Management of Patients With Nonviral Hepatic Disorders

Management of Patients With Nonviral Hepatic Disorders

Certain chemicals have toxic effects on the liver and when taken by mouth, inhaled, or injected parenterally produce acute liver cell necrosis, or toxic hepatitis. The chemicals most commonly implicated in this disease are carbon tetrachloride, phosphorus, chloroform, and gold compounds. These substances are true he-patotoxins. Many medications may induce hepatitis but are sen-sitizing rather than toxic. The result, drug-induced hepatitis, is similar to acute viral hepatitis, but parenchymal destruction tends to be more extensive. Some medications that can lead to hepati-tis are isoniazid, halothane, acetaminophen, and certain antibi-otics, antimetabolites, and anesthetic agents.

TOXIC HEPATITIS

Toxic hepatitis resembles viral hepatitis in onset. Obtaining a history of exposure to hepatotoxic chemicals, medications, or other agents assists in early treatment and removal of the of-fending agent. Anorexia, nausea, and vomiting are the usual symptoms; jaundice and hepatomegaly are noted on physical as-sessment. Symptoms are more intense for the more severely toxic patient.

Recovery from acute toxic hepatitis is rapid if the hepatotoxin is identified early and removed or if exposure to the agent has been limited. Recovery is unlikely if there is a prolonged period between exposure and onset of symptoms. There are no effective antidotes. The fever rises; the patient becomes toxic and pros-trated. Vomiting may be persistent, with the emesis containing blood. Clotting abnormalities may be severe, and hemorrhages may appear under the skin. The severe GI symptoms may lead to vascular collapse. Delirium, coma, and seizures develop, and within a few days the patient may die of fulminant hepatic fail-ure (discussed below) unless he or she receives a liver transplant.

Short of liver transplantation, few treatment options are avail-able. Therapy is directed toward restoring and maintaining fluid and electrolyte balance, blood replacement, and comfort and sup-portive measures. A few patients recover from acute toxic hepati-tis only to develop chronic liver disease. If the liver heals, there may be scarring, followed by postnecrotic cirrhosis.

DRUG-INDUCED HEPATITIS

Drug-induced hepatitis is responsible for 20% to 25% of cases of acute hepatic failure in the United States (Maddrey, Schiff & Sorrell, 2001). Manifestations of sensitivity to a medication may occur on the first day of its use or not until several months later, depending on the medication. Usually the onset is abrupt, with chills, fever, rash, pruritus, arthralgia, anorexia, and nausea. Later, there may be jaundice and dark urine and an enlarged and tender liver. When the offending medication is withdrawn, symptoms may gradually subside. However, reactions may be severe and even fatal, even though the medication is stopped. If fever, rash, or pruritus occurs from any medication, its use should be stopped immediately.

Although any medication can affect liver function, use of acet-aminophen (found in many over-the counter medications used to treat fever and pain) has been identified as the leading cause of acute liver failure (Ostapowicz, Fontana, Schiodt, et al., 2002). Others commonly associated with liver injury include but are not limited to anesthetic agents, medications used to treat rheumatic and musculoskeletal disease, antidepressants, psychotropic med-ications, anticonvulsants, and anti-tuberculosis agents.

Inhalational agents of the halothane family (halokanes) are metabolized by the liver and excreted in bile. These volatile anes-thetics may also decrease hepatic blood flow. Halothane hepatitis is a dreaded but rare complication of halothane administration. Sevoflurane and desflurane may have less hepatotoxic effects than halokanes. Nitrous oxide, an adjunct to halokanes, is not hepa-totoxic. Because it undergoes little hepatic metabolism, isoflurane is considered the anesthetic agent of choice in patients with liver disease (Bacon & Di Bisceglie, 2000).

Although its efficacy is uncertain, a short course of high-dose corticosteroids may be used in patients with severe hypersensitiv-ity. Liver transplantation is an option for drug-induced hepatitis, but outcomes may not be as successful as with other causes of liver failure.

