who have never before laid their eyes on the human abdomen. "A large lobed glandular organ in the abdomen"; "the largest and heaviest glandular organ in the body, ...high up in the abdominal cavity occupying most of the right hypochondrial region"; "a continuous mass of parenchymal cells tunneled by vessels through which venous blood flows on its way from the gut to the heart"; etc. Still, it is included here because CICM examiners often like an opening statement, even if it has no meaning beyond signalling that the exam candidate also appreciates well-crafted opening statements.
At least Lasts' Anatomy is keeping it real. "Its form has nothing to do with its function; the large wedge-shaped mass ...is merely a cast of the cavity into which it grows". This in fact true: a developmentally heterotopic liver (i.e a lump of liver tissue that accidentally grows in some random location) is often of an irregular appearance as if it were poured into the space it occupies. The anatomical relations of an orthotopic liver (in its right place) are usually as follows:
Those ligaments are probably of some importance in their role of keeping the liver in its position, high in the abdomen and partially protected by the rib cage. Still, most of the work is done by other supporting structures; specifically "the stability of the liver in its normal position is maintained principally by the three major hepatic veins attached to the inferior vena cava", according to Mahadevan (2020). The phrase "the stability of the liver" implies some sort of horrifying scenario where one might have a liver that is somehow unstable, loose and free to drop ungracefully into the pelvis with a moist plopping sound like a wet sock hitting the bathroom floor. Reader, this is no joke. Unlike a lot of abdominal content, this is a heavy solid blood-filled object, and it will move around considerably if given half a chance. For example, Martin et al (2007) reported a case of a patient with an exceptionally lax mesocolon whose liver shifted listlessly across the abdomen, settling into any dependent position as the patient turned from left to right.
Drawing boundaries for the regions of the liver has been a geopolitical nightmare akin to trying to redraw the borders of European states following the first World War. Each famous anatomist who had taken up this challenge seems to have gerrymandered the anatomical and functional boundaries in some logical-sounding but maddeningly different way. For example, the liver has been divided into eight segments, based mainly on the branches of its major vessels, into anatomical lobes which correspond to the visible grooves formed by ligaments and fissures, into functional "hemilivers" delineated by blood supply and biliary drainage (separated by an imaginary line running from the middle hepatic vein to the middle of the gallbladder), and into four sectors, divided anatomically by the hepatic veins.
It appears the main cause of this disagreeable state is the fact that in humans the macroscopic anatomical divisions of the lobes are rather meaningless, as they have no relationship to the way the liver is going to behave when injured, cut, or infected. Sure, ligaments and their boundaries are important, but people who handle livers all day (eg. surgeons) or those who embolise things into them (oncologists and radiologists) are much more interested in watershed areas between blood supply territories. Finding relatively less vascularised watershed boundaries was actually an essential precondition for things we take for granted these days, like for example segmental liver resections. For this reason, the adoption of the blood-supply-based eight-segment classification system has been probably more widespread, and if the trainee feels the need to learn any specific classification system, let it be that one.
Realistically if we're going to be so focused on the circulatory connections then even this level of complexity is probably insufficient and some authors have proposed systems incorporating twenty vascular segments (Majno et al, 2013).
In textbooks, the discussion of this confusing mess is usually helped along with an equally confusing diagram of a liver appearing to be caught mid-explosion, separating into segments like a fragmentation grenade. It is still actually better than the original diagram from Claude Couinaud's "Le foie: études anatomiques et chirurgicales", which is shown alongside it below.
The likelihood of being asked to identify any individual segment (eg. "which segment is this?") is very small, and the likelihood of being asked to describe the macrostructural organisation of the liver (in writing) is probably only slightly higher. Still, it could not hurt to organise this information into a slightly clearer diagram:
Though the circulation of the liver is discussed in a detailed chapter all to itself, as well as in the chapter dedicated to portal systems, it probably would not hurt to refresh the reader's memory briefly, that:
This may or may not be clearer with a diagram:
The assumption is made here that broad overviews and crude schematics are that one would require for a passing grade in the CICM primary exam, but in the event that somebody requires more detail and precision, Ellis (2011) is an excellent reference with very clear diagrams.
