Background

Drugs are an important cause of liver injury. More than 900 drugs, toxins, and herbs have been

reported to cause liver injury, and drugs account for 20-40% of all instances of fulminant hepatic

failure. Approximately 75% of the idiosyncratic drug reactions result in liver transplantation or death.

Drug-induced hepatic injury is the most common reason cited for withdrawal of an approved drug.

Physicians must be vigilant in identifying drug-related liver injury because early detection can

decrease the severity of hepatotoxicity if the drug is discontinued. The manifestations of drug-induced

hepatotoxicity are highly variable, ranging from asymptomatic elevation of liver enzymes to

fulminant hepatic failure. Knowledge of the commonly implicated agents and a high index of

suspicion are essential in diagnosis.2

Manifestations of Liver Dysfunction

Whether a result of hepatocyte dysfunction or portal-to-systemic shunting, prominent features of liver

disease are manifestations of failure of normal functions. An understanding of these mechanisms

offers insight into the probable causes of illness in a patient with acute or chronic liver disease.

Diminished Energy Generation & Substrate Interconversion

A first category of altered liver function involves the intermediary metabolism of carbohydrates, fats,

and proteins.

Carbohydrate Metabolism

Severe liver disease can result in either hypo- or hyperglycemia. Hypoglycemia results largely from a

decrease in functional hepatocyte mass, whereas hyperglycemia is a result of portal-to-systemic

shunting, which decreases the efficiency of postprandial extraction of glucose from portal blood by

hepatocytes, thus elevating systemic blood glucose concentration.

Lipid Metabolism

Disturbance of lipid metabolism in the liver can result in syndromes of fat accumulation within the

liver early in the course of liver injury. Perhaps this is because the complex steps in assembly of

lipoprotein particles for export of cholesterol and triglycerides from the liver are more sensitive to

1

disruption than the pathways of lipid synthesis. Such disruption results in a buildup of fat that cannot

be exported in the form of VLDL.

In certain chronic liver diseases such as primary biliary cirrhosis, bile flow decreases as a result of

destruction of bile ducts. The decrease in bile flow results in decreased lipid clearance via bile, with

consequent hyperlipidemia. These patients often develop subcutaneous accumulations of cholesterol

termed xanthomas.

Protein Metabolism

Any disturbance of protein metabolism in the liver can result in a syndrome of altered mental status

and confusion known as hepatic encephalopathy. As with carbohydrate metabolism, altered protein

metabolism can result from either hepatocyte failure or portal-to-systemic shunting, with the net effect

of elevation of blood concentrations of centrally acting toxins, including ammonia generated by

amino acid metabolism.7

Table 1. Categories of Liver Disease by Presentation.4

Cholestasis 

  Reactions to certain classes of drugs (including anabolic steroids, oral contraceptives, phenothiazines, erythromycins, oral hypoglycemic and antithyroid drugs)

  Direct causes (intrahepatic biliary atresia, cholangiocarcinoma, viral hepatitis, alcoholic hepatitis, primary biliary cirrhosis, pericholangitis)

Secondary causes (postoperative, endotoxins, total parenteral nutrition, sickle cell crisis, hypophysectomy, some porphyrias)

Acute hepatitis 

  Viral and bacterial, including hepatitis viruses A, B, C, D, and E, herpes simplex virus, cytomegalovirus, Epstein-Barr virus, yellow fever virus, brucella, leptospira

  Reactions to certain classes of drugs (anesthetics such as halothane, anticonvulsants such as phenytoin, antihypertensives such as methyldopa, chemotherapeutic agents such as isoniazid, and thiazide diuretics such as hydrochlorothiazide)

  Poisons (such as ethanol); reactions to drugs

Fulminant hepatic failure 

  Infections (with hepatitis viruses A, B, and D, yellow fever virus, cytomegalovirus; herpes simplex

2

virus, and Coxiella burnetii) 

  Poisons and toxins, chemicals, herbal remedies, and drugs (Amanita phalloides toxin, phosphorus, ethanol; solvents, including carbon tetrachloride and dimethylformamide; anesthetics, including halothane; analgesics, including acetaminophen; antimicrobials, including tetracycline and isoniazid; and other drugs, including methyldopa, monoamine oxidase inhibitors, valproate, methylenedioxymethamphetamine [Ecstasy])

  Ischemia and hypoxia (vascular occlusion, circulatory failure, heat stroke, gram-negative sepsis with shock, congestive heart failure, pericardial tamponade, Budd-Chiari syndrome)

  Miscellaneous metabolic anomalies (acute fatty liver of pregnancy, Reye's syndrome, Wilson's disease, galactosemia, tyrosinemia)

