liver as an organ

7/18/2019 Liver as an Organ

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70 The Liver as an Organ This chapter summarizes the liver's diferent unctions, including:

(1) ltration and storage o blood;() metabolism o carboh!drates, proteins, ats, hormones, and oreign chemicals;(") ormation o bile;(#) storage o vitamins and iron;($) ormation o coagulation actors%

&h!siologic natom! o the iver

• The liver is the largest organ in the bod!, contributing about percent o the total bod! eight, or about 1%$ *ilograms ("%"pounds) in the average adult human% The basic unctional unit o the liver is the liver lobule, hich is a c!lindrical structureseveral millimeters in length and +% to millimeters in diameter% The human liver contains $+,+++ to 1++,+++ individuallobules%

• The liver lobule, shon in cut-aa! ormat in .igure /+-1, is constructed around a central vein that empties into the hepatic

veins and then into the vena cava%• The lobule itsel is composed principall! o man! liver cellular plates (to o hich are shon in .igure /+-1) that radiate

rom the central vein li*e spo*es in a heel% 0ach hepatic plate is usuall! to cells thic*, and beteen the adacent cells liesmall bile canaliculi that empt! into bile ducts in the brous septa separating the adacent liver lobules%

• 2n the septa are small portal venules that receive their blood mainl! rom the venous out3o o the gastrointestinal tract b!a! o the portal vein% .rom these venules blood 3os into 3at, branching hepatic sinusoids that lie beteen the hepaticplates and then into the central vein% Thus, the hepatic cells are e4posed continuousl! to portal venous blood%

• Hepatic arterioles are also present in the interlobular septa% These arterioles suppl! arterial blood to the septal tissues

beteen the adacent lobules, and man! o the small arterioles also empt! directl! into the hepatic sinusoids, mostre5uentl! empt!ing into those located about one-third the distance rom the interlobular septa, as shon in .igure /+-1%

• 2n addition to the hepatic cells, the venous sinusoids are lined b! to other cell t!pes:o (1) t!pical endothelial cells

o () large 6upfer cells (also called reticuloendothelial cells), hich are resident macrophages that line the sinusoids

and are capable o phagoc!tizing bacteria and other oreign matter in the hepatic sinus blood%

• The endothelial lining of the sinusoids has e4tremel! large pores, some o hich are almost 1 micrometer in diameter%

7eneath this lining, l!ing beteen the endothelial cells and the hepatic cells, are narro tissue spaces called the spaces of

Disse, also *non as the perisinusoidal spaces% The millions o spaces o 8isse connect ith l!mphatic vessels in theinterlobular septa% Thereore, e4cess 3uid in these spaces is removed through the l!mphatics% 7ecause o the large pores inthe endothelium, substances in the plasma move reel! into the spaces o 8isse% 0ven large portions o the plasma proteinsdifuse reel! into these spaces%

Hepatic Vascular and Lymph Systems

• The unction o the hepatic vascular s!stem is discussed in 9hapter 1$ in connection ith the portal veins and can besummarized as ollos% 7lood .los Through the iver rom the &ortal ein and epatic rter!

The Liver Has High Blood lo! and Lo! Vascular "esistance

• bout 1+$+ milliliters o blood 3os rom the portal vein into the liver sinusoids each minute, and an additional "++ milliliters3os into the sinusoids rom the hepatic arter!, the total averaging about 1"$+ ml<min% This amounts to / percent o theresting cardiac output%

• The pressure in the portal vein leading into the liver averages about = mm g and the pressure in the hepatic vein leadingrom the liver into the vena cava normall! averages almost e4actl! + mm g% This small pressure diference, onl! = mm g,shos that the resistance to blood 3o through the hepatic sinusoids is normall! ver! lo, especiall! hen one considersthat about 1"$+ milliliters o blood 3os b! this route each minute%

#irrhosis of the Liver $reatly %ncreases "esistance to Blood lo!