Beyond the segment-level geographic divisions, the next strata of liver architecture is the hepatic lobule. These little polyhedrons were first discovered by Kiernan in 1833, and sometimes end up referred to as "Kiernan's lobules". The best modern reference about this anatomical subunit is Zbigniew (2001), whose whole book is gold, but you don't need to read it all, as there is only a simple diagram and a few structures to label. To score full marks in some hypothetical written exam question, one would need to produce a diagram containing the following essential elements:
The most stripped-down minimalist version of this would be a flat diagram of some sort, where you only draw one sinusoid connector, and label only the essential elements:
Additionally, a couple of other portal tract structures are sometimes mentioned in the literature, though not in every textbook:
There are of course some magnificent examples of liver art in the literature, which are a joy to look at, but which convey exactly the same information. For example, below are some beautifully shaded charcoals from Rappaport et al (1954) and Hamilton (1976).
At this stage, one must carefully undeceive the reader, who may by this stage have become accustomed to seeing cylindrical hexagonal structures everywhere. This shape is a mirage, a figment of the artist's imagination generated by the need to teach a complex concept, and has nothing to do with the real organisation of the human liver. It just so happens that Francis Kiernan, describing liver lobules for the first time, was writing about his findings in animal livers, and it just so happens that many animals have very clear connective tissue boundaries that separate their lobules from each other, giving their livers a polygonal appearance in cross-section. Not so for the human liver, which has fewer such boundaries, and which looks a lot more homogeneous histologically. For example, here is a black-and-white specimen of a porcine liver from Ekataksin et al (1991) and a human sample from Al-Maaini et al (2008): both were prepared with stains designed to accentuate connective tissue.
Yes, there is some certainty and regularity to the microvascular blood supply. To borrow some words from Kruepunga et al (2019):
"Typically, ~6 such terminal parenchymal portal twigs, accompanied by arterial and ductular twigs, embrace a piece of parenchyma that has a terminal hepatic vein as its central axis"
However these pieces of parenchyma are not cylinders, as the vessels describing their corners and centres are not politely parallel - they branch chaotically in three dimensions, wrapping around irregularly sized pieces of tissue. In case you're having some trouble visualising this, one might expect this day and age to have brought forth some beautiful 3-D renders, but in fact that is not the case. Instead we need to turn to the early 20th century. A rendering can be approximated using the excellent artwork of Franklin Paradise Johnson (1918), who cooked formalin-hardened pig liver in some hydrochloric acid until the lobules separated by gentle shaking. The images he created of these lobules remain the most remarkable and informative, a hundred years later. They are retouched and presented with colour, below, with the greatest respect to the originals.
From these images, the reader should develop a more accurate impression of the mammalian liver lobule; which is to say, "a random lump of random size and with no specific geometrical pattern". Likely the human lobules are the same as this, except more difficult to separate and perhaps with more irregular borders. Each lobule is unique, bearing on its sides the impression of neighbouring structures, which may in some cases produce a polyhedral appearance (as soft geometric solids filling a space tend to take on a more regular appearance the more they are packed). They also vary in size dramatically - Johnson reported that the greatest lobules were some 64 times larger than the smallest - and tend to clump or branch into what Kiernan called "compound lobules".
