Cholestatic Disease
Cholestasis is defined as impaired biliary flow. Dysfunction
of the bile transporter is the main cause of intrahepatic cholestasis (inherited
or acquired), whereas mechanical obstructions to bile flow is the chief cause of
extrahepatic cholestasis. Pruritus is an early symptom of cholestasis, which results
from retained bile salts.[370]
[371]
[372]
[373]
As
cholestasis
progresses, jaundice develops and increases in severity.[370]
[374]
The stool becomes lighter in color and the
urine darkens, because bile pigments are diverted from the gastrointestinal tract
to the kidney for excretion. Laboratory tests show increased blood levels of the
major constituents of bile: namely, bile acids, cholesterol, bilirubin, hepatic
enzymes in bile (AP, GGTP, 5'-NT, leucine aminopeptidase) and immunoglobulin A.
Unconjugated bilirubin is the most toxic of the biliary substances. It disrupts
essential metabolic pathways (e.g., oxidative phosphorylation, tricarboxylic acid
cycle, glycogenesis) and, at high concentrations, causes membrane dysfunction.
The pathogenesis of cholestatic disorders is complex,[371]
[375]
[376]
[377]
and the etiology is vast ( Table 19-4
).
[165]
[373]
[378]
[379]
[380]
[381]
[382]
[383]
[384]
[385]
[386]
[387]
[388]
[389]
[390]
[391]
[392]
[393]
[394]
[395]
[396]
[397]
[398]
[399]
[400]
[401]
[402]
[403]
[404]
[405]
Cholestatic disorders can induce pathologic changes throughout the body, variably
affecting elimination and pharmacokinetics.[406]
[407]
[408]
[409]
[410]
For many drugs, their alpha-phase of disposition
increases and their initial elimination decreases.[411]
[412]
Treatments for the symptoms of cholestasis
have been reviewed elsewhere.[379]
[383]
[384]
[413]
[414]
Coagulation Disorders
Coagulopathy may develop after brief periods of disrupted biliary
flow. Enteric absorption of fat-soluble vitamins, such as vitamin K, depends on
the presence of bile in the gut and an intact enterohepatic circulation. Patients
with obstructive jaundice or receiving warfarin therapy usually produce vitamin K-dependent
factors at the normal rate, but the factors lack the γ-carboxyl glutamic acid
residues needed for coagulant activity. If a coagulopathy is purely cholestatic,
it should be correctable by parenteral vitamin K. Failure of vitamin K therapy implies
severe liver disease, which can be caused by prolonged biliary obstruction. In such
settings, particularly when surgery is urgently needed, the hemostatic abnormality
can usually be corrected by giving fresh frozen plasma (and platelets, if needed).
[115]
Renal Dysfunction
Hepatocellular disease and obstructive jaundice impede the transfer
of blood from the splanchnic to the central circulation. Changes in the splanchnic
vasculature and decreases in effective plasma volume predispose to renal hypoperfusion.
Mild-to-moderate hemorrhage is likely to
cause severe hypotension (see following discussion of cardiovascular dysfunction).
The risk of prerenal ARF therefore increases. Prolonged tubular ischemia can cause
ATN. Bilirubin, which is toxic to renal tubules, may play a role in the pathogenesis
of ATN in jaundiced patients.
Cardiovascular Dysfunction
The hemodynamic changes associated with cholestasis are qualitatively
similar to those induced by cirrhosis, but usually not as severe. These changes
often include (1) increased cardiac output, owing to decreased total peripheral vascular
resistance; (2) decreased portal venous flow, secondary to increased portal venous
resistance; and (3) decreased vascular responsiveness to endogenous vasoconstrictors
(e.g., catecholamines) and vasopressor therapy.[415]
The mechanisms by which cholestasis induces cardiovascular changes
remain unclear, and clarifying them is not trivial. Bile is a complex mixture of
chemicals, with various types, amounts, and proportions of bilirubins and bile salts.
Biliary constituents may affect cardiovascular performance directly or indirectly
by modulating reflexes that preserve circulatory homeostasis. Furthermore, disease-specific
pathophysiologic changes (e.g., primary biliary cirrhosis vs. choledocholithiasis)
may influence cardiovascular responses to the constituents of bile. Thus, it is
not surprising that laboratory studies have yet to provide a coherent view of the
cardiovascular effects of cholestasis.
The cardiac effects of bile salts (primary, conjugated, and secondary)
have been studied in isolated rat ventricular muscle preparations, using bile salt
concentrations similar to those in patients with cholestatic jaundice. Bile salts
were noted to decrease peak tension, rate of rise of tension, contractile duration,
and action potential duration. In voltage clamp experiments in rat ventricular myocytes,
sodium taurocholate decreases the slow inward current and slightly increases the
outward potassium current. Thus, negative inotropic effects of bile salts may result
from altered membrane currents.[416]
Laboratory studies have also shown that increased concentrations
of bile salts in blood (cholemia) can depress cardiovascular function and blunt cardiovascular
responses to norepinephrine, angiotensin II, and isoproterenol.[415]
[416]
[417]
[418]
However, other experiments have demonstrated that acute cholestasis can rapidly
depress the heart without altering the responsiveness of cardiac β-adrenoceptors.
[417]
For example, rats subjected to bile duct
ligation
displayed cardiomyopathic changes 3 days later.[417]
After a 3-day period of extrahepatic cholestasis, the rats were pithed; subsequent
experiments revealed intact β-adrenoceptors despite global decreases of myocardial
contractility.
Subsequent studies in animals show that cholestasis markedly decreases
homeostatic reflex responses to losses of intravascular blood volume.[418]
In normal rats, a 10% loss of blood volume does not decrease arterial pressure,
whereas the same blood loss in the presence of cholestasis causes a 50% decline in
blood pressure. Normal animals compensate for the blood loss by mobilizing 15% of
the blood volume from their pulmonary and splanchnic vascular beds. However, animals
with cholestasis mobilize
only 7% of the pulmonary blood volume and none of the splanchnic blood volume.[418]
Thus, cholestasis can decrease the ability of the major physiologic blood reservoirs
(splanchnic and pulmonary vasculatures) to transfer blood to the central circulation.
Mild-to-moderate hypovolemia may therefore cause marked arterial hypotension. If
these experimental findings are clinically relevant, patients with obstructed biliary
flow would need rapid replacement of perioperative fluid losses to avert severe hypotension.
The anesthesiologist should also be aware that biliary decompression can cause severe
cardiovascular collapse.[419]