>hen liver parench!mal cells are destro!ed, the! are replaced ith brous tissue that eventuall! contracts around the bloodvessels, thereb! greatl! impeding the 3o o portal blood through the liver%

This disease process is *non as cirrhosis o the liver % 2t results most commonl! rom chronic alcoholism or rom e4cess ataccumulation in the liver and subse5uent liver in3ammation, a condition called nonalcoholic steatohepatitis& or '(SH %

less severe orm o at accumulation and in3ammation o the liver, nonalcoholic fatty liver disease )'(LD*, is themost common cause o liver disease in man! industrialized countries, including the ?nited @tates, and is usuall! associatedith obesit! and t!pe 22 diabetes 9irrhosis can also ollo ingestion o poisons such as carbon tetrachloride, viral diseasessuch as inectious hepatitis, obstruction o the bile ducts, and inectious processes in the bile ducts%

The portal s!stem is also occasionall! bloc*ed b! a large clot that develops in the portal vein or its maor branches% >henthe portal s!stem is suddenl! bloc*ed, the return o blood rom the intestines and spleen through the liver portal blood 3os!stem to the s!stemic circulation is tremendousl! impeded, resulting in portal hypertension and increasing the capillar!pressure in the intestinal all to 1$ to + mm g above normal% The patient oten dies ithin a e hours because oe4cessive loss o 3uid rom the capillaries into the lumens and alls o the intestines%

The Liver unctions as a Blood "eservoir



• 7ecause the liver is an e4pandable organ, large 5uantities o blood can be stored in its blood vessels% 2ts normal bloodvolume, including both that in the hepatic veins and that in the hepatic sinuses, is about #$+ milliliters, or almost 1+ percento the bod!'s total blood volume%

• >hen high pressure in the right atrium causes bac*pressure in the liver, the liver e4pands, and +%$ to 1 liter o e4trablood is occasionall! stored in the hepatic veins and sinuses% This occurs especiall! in cardiac ailure ith peripheralcongestion, hich is discussed in 9hapter % Thus, in efect, the liver is a large, e4pandable, venous organ capable o actingas a valuable blood reservoir in times o e4cess blood volume and capable o suppl!ing e4tra blood in times o diminishedblood volume%

The Liver Has Very High Lymph lo!

• 7ecause the pores in the hepatic sinusoids are ver! permeable and allo read! passage o both 3uid and proteins into

the spaces o 8isse

• the l!mph draining rom the liver usuall! has a protein concentration o about A g<dl, hich is onl! slightl! less than the

protein concentration o plasma%

• lso, the high permeabilit! o the liver sinusoid epithelium allos large 5uantities o l!mph to orm%

High Hepatic Vascular +ressures #an #ause luid Transudation into the (bdominal #avity from the Liver and +ortal#apillaries,(scites

• >hen the pressure in the hepatic veins rises onl! " to / mm g above normal, e4cessive amounts o 3uid begin totransude into the l!mph and lea* through the outer surace o the liver capsule directl! into the abdominal cavit!% This 3uidis almost pure plasma, the BseatingB rom the surace o the liver can be so great that it causes large amounts o ree 3uidin the abdominal cavit!, hich is called ascites%

• Bloc-age of portal .o! through the liver also causes high capillar! pressures in the entire portal vascular s!stem o the

gastrointestinal tract, resulting in edema o the gut all and transudation o 3uid through the serosa o the gut into theabdominal cavit!% This, too, can cause ascites%

"egulation of Liver /ass,"egeneration• The liver possesses a remar*able abilit! to restore itsel ater signicant hepatic tissue loss rom either partial hepatectom!

or acute liver inur!, as long as the inur! is uncomplicated b! viral inection or in3ammation%