So finally in this functional anatomy page we are moving soundly in the direction of the "functional" and away from the "anatomy". The parenchyma of the liver between portal veins and central veins is spanned by highly porous capillaries with a rather highly conserved length, on average about 385 μm in humans. When these caught the eye of some nameless histologist, perhaps around 1900, they called them "sinusoid", not because of a sine-wave undulating geometric shape, but because they are sinus-like - i.e. not just long straight pipes like other blood vessels, but more like blood-filled cavities. The specific explanation offered by Charles Minot (1900), to whom the discovery of sinusoids is occasionally attributed, was actually rather cumbersome and involved a lot of callouts to developmental morphology:
“The proliferating tubules or trabeculae of an organ encounter a large vessel and invade its lumen, pushing the endothelium of the large vessel before them. By the convolution or anastomosis of the tubules or trabeculae, the lumen of large vessels becomes to be subdivided into small ones, while capillaries send out vascular sprouts to ramify into the mesenchyme”
As one might imagine, a lot of Minot's contemporaries responded with "so how is this not just a large capillary?" and that remains a really good question. They are not in fact much larger than other capillaries, i.e. around 8-10 μm. Their shape, however, is much more irregular than that of normal capillaries, and they connect to each other extensively, looking a little like the capillary sheet of the pulmonary circulation. Here, this colourised SEM image illustrates the concept better than words:
Other unique features include a near-absent discontinuous basement membrane, and the presence of numerous bristlecoated micropinocytotic vesicles. Clearly this is a vascular endothelium that encourages the movement of molecules of all sizes. Most of the time when sinusoids are discussed people tend to also mention the unique cellular population of the sinusoid environment, for example Kupffer cells, phagocytic descendants of the monocyte lineage which sit in the lumen of the sinusoids and which are responsible for clearing products of bacterial activity which are abundant in portal blood. Hepatic stellate cells are also occasionally mentioned, as they contribute to several clinically important pathological processes (for example, cirrhosis).
At the most basic level, an exam candidate would only need to produce a very simple diagram to describe this structure with labels for the following essential elements:
If one were feeling extremely generous, one could also add the biliary canaliculi. The whole thing could even look as simple as this:
This stripped-down minimalist diagram is actually representative of what one might see from the middle of the peer-reviewed literature range (eg. Wardle et al, 1987).
Artwork from the sort of publications that can afford professional artists is also available, for example this one from Ehrlich et al (2019), but here it is probably unnecessary, as firstly the natural beauty of the liver speaks for itself and requires no artistic embellishment, and secondly the reader, having gotten this far, now probably has a pretty good understanding of what these structures look like. Therefore, the SEM images which follow (from the excellent min-atlas by Mocci et al, 2014) are offered here mainly for aesthetic reasons. For example, here is a nice rectangular chunk of liver biopsy material, with a higher magnification focus on a portal tract where a portal vein, hepatic artery and biliary ductile can be seen nestled together within a dense connective tissue sheath:
Note the relative size and shape of the vessels. The hepatic artery appears puny next to the cavernous hollow of the portal vein. It would surprise nobody to learn that most of the hepatic blood supply comes from the latter. To move closer to the sinusoids themselves, the hepatocyte muralium is revealed in greater detail, with the fine channels of the biliary canaliculi now visible as they thread between the hepatocytes (outlined as the fine green lines in the image below).
Muralium is just an intelligent-sounding Latinisation of "wall". The term is often used to describe the complex structure of interconnected hepatocytes, and probably refers to the fact that they look like brickwork - though, looking at the workmanship in this diagram from Elias (1949), one must remark that the bricklayer is clearly on acid.
To be fair, "muralium" is not the worst possible example of nomenclatural overengineering, as Hans Elias pointed out that prior to his introduction of the term, words like cord, trabecula, column, Strang, cordone, and labyrinthis hepaticus were being thrown around irresponsibly in the routine parlance of liver histologists. Fortunately there is no need to know the names of these structural concepts, as it is enough for the reader to accept that the topography of hepatocytes is intentionally highly complex to maximise their contact with the bloodstream.
The tributary sinusoids ultimately converge to empty into a hepatic central lobular vein. In the SEM image below (Motta, 1984) one may see numerous fenestrations from the openings of these tributaries in the wall of the central lobular vein as it runs through the hepatic parenchyma to empty into the sublobular vein, seen as a cliff falling away into the distance of the right lower corner:
From the tone of the discussion, the casual reader will by now have correctly realised that a major digression from examinable material is taking place. For those who are understandably enraged by this development, a link to liver questions from the CICM exam is offered here as an escape tunnel of sorts. For the others, what follows is a self-indulgent expedition into the finer detail of hepatic sinusoids (caveat lector).
Moving from the lumen of the sinusoid in an inwardly direction, the first thing to encounter will be Kuppfer cells, which typically hang out in the lumen.