FULMINANT HEPATIC FAILURE

Fulminant hepatic failure is the clinical syndrome of suddenand severely impaired liver function in a previously healthy per-son. According to the original and generally accepted definition, fulminant hepatic failure develops within 8 weeks of the first symptoms of jaundice (Maddrey et al., 2001). Patterns of the progression from jaundice to encephalopathy have been identi-fied and have led to proposals of time-based classifications, but no agreement as to these classifications has been reached. How-ever, three categories are frequently cited: hyperacute, acute, and subacute liver failure. In hyperacute liver failure, the duration of jaundice before the onset of encephalopathy is 0 to 7 days; in acute liver failure, it is 8 to 28 days; and in subacute liver failure, it is 28 to 72 days. The prognosis for fulminant hepatic failure is much worse than for chronic liver failure. However, in fulminant failure, the hepatic lesion is potentially reversible, with survival rates of approximately 50% to 85% (survival rates depend greatly on the etiology of liver failure). Those who do not survive die of massive hepatocellular injury and necrosis (Maddrey et al., 2001).

Viral hepatitis is a common cause of fulminant hepatic failure; other causes include toxic medications (eg, acetaminophen) and chemicals (eg, carbon tetrachloride), metabolic disturbances (Wil-son’s disease, a hereditary syndrome with deposition of copper in the liver), and structural changes (Budd-Chiari syndrome, an ob-struction to outflow in major hepatic veins).

Jaundice and profound anorexia may be the initial reasons the patient seeks health care. Fulminant hepatic failure is often accompanied by coagulation defects, renal failure and elec-trolyte disturbances, infection, hypoglycemia, encephalopathy, and cerebral edema.

Management

The key to optimizing treatment is rapid recognition of acute liver failure and intensive interventions. Treatment modalities may in-clude plasma exchanges (plasmapheresis) or charcoal hemoper-fusion for the removal (theoretically) of potentially harmful metabolites (Kaptanoglu & Blei, 2000); however, more clinical trials are needed to determine their effects or outcomes. Hepato-cytes within synthetic fiber columns have been tested as liver sup-port systems (liver assist devices) and a bridge to transplantation.

Research into interventions for acute liver failure has begun to focus on techniques that combine the efficacy of a whole liver with the convenience and biocompatibility of hemodialysis. The acronyms ELAD (extracorporeal liver assist devices) and BAL (bioartificial liver) have been used to describe these hybrid devices. These temporary devices help patients to survive until transplanta-tion is possible. The BAL exposes separated plasma to a cartridge containing porcine liver cells after the plasma has flowed through a charcoal column that removes substances toxic to hepatocytes. The ELAD device exposes whole blood to cartridges containing human hepatoblastoma cells, resulting in removal of toxic sub-stances. Similar extracorporeal circuits using xenografts will likely be studied in the near future (Maddrey et al., 2001). Although these approaches appear promising, controlled studies are required.

There is a high risk for cerebral edema, a life-threatening complication, in patients with fulminant liver failure with stage 4 encephalopathy. The cause is not fully understood, although disruption of the blood–brain barrier and plasma leaking into the cerebrospinal fluid has been proposed as one theory (Sherlock & Dooley, 2002). These patients require intracranial pressure mon-itoring. Measures to promote adequate cerebral perfusion include careful fluid balance and hemodynamic assessments, a quiet en-vironment, and diuresis with mannitol, an osmotic diuretic.

To prevent surges in intracranial pressure related to agitation, barbiturate anesthesia or pharmacologic paralysis and sedation are indicated. Other support measures include monitoring for and treating hypoglycemia, coagulopathies, and infection. Despite these treatment modalities, the mortality rate remains high. Con-sequently, liver transplantation has become the treatment of choice for fulminant hepatic failure.

HEPATIC CIRRHOSIS

Cirrhosis is a chronic disease characterized by replacement of nor-mal liver tissue with diffuse fibrosis that disrupts the structure and function of the liver. There are three types of cirrhosis or scarring of the liver:

•        Alcoholic cirrhosis, in which the scar tissue characteristi-cally surrounds the portal areas. This is most frequently due to chronic alcoholism and is the most common type of cirrhosis.

•        Postnecrotic cirrhosis, in which there are broad bands of scar tissue as a late result of a previous bout of acute viral hepatitis.

•        Biliary cirrhosis, in which scarring occurs in the liver around the bile ducts. This type usually is the result of chronic bil-iary obstruction and infection (cholangitis); it is much less common than the other two types.

