Factor VII deficiency
pH 7.4 PCO2
B. Mechanisms and Consequences of Cholestasis
Portal Hypertension
Venous blood from stomach, intestines, spleen, pancreas, and gallbladder passes via the portal vein to the liver where, in the sinusoids after mixture with oxygen-rich blood of the hepatic artery, it comes into close contact with the he-patocytes (→A 1). About 15 % of cardiac output flows through the liver, yet its resistance to flow is so low that the normal portal vein pres-sure is only 4–8 mmHg.
If the cross-sectional area of the liverʼs vas-cular bed is restricted, portal vein pressure ris-es and portal hypertension develops. Its causris-es can be an increased resistance in the following vascular areas, although strict separation into three forms of intrahepatic obstructions is not always present or possible:
◆Prehepatic: portal vein thrombosis (→A2);
◆Posthepatic: right heart failure, constrictive pericarditis, etc. (→A 2 and p. 244);
◆Intrahepatic (→A 1):
– presinusoidal: chronic hepatitis, primary biliary cirrhosis, granuloma in schistosomia-sis, tuberculoschistosomia-sis, leukemia, etc.
– sinusoidal: acute hepatitis, damage from al-cohol (fatty liver, cirrhosis), toxins, amyloi-dosis, etc.
- postsinusoidal: venous occlusive disease of the venules and small veins; Budd–Chiari syndrome (obstruction of the large hepatic veins).
Enlargement of the hepatocytes (fat deposition, cell swelling, hyperplasia) and increased pro-duction of extracellular matrix (→p. 186) both contribute to sinusoidal obstruction. As the ex-tracellular matrix also impairs the exchange of substances and gases between sinusoids and hepatocytes, cell swelling is further increased.
Amyloid depositions can have a similar obstruc-tive effect. Finally, in acute hepatitis and acute liver necrosis the sinusoidal space can also be obstructed by cell debris.
Consequences of portal hypertension.
Wherever the site of obstruction, an increased portal vein pressure will lead to disorders in the preceding organs (malabsorption, spleno-megaly with anemia and thrombocytopenia) as well as to blood flowing from abdominal or-gans via vascular channels that bypass the liver.
These portal bypass circuits (→A 3) use collat-eral vessels that are normally thin-walled but
are now greatly dilated (formation of varices;
“hemorrhoids” of the rectal venous plexus;
caput medusae at the paraumbilical veins). The enlarged esophageal veins are particularly in danger of rupturing. This fact, especially to-gether with thrombocytopenia (see above) and a deficiency in clotting factors (reduced synthe-sis in a damaged liver), can lead to massive bleeding that can be acutely life-threatening.
The vasodilators liberated in portal hyper-tension (glucagon, VIP, substance P, prostacy-clins, NO, etc.) also lead to a fall in systemic blood pressure. This will cause a compensatory rise in cardiac output, resulting in hy-perperfusion of the abdominal organs and the collateral (bypass) circuits.
Liver function is usually unimpaired in pre-hepatic and presinusoidal obstruction, because blood supply is assured through a compensato-ry increase in flow from the hepatic artecompensato-ry. Still, in sinusoidal, postsinusoidal, and posthepatic obstruction liver damage is usually the cause and then in part also the result of the obstruc-tion. As a consequence, drainage of proterich hepatic lymph is impaired and the in-creased portal pressure, sometimes in synergy with a reduction in the plasmaʼs osmotic pres-sure due to liver damage (hypoalbuminemia), pushes a protein-rich fluid into the abdominal cavity, i.e., ascites develops. This causes second-ary hyperaldosteronism (→p. 188) that results in an increase in extracellular volume.
As blood from the intestine bypasses the liv-er, toxic substances (NH3, biogenic amines, short-chain fatty acids, etc.) that are normally extracted from portal blood by the liver cells reach the central nervous system, among other organs, so that portalsystemic (“hepatic”) en-cephalopathy develops (→p. 188).
184
6Stomach,Intestines,Liver
Plate6.20PortalHypertension
185 1
2
3 Posthepatic obstruction
Prehepatic obstruction
Sinusoidal, postsinusoidal
posthepaticand obstruction
obstructionsAll
Ascites
Portalhypertension
Spleno-megaly Vasodilation Blood pressure
CO Aldosterone
ECV
Thrombocytes
Bleeding
Varices
Encephalopathy
Malab-sorption
Sup. v. cav a
Esoph.vv.
Para-umbilical vv.
Portal v.
Int. iliaca v.
Rectal venous plexus Portal collateral circulation
(after Schiebler u. Schmidt)
Liver damage
Hypalbu-minemia
Clotting factors
Right heart failure, constrictive pericarditis
Portal vein thrombosis Alcohol, fatty liver
Acute hepatitis, amyloidosis Fibrosis,
cirrhosis
Granulomas
Intrahepatic obstructions:
postsinusoidal
sinusoidal
presinusoidal
Bile duct Branch of
portal v.