When Karl Wilhelm von Kupffer first described them he conflated them with the hepatic stellate cells (his original drawings can be seen below), and referred to them as Sternzellen.
These cells come from a monocyte lineage and are related to macrophages. That might make you think of them as motile patrolling phagocytes, and this is helped by images like the one above (in the SEM microphotograph it looks like the Kupffer cell is about to slink off down into the opening of a nearby sinusoid). In fact, though they are capable of movement, they are pretty sedentary; because they are exposed to constantly flowing blood, they have no need to move - they can afford to stay in place and capture passing debris with their pseudopods, like sea anemones.
Kupffer cells are numerous, and in general they are the largest population of tissue resident macrophages in the body (80-90% of the total). The reader may be surprised to learn that the cell population of the liver is 15% Kupffer cells by mass, i.e. they are carrying around about 100-150g of them (Kolios et al, 2006). As far as monocytes go, they have considerable longevity- most survive for months, and Steinhoff et al (1989) found some donor Kupffer cells still crawling around in graft livers up to a year after transplantation.
What do they do, one might ask? Wardle et al (1987) summarise their functions reasonably well. In short, they identify and engulf various large macromolecules. Their phagocytic role and their metabolic roles are essentially the same role (they phagocytose things, and then metabolise them). When you hear that something or some drug is "metabolised by the reticuloendothelial system", virtually this means that most of the work is being done by Kupffer cells.
To list their jobs:
Numerous other physiological activities are attributed to this lineage, well beyond the scope of even this verbose article, and moreover the function and dysfunction of Kuffer cells is implicated in the pathogenesis of numerous liver diseases (alcoholic cirrhosis, viral hepatitis, drug-induced hepatotoxicity, NASH, etc etc). A detailed review of these matters is somewhat beyond the author's interest and abilities, and so the reader is instead redirected to works by Bilzer et al (2006) or Ma et al (2017) who have done this topic justice.
The most important characteristic of these endothelial cells are their fenestrations, the major difference between t. In fact, when these fenestrations start to disappear in the context of various disease states, the process is referred to as "capillarisation" and tends to be associated with the development of fibrosis and portal hypertension. Some of those fenestrae are so large (up to 300 nm) that details of the structures in the space of Disse can be seen through them, poking through like toes through the hole in a sock.
From looking at these abundant pores, one must come to the conclusion that these endothelial cells cannot possibly play any sort of serious barrier function. In fact, the opposite is the case: the role of this endothelial lining is to facilitate transport and absorption on every scale. Sørensen et al (2011) report that these cells have some of the highest capacity for endocytosis out of all endothelia. This is the main role of this layer: to enhance the bidirectional transit of substances to and from the hepatocytes. Another interesting feature is their almost total reliance on anaerobic metabolism: these cells produce quite a large amount of lactate, which is then recycled by the hepatocytes as a metabolic substrate.
Below is the first pictorial description of this space by Joseph Disse in 1890 (the C.sch in his drawing is referring to Capillarscheiden or capillary sheath). It's pronounced Diss-uh, until we all decide to rename it as the perisinusoidal space.
This tiny crowded volume is attributed a great importance, being called things like "the liver hub" and "a stem cell niche". Without speaking disrespectfully of the space, one must point out that in reality the most important role is played by the specific cellular contents. The space of Disse is just a 500-1000nm space between the flat and porous endothelial layer of the sinusoid and the hepatocytes, filled with blood plasma and a tangled forest of hepatocyte microvilli. As you can see from the SEM images below (where it is a pale yellow), it's a messy cluttered environment.
Though the high porosity of the sinusoidal endothelium means it really can't filter even large molecules in a meaningful way, it can at least cordon the space of Disse from cellular components of the blood, and therefore one should not normally expect to find erythrocytes in there. The most important residents of the space of Disse are:
Interestingly, the space is also innervated. Unmyelinated sympathetic fibres appear to be connected to hepatocytes directly, or to hepatic stellate cells, which are then used as intermediaries to change the behaviour of hepatocytes. Bioulac-Sage et al (1990) suggested that these may be involved in the regulation of sinusoidal blood flow and the release of glucose from hepatocytes.