The portion of the liver chiefly involved in cirrhosis consists of the portal and the periportal spaces, where the bile canaliculi of each lobule communicate to form the liver bile ducts. These areas become the sites of inflammation, and the bile ducts be-come occluded with inspissated (thickened) bile and pus. The liver attempts to form new bile channels; hence, there is an over-growth of tissue made up largely of disconnected, newly formed bile ducts and surrounded by scar tissue.

Clinical manifestations include intermittent jaundice and fever. Initially the liver is enlarged, hard, and irregular, but even-tually it atrophies.

Pathophysiology

Although several factors have been implicated in the etiology of cirrhosis, alcohol consumption is considered the major causative factor. Cirrhosis occurs with greatest frequency among alcoholics. Although nutritional deficiency with reduced protein intake con-tributes to liver destruction in cirrhosis, excessive alcohol intake is the major causative factor in fatty liver and its consequences. Cirrhosis, however, has also occurred in people who do not con-sume alcohol and in those who consume a normal diet and have a high alcohol intake.

Some people appear to be more susceptible than others to this disease, whether or not they are alcoholics or malnourished. Other factors may play a role, including exposure to certain chemicals (carbon tetrachloride, chlorinated naphthalene, arsenic, or phos-phorus) or infectious schistosomiasis. Twice as many men as women are affected, although women are at greater risk of devel-oping alcohol-induced liver disease for an as yet undiscovered reason. Most patients are between 40 and 60 years of age. Each year more than 25,000 people die of chronic liver diseases and cirrhosis in the United States (NIDDK, 2000).

Alcoholic cirrhosis is characterized by episodes of necrosis in-volving the liver cells, sometimes occurring repeatedly throughout the course of the disease. The destroyed liver cells are replaced grad-ually by scar tissue; eventually the amount of scar tissue exceeds that of the functioning liver tissue. Islands of residual normal tissue and regenerating liver tissue may project from the constricted areas, giv-ing the cirrhotic liver its characteristic hobnail appearance. The dis-ease usually has an insidious onset and a protracted course, occasionally proceeding over a period of 30 or more years.

The prognosis of different forms of cirrhosis caused by vari-ous liver diseases has been investigated in several studies. Of the many prognostic indicators, the Child’s classification seems most useful in predicting the outcome of patients with liver disease (Table 39-5). It is also used in choosing management approaches.

Clinical Manifestations

Signs and symptoms of cirrhosis increase in severity as the disease progresses. The severity of the manifestations helps to categorize the disorder into two main presentations (Chart 39-10).

Compensated cirrhosis, with its less severe, often vague symp-toms, may be discovered secondarily at a routine physical exam-ination. The hallmarks of decompensated cirrhosis result from failure of the liver to synthesize proteins, clotting factors, and other substances and manifestations of portal hypertension.

LIVER ENLARGEMENT

Early in the course of cirrhosis, the liver tends to be large and its cells loaded with fat. The liver is firm and has a sharp edge no-ticeable on palpation. Abdominal pain may be present because of recent, rapid enlargement of the liver, producing tension on the fibrous covering of the liver (Glisson’s capsule). Later in the dis-ease, the liver decreases in size as scar tissue contracts the liver tis-sue. The liver edge, if palpable, is nodular.

PORTAL OBSTRUCTION AND ASCITES

These late manifestations are due partly to chronic failure of liver function and partly to obstruction of the portal circula-tion. Practically all the blood from the digestive organs is col-lected in the portal veins and carried to the liver. Because a cirrhotic liver does not allow the blood free passage, it backs up into the spleen and the GI tract and these organs become the seat of chronic passive congestion; that is, they are stagnant with blood and thus cannot function properly. Indigestion and altered bowel function result. Fluid rich in protein may accu-mulate in the peritoneal cavity, producing ascites. This can be demonstrated through percussion for shifting dullness or a fluid wave (see Fig. 39-5).

INFECTION AND PERITONITIS

Bacterial peritonitis may develop in cirrhotic patients with as-cites in the absence of an intra-abdominal source of infection or an abscess. This condition is referred to as spontaneous bacte-rial peritonitis. Bacteremia is believed to be the most likely route of infection. Clinical signs may be absent; paracentesis may be necessary for diagnosis. Antibiotic therapy is effective in the treatment and prevention of recurrent episodes of spontaneous bacterial peritonitis.

