Page 619 - Robbins Basic Pathology by Vinay Kumar, Abul K. Abbas, Jon C. Aster

Clinical Syndromes 605

widespread effects and patients are highly susceptible to Mononuclear phagocytic cell
failure of multiple organ systems. Thus, respiratory failure
with pneumonia and sepsis can give rise to renal failure Heme
and thus claim the lives of many individuals with hepatic oxygenase
failure. A coagulopathy develops, attributable to impaired
hepatic synthesis of blood clotting factors. The resultant HEME 1
bleeding tendency may lead to massive gastrointestinal
hemorrhage as well as bleeding elsewhere. Intestinal Senescent BILIVERDIN Biliverdin
absorption of blood places a metabolic load on the liver erythrocytes reductase
that worsens the severity of hepatic failure. 2
BILIRUBIN–
The outlook with full-blown hepatic failure is particu-
larly grave for persons with chronic liver disease. A rapid ALBUMIN COMPLEX
downhill course is usual, with death occurring within
weeks to a few months in about 80% of cases. About 40% Hepatocyte Blood
of patients with acute liver failure may recover spontane-
ously. Liver transplantation in acute or chronic liver failure Bilirubin
can be curative, however. Conditions contributing to the glucuronides
extraordinary morbidity and eventual mortality associated
with severe liver disease are discussed next. 3

Jaundice and Cholestasis 4 Liver
Bile ducts
Jaundice results from the retention of bile. Hepatic bile
formation serves two major functions. First, bile constitutes Bile Duodenum
the primary pathway for the elimination of bilirubin, excess canaliculus
cholesterol, and xenobiotics that are insufficiently water-
soluble to be excreted in the urine. Second, secreted bile Colon
salts and phospholipid molecules promote emulsification
of dietary fat in the lumen of the gut. Bile formation is a 5
complex process and is readily disrupted by a variety of Urobilinogen
hepatic insults. Thus, jaundice, a yellow discoloration of
skin and sclerae (icterus), occurs when systemic retention Figure 15–1 Bilirubin metabolism and elimination. 1, Normal bilirubin
of bilirubin produces serum levels above 2.0 mg/dL (the production (0.2 to 0.3 g/day) is derived primarily from the breakdown
normal level in adults is below 1.2 mg/dL). Cholestasis is of senescent circulating red cells, with a minor contribution from degrada-
defined as systemic retention of not only bilirubin but also tion of tissue heme-containing proteins. 2, Extrahepatic bilirubin is bound
other solutes eliminated in bile (particularly bile salts and to serum albumin and delivered to the liver. 3 and 4, Hepatocellular
cholesterol). uptake (3) and glucuronidation (4) by glucuronosyltransferase in the hepa-
tocytes generate bilirubin monoglucuronides and diglucuronides, which
Bilirubin and Bile Acids are water-soluble and readily excreted into bile. 5, Gut bacteria decon-
jugate the bilirubin and degrade it to colorless urobilinogens. The urobi-
Bilirubin is the end product of heme degradation (Fig. linogens and the residue of intact pigments are excreted in the feces, with
15–1). Most of the daily production (0.2 to 0.3 g) is derived some reabsorption and reexcretion into bile.
from breakdown of senescent red cells within mononuclear
phagocytes, with the remainder derived primarily from the deconjugated by gut bacterial β-glucuronidases and
turnover of hepatic hemoproteins. Excessive destruction of degraded to colorless urobilinogens. The urobilinogens
erythroid progenitors in the bone marrow due to intramed- and the residue of intact pigment are largely excreted in
ullary apoptosis (ineffective erythropoiesis) is an important feces. Approximately 20% of the urobilinogens are reab-
cause of jaundice in hematologic disorders (Chapter 11). sorbed in the ileum and colon, returned to the liver, and
Whatever the source, heme oxygenase oxidizes heme to promptly reexcreted into bile. Conjugated and unconju-
biliverdin, which is then reduced to bilirubin by biliverdin gated bile acids also are reabsorbed in the ileum and
reductase. Bilirubin thus formed outside the liver in cells returned to the liver by the enterohepatic circulation.
of the mononuclear phagocyte system (including the
spleen) is released and bound to serum albumin. Hepato-
cellular processing of bilirubin involves the following
sequence:
1. Carrier-mediated uptake at the sinusoidal membrane
2. Cytosolic protein binding and delivery to the endoplas-

mic reticulum
3. Conjugation with one or two molecules of glucuronic

acid by bilirubin uridine diphosphate–glucuronosyl-
transferase
4. Excretion of the water-soluble, nontoxic bilirubin glu­
curonides into bile. Most bilirubin glucuronides are