C. The most serious, and often the proximate cause of death, is acute cerebral edema and intracranial hypertension (Table 45-4).

D. Coagulopathy is a necessary finding for the diagnosis of ALF; however, clinically significant spontaneous bleeding is uncommon. Correction of thrombocytopenia to ≥50,000 /mm³ and INR to ≤1.5 are suggested for the bleeding patient or the patient about to undergo an invasive procedure.

E. Hypotension in ALF may be the result of several days of gastrointestinal losses, poor intake, or myocardial dysfunction but likely includes a component of decreased arterial tone as liver necrosis progresses.

1. Vasopressors (norepinephrine, dopamine) may be used to treat either systemic hypotension or to maintain an adequate cerebral perfusion pressure.

2. The use of arginine vasopressin or its analogs cannot be recommended because there is evidence that their use is associated with increases in intrahepatic cholestasis of pregnancy (ICP).

VI. ACUTE HEPATITIS

A. The most common causes of acute viral hepatitis are, collectively, the five identified viral hepatitides: A (HAV), B (HBV), C (HCV), D (HDV or delta-virus), and E (HEV).

1. HAV and HBV have been well characterized, and vaccines have been developed to prevent their transmission.

2. A vaccine is not available for HCV, but the number of reported new cases is decreasing most likely due to better screening of transfused blood products and the adoption of universal precautions.

B. The diagnosis of acute hepatitis is made on the basis of classic signs (jaundice, fever, arthralgia) and symptoms (may be nonspecific such as fatigue or poor appetite) together with laboratory studies. Many infections are subclinical.

C. Incubation periods can be several weeks to even months, and patients may undergo surgery without awareness of illness. For this reason, viral hepatitis should be part of the differential diagnosis when there is any evidence of postoperative liver injury.

VII. ALCOHOLIC HEPATITIS. Alcoholic hepatitis is the syndrome marked by the development of jaundice and liver dysfunction in the setting of heavy alcohol use.

VIII. DRUG-INDUCED LIVER INJURY. Drug-induced liver injury (DILI) is largely a diagnosis of exclusion and should always be considered when formulating the differential diagnosis of patients presenting with liver abnormalities.

A. DILI is a serious problem for the pharmaceutical industry because it is the most common reason for regulatory actions such as failure of approval, removal from market, or restrictions on indications for use.

B. Nonacetaminophen drug-induced idiosyncratic liver injury accounts for 11% to 13% of cases of ALF, and with a 20% rate of survival with supportive care, it has a poorer than average rate of spontaneous recovery.

C. In anesthesiology, perhaps the best-known potentially hepatotoxic drug is halothane.

IX. PREGNANCY-RELATED LIVER DISEASES

A. Abnormalities in liver studies occur in 3% to 5% of pregnancies

B. The most common causes are hyperemesis gravidarum, intrahepatic cholestasis of pregnancy, preeclampsia, preeclampsia complicated by hemolysis, low platelet count, and elevated liver enzymes (HELLP syndrome) and acute fatty liver of pregnancy (Table 45-5).

X. CIRRHOSIS AND PORTAL HYPERTENSION

A. Cirrhosis is the end product of the long course of chronic liver disease, during which there have been either steady or recurrent episodes of parenchymal inflammation and necrosis.

B. Increased resistance to blood flow through the liver leads to portal hypertension. When portal hypertension becomes severe (generally defined as a hepatic venous pressure gradient of >10–12 mm Hg), chronic liver disease becomes a systemic illness, affecting other organ systems as well.

XI. HEMOSTASIS. Hemostasis is a dynamic process that is the product of interaction between coagulation, platelets, and fibrinolysis, resulting in the formation and revision of clot. Liver disease affects all three of these components, both quantitatively and qualitatively.

A. The liver is the site of synthesis for all procoagulant and anticoagulant factors, with the exception of tissue thromboplastin (III), calcium (IV), and von Willebrand factor (VIII). It is also the site for clearance of activated factors.

B. Cirrhotic patients are customarily considered to have a bleeding diathesis on the basis of abnormalities in conventional tests of coagulation such as prothrombin time (PT) and partial thromboplastin time (PTT) (yet PT and PTT abnormalities correlate poorly with bleeding complications).

C. Platelets provide primary hemostasis by interaction with the vessel wall at the site of injury and forming a physical plug. (Thrombocytopenia is a well-known feature of cirrhosis.)

1. A second function of platelets is to promote thrombin generation.

2. Platelet counts below a threshold of 100,000/mm³ negatively correlate with thrombin production. Platelet transfusions are not indicated in the absence of bleeding.

D. The fibrinolytic system limits and revises clot formation (accelerated fibrinolysis common in patients with cirrhosis).

E. Disseminated intravascular coagulation (DIC) is primarily a thrombotic diathesis followed by widespread secondary fibrinolysis. As factors are consumed, DIC becomes a bleeding diathesis of factor and platelet deficiency. It is generally agreed on the basis of examination of these special assays that overt DIC is probably not a feature of stable chronic liver disease.

XII. CARDIAC MANIFESTATIONS

A. Patients with cirrhosis typically have a hyperdynamic circulation characterized by a high cardiac output, low arterial blood pressure, and low systemic vascular resistance.

1. At the heart of these circulatory changes is portal hypertension, which causes local production of vasodilators such as natriuretic peptides, vasoactive intestinal peptide, endotoxin, glucagon, and especially nitric oxide.

2. Elevated production of nitric oxide has been observed to precede the formation of the hyperdynamic circulation in cirrhosis, and inhibition of nitric oxide formation has been shown to increase arterial pressure in cirrhotic patients.

3. Elevated cardiac output is only a consequence of the profound decrease in afterload resulting from the dilated peripheral circulation.

B. Autonomic dysfunction is another characteristic of the altered cirrhotic cardiovascular system.

XIII. RENAL DYSFUNCTION. Renal dysfunction in cirrhosis is characterized by seemingly inappropriate avid retention of sodium and free water together with renal hypoperfusion and consequent decreased glomerular filtration.

A. The extreme manifestation of this is the hepatorenal syndrome (HRS), a prerenal functional abnormality that is the renal response to the circulatory abnormalities of advanced cirrhosis (Fig. 45-2).

1. Type I HRS is characterized by rapidly progressive renal failure, typically represented by at least a doubling of serum creatinine over the course of 2 weeks in close proximity to a precipitating cause such as spontaneous bacterial peritonitis, sepsis, gastrointestinal bleeding, or surgical stress.

a. Patients with type I HRS have a median survival time of 2 to 4 weeks without therapy.

b. When patient with type I HRS respond to medical therapy, the response is usually sustained.

2. Type II HRS is more indolent and may be considered the expected consequence of continuous and progressive activity of the circulatory homeostatic triad of the sympathetic, renin–angiotensin–aldosterone, and vasopressin systems in an attempt to compensate for the progressive loss of effective circulating blood volume to the increasingly dilated splanchnic vasculature.

a. The most compelling clinical problem in these patients is refractory ascites.

b. Patients with type II HRS have a median survival time of about 6 months.

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