Chronic hepatitis 

  Viral hepatitis (types B, C, and D)

  Primary autoimmune disorders (idiopathic autoimmune chronic hepatitis, primary biliary cirrhosis, and sclerosing cholangitis)

  Therapeutic drug–induced (methyldopa, nitrofurantoin, oxyphenisatin-containing laxatives)

Genetic diseases (Wilson's disease, -antiprotease deficiency)

  Infiltrative disorders (sarcoidosis, amyloidosis, hemochromatosis)

Cirrhosis 

  Infectious (viral hepatitis types B, C, and D and toxoplasmosis)

  Genetic diseases (Wilson's disease, hemochromatosis, -antiprotease deficiency, glycogen storage diseases, Fanconi's syndrome, cystic fibrosis)

  Drugs and poisons (eg, methotrexate, alcohol)

  Miscellaneous (sarcoidosis, graft-versus-host disease, inflammatory bowel disease, cystic fibrosis, jejunoileal bypass, diabetes mellitus)

Focal or extrinsic diseases with variable manifestations in the liver 

  Vascular (hepatic vein thrombosis, occlusion by parasites such as echinococcus or schistosoma)

  Biliary (duct obstruction due to stones or tumor or bacterial infection)

  Infectious (systemic sepsis; bacterial, fungal, or parasitic abscesses)

  Granulomatous diseases (sarcoidosis, tuberculosis)Infiltrative diseases (hemochromatosis, amyloidosis, Gaucher's disease and other lysosomal storage diseases, lymphoma)

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  Infiltrative diseases (hemochromatosis, amyloidosis, Gaucher's disease and other lysosomal storage diseases, lymphoma)

Loss of Solubilization & Storage Functions

Disordered Bile Secretion

The clinical significance of bile synthesis can be seen in the prominence of cholestasis—failure to

secrete bile—in many forms of liver disease. Cholestasis can occur as a result of extrahepatic

obstruction (eg, from a gallstone in the common bile duct) or selective dysfunction of the bile

synthetic and secretory machinery within the hepatocytes themselves (eg, from a reaction to certain

drugs). The mechanisms responsible for cholestatic drug reactions are not well understood.

Regardless of the mechanism, however, the clinical consequences of severe cholestasis may be

profound: A failure to secrete bile results in a failure to solubilize substances such as dietary lipids

and fat-soluble vitamins, resulting in malabsorption and deficiency states, respectively. Retained bile

salts are also cytotoxic, but in the setting of cholestasis hepatocytes adapt to decrease uptake of bile

salts by downregulating Ntcp while maintaining bile salt excretion. As a result, hepatic necrosis is

minimized in predominantly cholestatic syndromes, with the typical laboratory findings of minimally

elevated levels of AST and ALT in the presence of marked jaundice and high levels of bilirubin.

However, prolonged exposure to bile salts in chronic cholestatic diseases such as primary biliary

cirrhosis leads to portal tract cytotoxic injury and inflammation, leading eventually to fibrosis and

cirrhosis.

The solubilization function of bile works both to excrete and to absorb substances. Thus, in

cholestasis, endogenous substances that are normally excreted via the biliary tract can accumulate to

high levels. One such substance is bilirubin, a product of heme degradation. The buildup of bilirubin

results in jaundice (icterus), which is a yellow discoloration of the scleras and skin. In the adult, the

most significant feature of jaundice is that it serves as a readily monitored index of cholestasis, which

may occur alone or with other abnormalities in hepatocyte function (ie, as part of the presentation of

acute hepatitis). In the neonate, however, elevated bilirubin concentrations can be toxic to the

developing nervous system, producing a syndrome termed kernicterus.

Similarly, cholesterol is normally excreted either by conversion into bile acids or by forming

complexes, termed micelles, with preexisting (recycled) bile acids. In cholestasis, the resultant

buildup of bile acids can lead to their deposition in the skin. This is believed to cause intense itching,

4

or pruritus. Data suggest that in at least some patients cholestasis results in altered levels of

endogenous opioids. Altered endogenous opioid-mediated neurotransmission may be responsible for

pruritus instead of skin deposition of bile acids. Disorders of bile production are a basis for the

formation of cholesterol gallstones. Nevertheless, as mentioned, other hepatocyte functions are often

relatively well preserved in the face of significant cholestasis.

Hemolysis causes an unconjugated hyperbilirubinemia because the hepatic capacity to take up and

conjugate bilirubin is exceeded. Gilbert's syndrome reflects a genetic defect in bilirubin conjugation.