One additional factor which lends some importance to this space is the continuity of it with the lymphatics of the liver. According to Ohtani & Ohtani (2008), the liver is a major source of lymph, and hepatic lymph comprises some 50% of the total flow in the thoracic duct. This hepatic lymph is produced by the filtration of blood though the fenestrated sinusoidal capillaries, and is relatively protein-rich when it is compared to normal lymph or interstitial fluid.
These are also occasionally referred to as perisinusoidal fat-storing cells, sinusoidal pericytes, vitamin A-storing sinusoidal cells, sinusoidal lipocytes, hepatic interstitial cells, fat-storing liver cells or Ito cells. This list of pseudonyms should give the reader a reasonably accurate overview of what they are, what they do, where they live, and who discovered them (Toshio Ito). A lot of what has been written about this cell population can be safely put in the "intensivists don't need to know" basket and the interested reader is invited to review the excellent review article by Scott Friedman (2008), who refers to them as "enigmatic", "intriguing" and "a nexus in a complex sinusoidal milieu". To describe their functions for the disinterested critical care specialist, a list suffices:
The majority of the liver is composed of hepatocytes. To offer a peer-reviewed reference that describes these cells with the optimal ratio of detail to readability, it is hard to do better than Schulze et al (2019). Hepatocytes form the inner walls (muralium?) of the sinusoids, with the blood-facing surface area often quoted as 800m2, before one takes into account the effect of microvilli.
To discuss the functional anatomy of hepatocytes implies some mention of their structure, but unfortunately hepatocytes are not especially interesting from a structural standpoint. Ontologically, they originate from the foregut ectoderm, which basically makes them a highly modified version of an epithelial cell (if one were pushed one would have to describe them as "columnar", as the cells have a vaguely cuboidal polyhedral shape). Each is about three times larger than an erythrocyte, about 20-30 μm in diameter, with a large round nucleus (occasionally two), teeming inside with organelles (mainly endoplasmic reticulum, transport vacuoles and mitochondria). They are not attached to a tough basal lamina - instead each hepatocyte is surrounded by a low-density extracellular matrix. Each hepatocyte has a distinct apical and basal membrane, with different absorptive and secretory functions. Interestingly, the "apical" membrane is generally held to be the canalicular membrane, not the sinusoidal one - ie. hepatocytes have unusual polarity when compared to other cuboidal epithelial cells.
From a metabolic standpoint these cells are extremely versatile and can switch between metabolic fuel sources depending on what is most abundantly available (Rui , 2014). For example, where carbohydrate is in excess, the hepatocytes make use of glucose as their main metabolic substrate (and they will package some of it for later, as lipid). Where glucose is less available, they will switch to using fatty acid oxidation.
The answer to the question, "what is the functional role of hepatocytes", is basically the same as the answer to the question "what is the functional role of the liver". This question has appeared in the CICM exam enough times to merit its own page, which fortunately means that it is not necessary to repeat the discussion here. It will suffice to say that the hepatocytes are the main functional unit of the liver, and they perform in several specialised metabolic, synthetic, storage and excretory roles.
Being geographically located in the liver, the intrahepatic biliary tree probably needs to be included in any discussion of the functional anatomy of the liver. It has been added on at the very end of this already over-long chapter because of some puzzling logical choices on the part of the author, who for some reason decided to thread the discussion of hepatobiliary structures in the same order as they are encountered by an enterally absorbed cholesterol molecule. Extending this trend to its logical conclusion, the biliary tree can be described sequentially, moving from the canalicular membrane of the hepatocytes, all the way through the progressively widening branches of the biliary tree and out to the intestine. All of these various sizes of branches have different names, and occasionally there are several accepted names for each size. What follows has borrowed some measurements and nomenclature from Strazzabosco & Fabris (2008):
Cholangiocytes are distinct cells from hepatocytes (even though they both originate from the same stem cell precursors) and under normal circumstances there are no cells in the healthy liver which are in a state of transition from one to the other.
As the physiology of the biliary tree is discussed in detail elsewhere, the interested reader is redirected to Tabibian et al (2013). In summary, the most important structural and functional elements of these cells are
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