Hepatic dysfunction and liver transplantation

1

Describe normal liver anatomy. How is blood supply provided to the liver?

The human liver consists of four anatomic lobes (left, right, caudate, quadrate) and eight surgical lobes (I–VIII). The liver receives approximately 20% to 25% of the cardiac output and contains 10% to 15% of the total blood volume. Its blood supply is provided by the portal vein (75%) and hepatic artery (25%), where each vessel provides 50% of the liver’s oxygen requirements. Hepatic blood flow is regulated by the hepatic artery buffer response, which is mediated by adenosine and modulated by hypoxemia, hypercarbia, and acidosis. Sympathetic stimulation decreases hepatic blood flow.

2

What are the normal physiological functions of the liver?

Almost all plasma proteins are synthesized in the liver. These include albumin, α ₁ -acid glycoprotein, pseudocholinesterase, most coagulation factors, and anticoagulant proteins (i.e., protein C, S, and antithrombin III). Factor VIII is not synthesized by the liver. The liver is also involved in carbohydrate, lipid, and cholesterol metabolism, glucose homeostasis, and bile synthesis. The liver produces 20% of the body's heme. The liver also possesses immune function in that hepatic Kupffer cells filter splanchnic venous blood of bacteria. The liver serves as the main organ of drug metabolism and detoxification. Through three hepatic reactions (phases I, II, and III), drugs are metabolized to a more water-soluble form and excreted in the urine or bile. The liver metabolizes nitrogen-containing compounds to urea and ammonia.

3

Review the most common cause of parenchymal liver disease.

The most common causes of liver disease include viral hepatitis from hepatitis B virus (HBV) and hepatitis C virus (HCV), alcoholism, and nonalcoholic steatohepatitis (NASH). NASH will likely become the most common indication for liver transplantation in the United States because of advancements in treatment for viral hepatitis, including the HBV vaccine and antiviral treatments for HCV. Other causes of liver disease include viruses, such as Epstein-Barr virus and cytomegalovirus, autoimmune hepatitis, hemochromatosis, primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC), and drug-induced liver injury (DILI). DILI can mimic acute viral hepatitis and is most commonly caused by alcohol, acetaminophen, antibiotics, and nonsteroidal antiinflammatory drugs.

4

What is cirrhosis?

Cirrhosis is the sequela of long-term liver disease characterized by diffuse hepatocyte death, with resultant fibrosis and nodular hepatocellular regeneration. Distortion of hepatic circulation further propagates cellular damage and results in progressive reduction of hepatocytes, eventually manifesting as impaired organ function. Hepatic synthetic failure, indicated by a prolonged prothrombin time (PT), hypoalbuminemia, and impaired detoxification mechanisms causing hepatic encephalopathy, is often termed end-stage liver disease (ESLD).

5

Describe the neurologic derangements in patients with cirrhosis.

Several neurologic complications are associated with cirrhosis. Hepatic encephalopathy, ranging from confusion to coma is a common sequela of cirrhosis. Factors associated with encephalopathy include ammonia, blood-brain barrier alterations, and changes to central nervous system (CNS) neurotransmission. Although increased ammonia levels do not directly correlate with the degree of encephalopathy, treatment consists of lactulose to reduce ammonia absorption, and rifaximin to reduce ammonia production by urease-producing bacteria in the gut.

Acute liver failure, formerly called fulminant hepatic failure , often causes severe cerebral edema, leading to intracranial hypertension. It must be appreciated that one of the more common causes of death in acute liver failure is brain stem herniation. In contrast, cerebral edema in patients with chronic liver disease is less severe and generally does not cause intracranial hypertension, unless they develop acute or chronic liver failure.

6

Is cirrhosis a risk factor for sepsis?

Yes, and sepsis is a major cause of mortality in patients with cirrhosis. Patient with cirrhosis are immunocompromised and although the exact mechanism is complex, both the innate and adaptive immune systems are affected. Specifically, the liver is the main source of the complement system and secreted pattern-recognition receptors (toll-like receptors, etc.). The synthesis of these crucial proteins is impaired in cirrhosis. This is also complicated by the fact that the liver is the first organ in direct contact with translocated gut bacteria via the portal vein.

Note that there are frequently other factors contributing to immunodeficiency in this patient population because of the higher prevalence of malnutrition (alcohol abuse, ulcerative colitis, etc.) and immunosuppressive medications for autoimmune disorders (PBC, PSC, etc.).

7

Describe the cardiovascular changes in patients with cirrhosis. Why do these patients have a “hyperdynamic” circulation?