Thus, the findings in blood and urine are different from what is observed in hemolytic jaundice even

though the pathway of bilirubin metabolism is backed up at a similar initial point. Extrahepatic biliary

tract obstruction presents the other extreme, in which the actual pathway of bile formation is entirely

intact, at least initially. In obstruction, the bilirubin level in the urine is high because the backed-up

metabolite is conjugated and hence much more water soluble than unconjugated bilirubin, which

accumulates in hemolysis. Most forms of jaundice that result from liver dysfunction caused by

hepatocellular damage reflect variable degrees of overlap between unconjugated and conjugated

hyperbilirubinemia.

Impaired Drug Detoxification

Two features of the mechanisms of drug detoxification are of particular clinical importance. One is

the phenomenon of enzyme induction. It is observed that the presence in the bloodstream of any of

the large class of drugs inactivated by phase I enzymes increases the amount and activity of these

enzymes in the liver. This property of enzyme induction makes physiologic sense (as a response to the

body's need for increased biotransformation) but can have undesired effects as well: A patient who

chronically consumes large amounts of a substance that is metabolized by phase I enzymes (eg,

ethanol) will induce high levels of these enzymes and thus speed up the metabolism of other

substances metabolized by the same detoxifying enzymes (eg, antiseizure or anticoagulant

medications, resulting in subtherapeutic blood levels of the drugs).

A second clinically important phenomenon in drug metabolism is that phase I reactions often convert

relatively benign compounds into more reactive and hence more toxic ones. Normally, this heightened

reactivity of phase I reaction products serves to facilitate phase II reactions, making detoxification

more efficient. However, under certain conditions when phase II reactions are impaired (eg, during

glutathione deficiency from inadequate nutrition), continued phase I enzyme activity can cause

increased liver injury. This is because the products of many phase I reactions, in the absence of

glutathione, react with and damage cellular components. Such damage rapidly kills the hepatocyte.

5

Thus, the combined effects of certain common conditions can make the individual abnormally

sensitive to the toxic effects of drugs. For example, the combination of induced phase I activity (eg,

caused by alcoholism) with low phase II activity (eg, caused by low glutathione levels from

nutritional deprivation) can result in heightened generation of reactive intermediates with an

inadequate capacity to conjugate and detoxify them. A classic example of this phenomenon is

acetaminophen toxicity. As little as 2.5 g of acetaminophen can produce significant liver damage in

such susceptible individuals, whereas normal individuals have the capacity to detoxify 10 g/d or more.

Lipoprotein Dynamics and Dyslipidemias

The liver's role in lipid metabolism is illustrated by the genetic defect causing familial

hypercholesterolemia. Lack of a functional LDL receptor in such cases renders the liver unable to

clear LDL cholesterol from the bloodstream, resulting in markedly elevated serum cholesterol and

accelerated atherosclerosis and coronary artery disease. Heterozygotes with one normal LDL receptor

allele can be treated with drugs (eg, HMG-CoA reductase inhibitors) that inhibit endogenous

cholesterol synthesis and thus upregulate LDL receptor levels. However, there is no effective drug

therapy for homozygotes because they have no normal LDL receptors. Hepatic transplantation is

effective therapy for homozygous familial hypercholesterolemia because it provides a genetically

different liver with normal LDL receptors.

In acquired liver diseases, the serum cholesterol is elevated in biliary tract obstruction as a result of

blockage of cholesterol excretion in bile, and it is diminished in severe alcoholic cirrhosis, in which

fat malabsorption prevents cholesterol intake.

Altered Hepatic Binding and Storage Functions

Liver disease influences the liver's ability to store various substances. As a result, patients with liver

disease are at high risk for certain deficiency states such as folic acid and vitamin B12 deficiency.

Because these vitamins are needed for DNA synthesis, their deficiency results in macrocytic anemia

(low red blood cell count with large red cells reflecting abnormal nuclear maturation), a common

finding in patients with liver disease.

Diminished Synthesis & Secretion of Plasma Proteins

The clinical significance of liver protein synthesis and secretion derives from the wide range of

functions carried out by these proteins. For example, because albumin is the major contributor to

plasma oncotic pressure, hypoalbuminemia as a consequence of liver disease or nutritional deficiency

6

presents with marked edema formation. Other important proteins synthesized and secreted by the liver

include clotting factors and hormone-binding proteins.

Loss of Protective & Clearance Functions

A crucial protective function of the liver is its role as a filter of blood from the GI tract, by which

various substances are removed from portal blood before it reenters the systemic circulation.