(v. portae) Branch of hepatic a.
(a. hepatica)
Central veins Sinusoid
Bilecanaliculi Hepato-cytes
Danger of rupture Normal
pressure:
48 mmHg
Pressure
Rupture A. Causes and Consequences of Portal Hypertension
Fibrosis and Cirrhosis of the Liver
Liver cirrhosis is a disease in which necrosis, in-flammation, fibrosis, nodular regeneration, and formation of vascular anastomoses develop more or less simultaneously. It is usually caused by the long-term action of noxious factors, es-pecially alcohol abuse, which is the cause in 50 % of cases worldwide. While the probability of cirrhosis developing after a cumulative up-take of 13 kg ethanol/kg body weight is only about 20 %, it rises to over 90 % after 40 kg. The substance that is most responsible for the de-velopment of fibrosis, and thus cirrhosis, is the ethanol metabolite acetaldehyde. Cirrhosis can also be the final stage of viral hepatitis (20–40% of cirrhosis cases in Europe). In acute fulminant disease it may develop in a matter of weeks; in chronic recurrent disease after months or years. It can also occur after an ob-struction to blood outflow (congestive liver;
→p. 184) or after other liver damage, for exam-ple, as final stage of a storage disease (hemo-chromatosis, Wilsonʼs disease;→p. 270 ff.) or genetically determined enzyme deficiency.
Factors involved in liver-cell damage are:
◆ATP deficiency due to abnormal cellular en-ergy metabolism;
◆increased formation of highly reactive oxy-gen metabolites (•O2–,•HO2, H2O2) with
◆concomitant deficiency of antioxidants (e.g., glutathione) and/or damage of protective en-zymes (glutathione peroxidase, superoxide dismutase).
The O2metabolites react with, for example, un-saturated fatty acids in phospholipids (lipid peroxidation). This contributes to damage of plasma membranes and cell organelles (lyso-somes, endoplasmic reticulum). As a result, cy-tosolic Ca2+concentration rises, activating pro-teases and other enzymes so that the cells are ultimately irreversibly damaged.
Fibrosis of the liver develops in several steps (→A). When damaged hepatocytes die, lysoso-mal enzymes, among others, leak out and re-lease cytokines from the extracellular matrix.
These cytokines and the debris of the dead cells activate the Kupffer cells in the liver sinusoids (→A, center) and attract inflammatory cells (granulocytes, lymphocytes, and monocytes).
Diverse growth factors and cytokines are then liberated from the Kupffer cells and the
recruit-ed inflammatory cells. These growth factors and cytokines now
◆transform the fat-storing Ito cells of the liver into myofibroblasts
◆transform the immigrated monocytes into active macrophages
◆trigger the proliferation of fibroblasts The chemotactic action of transforming growth factorβ (TGF-β) and monocyte chemo-tactic protein 1 (MCP‑1), whose release from the Ito cells (stimulated by tumor necrosis fac-torα [TNF-α], platelet-derived growth factor [PDGF], and interleukins) strengthens these processes, as do a number of other signaling substances. As a result of these numerous in-teractions (the details of which are not yet en-tirely understood), the production of the ex-tracellular matrix is increased by myofibro-blasts and fibromyofibro-blasts, i.e., leading to an in-creased deposition of collagens (Types I, III, and IV), proteoglycans (decorin, biglycan, lumi-can, aggrecan), and glycoproteins (fibronectin, laminin, tenascin, undulin) in the Dissé space.
Fibrosis of the latter impairs the exchange of substances between sinusoid blood and hepa-tocytes, and increases the flow resistance in the sinusoids (→p. 184).
The excess amount of matrix can be broken down (by metalloproteases, in the first in-stance), and the hepatocytes may regenerate.
If the necroses are limited to the centers of the liver lobules (→A, top left), full restitution of the liverʼs structure is possible. However, if the necroses have broken through the peripheral parenchyma of the liver lobules, connective tis-sue septa are formed (→A, bottom). As a result, full functional regeneration is no longer possi-ble and nodules are formed (cirrhosis). The consequence of this is cholestasis (→p. 182), portal hypertension (→p. 184), and metabolic liver failure (→p. 188).
186
6Stomach,Intestines,Liver
Plate6.21FibrosisandCirrhosisoftheLiver
187 Noxious factors (alcohol,
viral hepatitis etc.)