GASTROINTESTINAL VARICES

The obstruction to blood flow through the liver resulting from the fibrotic changes also results in the formation of collateral blood ves-sels in the GI system and shunting of blood from the portal vessels into blood vessels with lower pressures. As a result, the patient with cirrhosis often has prominent, distended abdominal blood vessels, which are visible on abdominal inspection (caput medusae), and distended blood vessels throughout the GI tract. The esophagus, stomach, and lower rectum are common sites of collateral blood vessels. These distended blood vessels form varices or hemorrhoids, depending on their location (see Fig. 39-6).

Because these vessels were not intended to carry the high pres-sure and volume of blood imposed by cirrhosis, they may rup-ture and bleed. Therefore, assessment must include observation for occult and frank bleeding from the GI tract. Approximately 25% of patients develop minor hematemesis; others have pro-fuse hemorrhage from gastric and esophageal varices (Bacon & Di Bisceglie, 2000).

EDEMA

Another late symptom of cirrhosis is edema, which is attributed to chronic liver failure. A reduced plasma albumin concentration predisposes the patient to the formation of edema. Edema is gen-eralized but often affects lower extremities, upper extremities, and the presacral area. Facial edema is not typical. Overproduc-tion of aldosterone occurs, causing sodium and water retention and potassium excretion.

VITAMIN DEFICIENCY AND ANEMIA

Because of inadequate formation, use, and storage of certain vit-amins (notably vitamins A, C, and K), signs of their deficiency are common, particularly hemorrhagic phenomena associated with vitamin K deficiency. Chronic gastritis and impaired GI function, together with inadequate dietary intake and impaired liver function, account for the anemia often associated with cir-rhosis. The anemia and the patient’s poor nutritional status and poor state of health result in severe fatigue, which interferes with the ability to carry out routine daily activities.

MENTAL DETERIORATION

Additional clinical manifestations include deterioration of men-tal function with impending hepatic encephalopathy and hepatic coma. Neurologic assessment is indicated and includes the pa-tient’s general behavior, cognitive abilities, orientation to time and place, and speech patterns.

Assessment and Diagnostic Findings

The extent of liver disease and the type of treatment are deter-mined after reviewing the laboratory findings. Because the func-tions of the liver are complex, there are many diagnostic tests that may provide information about liver function (see Table 39-1). The patient needs to know why these tests are being performed and ways to cooperate.

In severe parenchymal liver dysfunction, the serum albumin level tends to decrease and the serum globulin level rises. Enzyme tests indicate liver cell damage: serum alkaline phosphatase, AST, ALT, and GGT levels increase, and the serum cholinesterase level may decrease. Bilirubin tests are performed to measure bile ex-cretion or bile retention; elevated levels can occur with cirrhosis and other liver disorders. Prothrombin time is prolonged.

Ultrasound scanning is used to measure the difference in density of parenchymal cells and scar tissue. CT, MRI, and ra-dioisotope liver scans give information about liver size and he-patic blood flow and obstruction. Diagnosis is confirmed by liver biopsy. Arterial blood gas analysis may reveal a ventilation– perfusion imbalance and hypoxia.

Medical Management

The management of the patient with cirrhosis is usually based on the presenting symptoms. For example, antacids are prescribed to decrease gastric distress and minimize the possibility of GI bleed-ing. Vitamins and nutritional supplements promote healing of damaged liver cells and improve the general nutritional status. Potassium-sparing diuretics (spironolactone [Aldactone], tri-amterene [Dyrenium]) may be indicated to decrease ascites, if present; these diuretics are preferable to other diuretic agents be-cause they minimize the fluid and electrolyte changes common with other agents. An adequate diet and avoidance of alcohol are essential. Although the fibrosis of the cirrhotic liver cannot be re-versed, its progression may be halted or slowed by such measures.

Preliminary studies indicate that colchicine, an anti-inflammatory agent used to treat the symptoms of gout, may in-crease the length of survival in patients with mild to moderate cirrhosis. Improved survival has been observed in patients with alcoholic cirrhosis. Colchicine is believed to reverse the fibrotic processes in cirrhosis, and this has improved survival (Bacon & Di Bisceglie, 2000).