Clearance of Bacteria and Endotoxin

Clearance of bacteria by Kupffer cells of the liver is the final line of defense in keeping gut-derived

bacteria out of the systemic circulation. Loss of this capacity in liver disease as a result of portal-to-

systemic shunting may help to explain why, in patients with severe liver disease, infections can

rapidly become systemic and result in sepsis.

Altered Ammonia Metabolism

Impairment of the liver's ability to detoxify ammonia to urea leads to hepatic encephalopathy,

manifested as an altered mental status. This may be an early manifestation of acute fulminant hepatitis

with massive hepatocellular dysfunction even before the development of maximal hepatocellular

necrosis. It can be a final step in progressive chronic liver disease with diminished hepatocyte

functional capacity. Most often it is a consequence of an increased ammonia load in a patient with

marginal liver function or significant portal-to-systemic shunting. Thus, encephalopathy may occur as

a first sign of renewed GI bleeding (as a result of increased production of ammonia and other products

caused by breakdown of blood protein by GI tract microbes) or may simply be due to increased

protein intake (eg, a cheeseburger eaten by a patient with cirrhosis). Finally, the development of

sepsis in these patients results in increased endogenous protein catabolism and, therefore, elevated

ammonia production in the face of a decreased capacity for ammonia detoxification because of the

liver disease. Thus, the development of encephalopathy in a patient with chronic liver disease calls for

investigation of possible acute GI bleeding as well as potentially catastrophic infection. Pending the

outcome of diagnostic studies (eg, serial hematocrit measurements and cultures of blood, urine, and

ascitic fluid), therapy is designed to improve mental status by diminishing the absorption of ammonia

and other noxious substances from the GI tract. When the patient is given the nonabsorbable

carbohydrate lactulose, whose metabolism by microbes creates an acidic environment, ammonia is

trapped as the charged NH4+ species in the gut lumen and excreted by the resultant osmotic diarrhea.

Thus, this toxin is prevented from ever entering the portal circulation, and the patient's mental status

gradually improves. Lactulose also selects for a gut bacterial flora that produces less ammonia.

7

Furthermore, the resulting elevated blood ammonia and other nitrogen-containing compounds can

upregulate peripheral receptors for endogenous benzodiazepine-like products. These effects may

contribute to altered systemic hemodynamics in liver disease.

Altered Hormone Clearance in Liver Disease

Normally, the liver removes from the bloodstream the fraction of steroid hormones not bound to

steroid hormone-binding globulin. On uptake by hepatocytes, these steroids are oxidized, conjugated,

and excreted into bile, where a fraction undergoes enterohepatic circulation. In liver disease

accompanied by significant portal-to-systemic shunting, steroid hormone clearance is diminished,

extraction of the enterohepatic circulated fraction is impaired, and enzymatic conversion of androgens

to estrogens (peripheral aromatization) is increased. The net effect is an elevation of blood estrogens,

which in turn alters hepatocyte protein synthesis and secretion and microsomal P450 activity.

Synthesis of some hepatic proteins increases, whereas synthesis of others is diminished. P450 activity

increases as the liver attempts to partially compensate for the higher blood estrogen levels by

increased metabolism. Thus, male patients with liver disease display both gonadal and pituitary

suppression as well as feminization.

Sodium & Water Balance

Patients with liver disease often display renal abnormalities and complications, most commonly

sodium retention and difficulty excreting water. An intrinsic renal lesion is apparently not involved,

because the kidneys of patients with liver disease typically function normally when transplanted into

patients whose liver is normal. Instead, renal abnormalities associated with liver disease are

functional, occurring because liver disease induces altered intravascular pressures and perhaps

because of elevated nitric oxide levels or loss of as yet poorly understood factors secreted from the

liver or the endothelium. By whatever homeostatic mechanisms, intravascular volume is perceived as

being inadequate when it is actually only maldistributed. Renal mechanisms of salt and water

retention are then stimulated to correct what has been sensed as volume depletion. 4

Jaundice

Essentials of Diagnosis

8

Results from accumulation of bilirubin in the body tissues; cause may be hepatic or

nonhepatic.

Hyperbilirubinemia may be due to abnormalities in the formation, transport, metabolism, and

excretion of bilirubin.

Total serum bilirubin is normally 0.2–1.2 mg/dL; jaundice may not be recognizable until

levels are about 3 mg/dL.

Evaluation of obstructive jaundice begins with ultrasonography and is usually followed by

cholangiography.

General Considerations

Jaundice (icterus) results from the accumulation of bilirubin—a product of heme metabolism—in the

body tissues (see photograph). Hyperbilirubinemia may be due to abnormalities in the formation,

transport, metabolism, and excretion of bilirubin. Total serum bilirubin is normally 0.2–1.2 mg/dL

(mean levels are higher in men than women and higher in whites and hispanics than blacks), and

jaundice may not be recognizable until levels are about 3 mg/dL.