• 9ontrol o this rapid regeneration o the liver is still poorl! understood, but hepatocyte gro!th factor )H$* appears to be

important in causing liver cell division and groth% C. is produced b! mesench!mal cells in the liver and in other tissues,but not b! hepatoc!tes% Dther groth actors, especiall! epidermal gro!th factor , and cyto-ines such as tumor necrosisactor and interleu*in-A ma! also be involved in stimulating regeneration o liver cells% although transorming gro!thfactor,, a c!to*ine secreted b! hepatic cells, is a potent inhibitor o liver cell prolieration and has been suggested as themain terminator o liver regeneration%

Hepatic /acrophage System Serves a Blood,#leansing unction

• 7lood 3oing through the intestinal capillaries pic*s up man! bacteria rom the intestines% 2ndeed, a sample o blood ta*enrom the portal veins beore it enters the liver almost ala!s gros colon bacilli hen cultured, hereas groth o colonbacilli rom blood in the s!stemic circulation is e4tremel! rare%

• @pecial high-speed motion pictures o the action o 1up2er cells, the large phagoc!tic macrophages thatline the hepatic venous sinuses, have demonstrated that these cells eEcientl! cleanse blood as it passes through thesinuses%

/etabolic unctions of the Liver

• The liver is a large, chemicall! reactant pool o cells that have a high rate o metabolism, sharing substrates and energ!rom one metabolic s!stem to another, processing and s!nthesizing multiple substances that are transported to other areaso the bod!, and perorming m!riad other metabolic unctions% .or these reasons, a maor share o the entire discipline o

biochemistr! is devoted to the metabolic reactions in the liver% 7ut here, let us summarize those metabolic unctions that areespeciall! important in understanding the integrated ph!siolog! o the bod!%#arbohydrate /etabolism

• 2n carboh!drate metabolism, the liver perorms the olloing unctions, as summarized in 9hapter A/:

1% @torage o large amounts o gl!cogen% 9onversion o galactose and ructose to glucose"% Cluconeogenesis#% .ormation o man! chemical compounds rom intermediate products o carboh!drate metabolism

• The liver is especiall! important or maintaining a normal blood glucose concentration%

• @torage o gl!cogen allos the liver to remove e4cess glucose rom the blood, store it, and then return it to the blood henthe blood glucose concentration begins to all too lo% This is called the glucose bu2er unction o the liver%

• 2n a person ith poor liver function, blood glucose concentration ater a meal rich in carboh!drates ma! rise to to threetimes as much as in a person ith normal liver unction%

• $luconeogenesis in the liver is also important in maintaining a normal blood glucose concentration becausegluconeogenesis occurs to a signicant e4tent onl! hen the glucose concentration alls belo normal% Then large amountso amino acids and gl!cerol rom trigl!cerides are converted into glucose, thereb! helping to maintain a relativel! normal

blood glucose concentration%at /etabolism

• lthough most cells o the bod! metabolize at, certain aspects o at metabolism occur mainl! in the liver% @pecic unctionso the liver in at metabolism, as summarized rom 9hapter A, are the olloing:

1% D4idation o att! acids to suppl! energ! or other bod! unctions% @!nthesis o large 5uantities o cholesterol, phospholipids, and most lipoproteins"% @!nthesis o at rom proteins and carboh!drates

• To derive energ! rom neutral ats, the fat is rst split into gl!cerol and att! acids; then the fatty acids are split b! beta-o4idation into to-carbon acet!l radicals that orm acet!l coenz!me (acetyl,#o()%

• This can enter the citric acid c!cle and be o4idized to liberate tremendous amounts o energ!% 7etao4idation can ta*e placein all cells o the bod!, but it occurs especiall! rapidl! in the hepatic cells% The liver cannot use all the acet!l-9o that isormed; instead, it is converted b! the condensation o to molecules o acet!l-9o into acetoacetic acid, a highl! solubleacid that passes rom the hepatic cells into the e4tracellular 3uid and is then transported throughout the bod! to beabsorbed b! other tissues%