Hepatocyte Necrosis
Matrix
Cytokines and other matrix components
Monocyte
Macrophage Myofibroblast
Extracellular matrix production
TGFb Ito (fat) cell
MCP-1 Liver lobule
Cirrhosis Growth factors
cytokinesand Kupffer cell
Cell debris
Cholestasis
Portal hypertension
Metabolic failure Collagen type I, III, IV
Proteoglycans Matrix glycoproteins
Granulocytes Lymphocytes
Chemotaxis
Enzyme leak
Fibrosis
Fibroblast proliferation Chemotaxis
Chemotaxis of inflammatory cells Activation of
Kupffer cells
Nodular regeneration with loss of lobular structure A. Fibrosis and Cirrhosis of the Liver
Liver Failure
(see also p. 184 ff.) Causes of acute liver failure (→A) are poisoning and inflammation, for example, fulminant cho-langitis or viral hepatitis (especially in hepatitis B and E). The causes of chronic liver failure that is accompanied by fibrosis (cirrhosis) of the liv-er (→p. 186) are (→A):◆inflammation, for example, chronic persis-tent viral hepatitis;
◆alcohol abuse, the most common cause;
◆in susceptible patients, side effects of drugs, for example, folic acid antagonists, phenyl-butazone;
◆Cardiovascular causes of impairment of ve-nous return, for example, in right heart fail-ure (→p. 184)
◆a number of inherited diseases (→chap. 8), for example, glycogen storage diseases, Wil-sonʼs disease, galactosemia, hemochromato-sis,α1-antitrypsin deficiency;
◆intrahepatic or posthepatic cholestasis (→p. 182) for prolonged periods, for exam-ple, in cystic fibrosis (→p. 176), a stone in the common bile duct (→p. 178 ff.), or tu-mors.
The most serious consequences of liver failure are:
◆Protein synthesis in the liver is reduced. This can lead to hypoalbuminemia that may result in ascites, i.e., an accumulation of extracellular fluid in the abdominal cavity, and other forms of edema (→p. 250). Plasma volume is reduced as a result, secondary hyperaldosteronism de-velops causing hypokalemia, which in turn en-courages alkalosis (→A, left). In addition, the reduced ability of the liver to synthesize causes a fall in the plasma concentration of clotting factors.
◆Cholestasis occurs (→p. 182), producing not only liver damage but also aggravating any bleeding tendency, because the lack of bile salts decreases micellar formation and with it the absorption of vitamin K from the intestine, so thatγ-carboxylation of the vitamin K-depen-dent clotting factors prothrombin (II), VII, IX, and X is reduced.
◆Portal hypertension develops (→p. 184) and may make the ascites worse because of lym-phatic flow impairment. It may cause thrombo-cytopenia resulting from splenomegaly, and may lead to the development of esophageal
varices. The deficiency in active clotting factors, thrombocytopenia, and varices are likely to cause severe bleeding. Finally, portal hyperten-sion can cause an exudative enteropathy. This will increase the ascites due to loss of albumin from the plasma, while at the same time favor-ing bacteria in the large intestine befavor-ing“fed”
with proteins that have passed into the intesti-nal lumen, and thus increasing the liberation of ammonium, which is toxic to the brain.
◆The hyperammonemia, which is partly re-sponsible for the encephalopathy (apathy, memory gaps, tremor, and ultimately liver coma,→p. 342) is increased because – gastrointestinal bleeding also contributes to
an increased supply of proteins to the colon;
– the failing liver is no longer sufficiently able to convert ammonium (NH3⇌ NH4+) to urea;
– the above-mentioned hypokalemia causes an intracellular acidosis which activates am-monium formation in the cells of the proxi-mal tubules and at the same time causes a systemic alkalosis. A respiratory component is added to the latter if the patient hyperven-tilates due to the encephalopathy.
Further substances that are toxic to the brain bypass the liver in portal hypertension and are therefore not extracted by it as would normally be the case. Those substances, such as amines, phenols, and short-chain fatty acids, are also in-volved in the encephalopathy. Lastly, the brain produces“false transmitters” (e.g., serotonin) from the aromatic amino acids, of which there are increased amounts in plasma when liver failure occurs. These transmitters probably play a part in the development of the encepha-lopathy.
Kidney function is impaired, giving rise to the hepatorenal syndrome (→p. 128).
188
6Stomach,Intestines,Liver
Plate6.22LiverFailure
189 + HCO3
H2N NH4+
NH2
C O Inflammations
(viral hepatitis, cholangitis, etc.)
Venous congestion (e.g. in right heart failure)
Acute
Chronic
Various inherited diseases
Hyper-ventilation Renal NH4+
production Hypokalemia
Alkalosis
Cirrhosis
absorptionFat
Vitamin K deficiency Varices
Enteric amino acid breakdown
Hyper-ammoniemia Ascites
Hyperaldo-steronism Gastrointestinal bleeding Exudative
enteropathy Clotting factors
Aromatic amino acids
Hypo-albuminemia Portal hypertension
Liver failure
Cholestasis Alcohol Toxins
(e.g. organic nutrients)
Phalloidin, amanitin
Urea
Encephalopathy
False transmitters