Cirrhosis causes increased vascular resistance within the hepatic circulation causing portal hypertension, which results in nitric oxide (a potent vasodilator) to be released from the splanchnic circulation. This leads to increased nitric oxide within the systemic circulation, causing venous and arterial vasodilation. Blood is sequestered primarily into the splanchnic circulation because of venodilation, causing a decrease in circulating blood volume. The decrease in circulating blood volume (venodilation) and decrease in systemic vascular resistance (SVR) (arterial vasodilation) activates the sympathetic nervous system, renin-angiotensin-aldosterone system (RAAS), and, in severe cases, the nonosmotic release of antidiuretic hormone (ADH). This compensatory response increases total blood volume by retention of salt and water, leading to hypervolemia, ascites, and in severe disease, hyponatremia. The decrease in SVR reduces cardiac afterload, which facilitates a compensatory, sympathetic-mediated increase in cardiac output (i.e., hyperdynamic circulation). Note, that the increase in cardiac output is necessary to prevent severe hypotension and organ failure from decreased perfusion. Mixed venous oxygen saturation is higher than normal in ESLD because of increased cardiac output and shunting from vasodilation.

8

Is coronary artery disease a common comorbidity in chronic liver disease?

Coronary artery disease (CAD), with impaired myocardial function (previously thought uncommon in patients with liver disease), may be present, especially when the patient has NASH. CAD in liver transplant patients older than 50 years of age occurs in the range of 5% to 27%. Abnormalities in both systolic and diastolic function (cirrhotic cardiomyopathy) may be present and may be masked by reduced cardiac afterload and high cardiac output. This is especially true in patients with a history of alcohol abuse.

9

What is hepatopulmonary syndrome?

Arterial hypoxemia with compensatory hyperventilation may be secondary to atelectasis from ascites/hydrothorax or from hepatopulmonary syndrome (HPS). HPS occurs in the setting of portal hypertension and is caused by pulmonary vasodilation, which leads to intrapulmonary arteriovenous (AV) shunting and hypoxemia. The features of HPS include platypnea (shortness of breath while standing), orthodeoxia (decreased saturation when upright), cyanosis, and finger clubbing. HPS can be diagnosed by preforming an agitated saline study on transthoracic echocardiography (TTE); saline microbubbles appearing in the left atrium within 3 to 6 cardiac cycles indicates HPS. The only definitive treatment that can HPS is liver transplantation.

10

What is portopulmonary hypertension?

Portopulmonary hypertension (PoPH), defined as a mean pulmonary artery pressure (PAP) greater than 25 mm Hg and pulmonary vascular resistance (PVR) over 240 dyn · sec/cm ⁵ , is seen in 3% to 5% reverse of patients with cirrhosis. PoPH is caused by intimal proliferation, smooth muscle hypertrophy, and fibrosis in the pulmonary arterial circulation, leading to an increase in PVR. PoPH is subdivided by severity (mild: 25–34 mm Hg, moderate: 35–44 mm Hg, severe: ≥ 45 mm Hg). Mild to moderate PoPH may be reversible with liver transplant; however, more severe PoPH may be irreversible and is associated with high intraoperative and postoperative mortality, secondary to right ventricular dysfunction. Severe PoPH is a contraindication to liver transplantation because it is associated with a high mortality rate.

Vasodilators reduce PAP and prolong survival in some patients with PoPH. Inhaled prostacyclin (iloprost) and inhaled nitric oxide (iNO) may be used to acutely reduce PAP and is more frequently used in the operating room or in the intensive care unit. Phosphodiesterase inhibitors, such as sildenafil or an infusion of prostaglandin I2 (epoprostenol), can be used to bridge patients to transplantation.

11

What is hepatorenal syndrome (HRS)? How does it differ from acute kidney injury (AKI) in patients with ESLD?

Both HRS and AKI can occur in cirrhotic patients and are characterized by oliguria and increases in serum creatinine. The etiology in both cases is renal hypoperfusion. Differentiation is important because treatment and prognosis vary.

HRS occurs in cirrhotic patients with portal hypertension and ascites. HRS is defined as a plasma creatinine of more than 1.5 mg/dL in patients with acute or chronic liver disease who do not improve with volume expansions in the absence of other renal disease. The etiology is thought to be renal hypoperfusion from decreased SVR and profound splanchnic sequestration of blood. RAAS and sympathetic stimulation increase salt and water retention to maintain blood pressure and, in severe cases, nonosmotic secretion of ADH, leading to hyponatremia.

AKI in cirrhosis is often caused by prerenal pathology. Prerenal AKI results from decreased blood flow to the kidneys from hypovolemia, such as hemorrhage (e.g., ruptured varices), splanchnic sequestration of blood, ascites formation, or dehydration. In contrast to HRS, restoring blood volume typically corrects prerenal AKI.

12

What are the gastrointestinal derangements that occur with cirrhosis?

Gastrointestinal (GI) complications result from portal hypertension (> 10 mm Hg). Portal hypertension leads to the development of portosystemic venous collaterals, including esophagogastric varices. Ruptured varices with hemorrhage account for a third of patient mortality. Ascites results from fluid sequestration because of portal hypertension. Patients with decompensated cirrhosis and ascites are prone to spontaneous bacterial peritonitis from translocation of bacteria from the GI tract.

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