• These tissues reconvert the acetoacetic acid into acet!l-9o and then o4idize it in the usual manner% Thus, the liver isresponsible or a maor part o the metabolism o ats% bout + percent o the cholesterol s!nthesized in the liver isconverted into bile salts, hich are secreted into the bile; the remainder is transported in the lipoproteins and carried b! theblood to the tissue cells ever!here in the bod!% +hospholipids are li*eise s!nthesized in the liver and transportedprincipall! in the lipoproteins% 7oth cholesterol and phospholipids are used b! the cells to orm membranes, intracellularstructures, and multiple chemical substances that are important to cellular unction%

• lmost all the at s!nthesis in the bod! rom carboh!drates and proteins also occurs in the liver% ter at is s!nthesized inthe liver, it is transported in the lipoproteins to the adipose tissue to be stored%

+rotein /etabolism

• The bod! cannot dispense ith the liver's contribution to protein metabolism or more than a e da!s ithout death

ensuing% The most important unctions o the liver in protein metabolism, as summarized rom 9hapter A=, are the olloing:1% 8eamination o amino acids% .ormation o urea or removal o ammonia rom the bod! 3uids"% .ormation o plasma proteins#% 2nterconversions o the various amino acids and s!nthesis o other compounds rom amino acids

• Deamination of amino acids is re5uired beore the! can be used or energ! or converted into carboh!drates or ats% small amount o deamination can occur in the other tissues o the bod!, especiall! in the *idne!s, but this is much lessimportant than the deamination o amino acids b! the liver%

• ormation of urea b! the liver removes ammonia rom the bod! 3uids%

• arge amounts o ammonia are ormed b! the deamination process, and additional amounts are continuall! ormed in thegut b! bacteria and then absorbed into the blood% Thereore, i the liver does not orm urea, the plasma ammoniaconcentration rises rapidl! and results in hepatic coma and death% 2ndeed, even greatl! decreased blood 3o through theliver-as occurs occasionall! hen a shunt develops beteen the portal vein and the vena cava-can cause e4cessiveammonia in the blood, an e4tremel! to4ic condition%

• 0ssentiall! all the plasma proteins, ith the e4ception o part o the gamma globulins, are ormed b! the hepatic cells% This accounts or about =+ percent o all the plasma proteins% The remaining gamma globulins are the antibodies ormedmainl! b! plasma cells in the l!mph tissue o the bod!%

•

2t is particularl! interesting that plasma protein depletion causes rapid mitosis o the hepatic cells and groth o the liverto a larger size; these efects are coupled ith rapid output o plasma proteins until the plasma concentration returns tonormal% >ith chronic liver disease (e%g%, cirrhosis), plasma proteins, such as albumin, ma! all to ver! lo levels, causinggeneralized edema and ascites, as e4plained in 9hapter =%

• mong the most important unctions o the liver is its abilit! to s!nthesize certain amino acids and to s!nthesize otherimportant chemical compounds rom amino acids% .or instance, the so-called nonessential amino acids can all bes!nthesized in the liver% To do this, a -eto acid having the same chemical composition (e4cept at the *eto o4!gen) as that othe amino acid to be ormed is s!nthesized%

• Then an amino radical is transerred through several stages o transamination rom an available amino acid to the *eto acidto ta*e the place o the *eto o4!gen%

Other /etabolic unctions of the LiverThe Liver %s a Storage Site for Vitamins

• The liver has a particular propensit! or storing vitamins and has long been *non as an e4cellent source o certain vitamins

in the treatment o patients% The vitamin stored in greatest 5uantit! in the liver is vitamin (, but large 5uantities o vitamin8 and vitamin 71 are normall! stored as ell%

• @uEcient 5uantities o vitamin can be stored to prevent vitamin decienc! or as long as 1+ months% @uEcient vitamin 8

can be stored to prevent decienc! or " to # months, and enough vitamin 71 can be stored to last or at least 1 !ear andma!be several !ears%The Liver Stores %ron as erritin

• 04cept or the iron in the hemoglobin o the blood, b! ar the greatest proportion o iron in the bod! is stored in the liver in

the orm o erritin% The hepatic cells contain large amounts o a protein called apoferritin, hich is capable o combiningreversibl! ith iron%

• Thereore, hen iron is available in the bod! 3uids in e4tra 5uantities, it combines ith apoerritin to orm ferritin and isstored in this orm in the hepatic cells until needed elsehere% >hen the iron in the circulating bod! 3uids reaches a lolevel, the erritin releases the iron% Thus, the apoferritin,ferritin system o the liver acts as a blood iron bufer , as ell asan iron storage medium% Dther unctions o the liver in relation to iron metabolism and red blood cell ormation areconsidered in 9hapter "%

The Liver orms the Blood Substances 3sed in #oagulation• @ubstances ormed in the liver that are used in the coagulation process include brinogen, prothrombin, accelerator globulin,

.actor 22, and several other important actors% Vitamin 1 is re5uired b! the metabolic processes o the liver or theormation o several o these substances, especiall! prothrombin and .actors 22, 2F, and F% 2n the absence o vitamin 6 , theconcentrations o all these decrease mar*edl! and this almost prevents blood coagulation%

The Liver "emoves or 45cretes Drugs& Hormones& and Other Substances• The active chemical medium o the liver is ell *non or its abilit! to deto4i! or e4crete into the bile man! drugs, including

sulonamides, penicillin, ampicillin, and er!throm!cin% 2n a similar manner, several o the hormones secreted b! theendocrine glands are either chemicall! altered or e4creted b! the liver, including thyro5ine and essentiall! all the steroidhormones, such as estrogen, cortisol, and aldosterone% Liver damage can lead to e4cess accumulation o one or more othese hormones in the bod! 3uids and thereore cause overactivit! o the hormonal s!stems%

• .inall!, one o the maor routes or e4creting calcium rom the bod! is secretion b! the liver into the bile, hich then passes

into the gut and is lost in the eces%/easurement of Bilirubin in the Bile as a #linical Diagnostic Tool

• The ormation o bile b! the liver and the unction o the bile salts in the digestive and absorptive processes o the intestinaltract are discussed in 9hapters A# and A$% 2n addition, man! substances are e4creted in the bile and then eliminated in theeces% Dne o these is the greenish !ello pigment bilirubin%

• This is a maor end product o hemoglobin degradation, as pointed out in 9hapter "% oever, it also provides ane4ceedingl! valuable tool or diagnosing both hemol!tic blood diseases and various t!pes o liver diseases%



• Thereore, hile reerring to .igure /+-, let us e4plain this% 7rie3!, hen the red blood cells have lived out their lie span (onaverage, 1+ da!s) and have become too ragile to e4ist in the circulator! s!stem, their cell membranes rupture, and thereleased haemoglobin is phagoc!tized b! tissue macrophages (also called the reticuloendothelial s!stem) throughout thebod!% The hemoglobin is rst split into globin and heme, and the heme ring is opened to give (1) ree iron, hich istransported in the blood b! transerrin, and () a straight chain o our p!rrole nuclei, hich is the substrate rom hichbilirubin ill eventuall! be ormed% The rst substance ormed is biliverdin, but this is rapidl! reduced to ree bilirubin, alsocalled uncon6ugated bilirubin& hich is graduall! released rom the macrophages into the plasma% This orm o bilirubinimmediatel! combines strongl! ith plasma albumin and is transported in this combination throughout the blood andinterstitial 3uids%

• >ithin hours, the uncon6ugated bilirubin is absorbed through the hepatic cell membrane% 2n passing to the inside o the

liver cells, it is released rom the plasma albumin and soon thereater conugated about + percent ith glucuronic acid toorm bilirubin glucuronide, about 1+ percent ith sulate to orm bilirubin sulate, and about 1+ percent ith a multitude o

other substances% 2n these orms, the bilirubin is e4creted rom the hepatoc!tes b! an active transport process into the bilecanaliculi and then into the intestines%

liver as an organ

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