Table 2. Classification of jaundice.7

Type of Hyperbilirubinemia Location and Cause

Unconjugated hyperbilirubinemia (predominant indirect-reacting bilirubin)

Increased bilirubin production (eg, hemolytic anemias, hemolytic reactions, hematoma, pulmonary infarction)

Impaired bilirubin uptake and storage (eg, posthepatitis hyperbilirubinemia, Gilbert syndrome, Crigler–Najjar syndrome, drug reactions)

Conjugated hyperbilirubinemia (predominant direct-reacting bilirubin)

HEREDITARY CHOLESTATIC SYNDROMES  

Faulty excretion of bilirubin conjugates (eg, Dubin-Johnson syndrome, Rotor syndrome) or mutation in genes coding for bile salt transport proteins (eg, progressive familial intrahepatic cholestasis syndromes, benign recurrent intrahepatic cholestasis, and some cases of intrahepatic cholestasis of pregnancy)

HEPATOCELLULAR DYSFUNCTION  

9

Type of Hyperbilirubinemia Location and Cause

Biliary epithelial damage (eg, hepatitis, hepatic cirrhosis)

Intrahepatic cholestasis (eg, certain drugs, biliary cirrhosis, sepsis, postoperative jaundice)

Hepatocellular damage or intrahepatic cholestasis resulting from miscellaneous causes (eg, spirochetal infections, infectious mononucleosis, cholangitis, sarcoidosis, lymphomas, industrial toxins)

BILIARY OBSTRUCTION  

Choledocholithiasis, biliary atresia, carcinoma of biliary duct, sclerosing cholangitis, choledochal cyst, external pressure on common duct, pancreatitis, pancreatic neoplasms

  Nature of Defect

Type of Hyperbilirubinemia

Clinical and Pathologic Characteristics

Gilbert syndrome

Reduced activity of glucuronyl transferase

Unconjugated (indirect) bilirubin

Benign, asymptomatic hereditary jaundice. Hyperbilirubinemia increased by 24- to 36-hour fast. No treatment required. Prognosis excellent.

Dubin–Johnson syndrome 

Faulty excretory function of hepatocytes

Conjugated (direct) bilirubin

Benign, asymptomatic hereditary jaundice. Gallbladder does not visualize on oral cholecystography. Liver darkly pigmented on gross examination. Biopsy shows centrilobular brown pigment. Prognosis excellent.

Rotor syndrome

Similar to Dubin–Johnson syndrome, but liver is not pigmented and the gallbladder is visualized on oral cholecystography. Prognosis excellent.

Benign recurrent intrahepatic

Cholestasis, often on a

Unconjugated plus conjugated (total)

Episodic attacks of jaundice, itching, and malaise. Onset in early life and may persist for a lifetime. Alkaline phosphatase

10

Table 3. Hyperbilirubinemic disorders.7

  Nature of Defect

Type of Hyperbilirubinemia

Clinical and Pathologic Characteristics

cholestasis 

familial basis bilirubin increased. Cholestasis found on liver biopsy. (Biopsy is normal during remission.) Prognosis excellent.

Intrahepatic cholestasis of pregnancy 

Benign cholestatic jaundice, usually occurring in the third trimester of pregnancy. Itching, gastrointestinal symptoms, and abnormal liver excretory function tests. Cholestasis noted on liver biopsy. Prognosis excellent, but recurrence with subsequent pregnancies or use of birth control pills is characteristic.

Clinical Findings

Unconjugated Hyperbilirubinemia

Stool and urine color are normal, and there is mild jaundice and indirect (unconjugated)

hyperbilirubinemia with no bilirubin in the urine. Splenomegaly occurs in hemolytic disorders except

in sickle cell anemia.

Conjugated Hyperbilirubinemia

Hereditary cholestatic syndromes or intrahepatic cholestasis

The patient may be asymptomatic; cholestasis is often accompanied by pruritus, light-colored stools,

and jaundice.

Table 4. Liver biochemical tests: Normal values and changes in two types of jaundice. 4

Tests Normal Values Hepatocellular Jaundice Uncomplicated Obstructive Jaundice

Bilirubin      

  Direct 0.1–0.3 mg/dL Increased Increased

  Indirect 0.2–0.7 mg/dL Increased Increased

11

Tests Normal Values Hepatocellular Jaundice Uncomplicated Obstructive Jaundice

Urine bilirubin None Increased Increased

Serum albumin/total protein

Albumin, 3.5–5.5 g/dL

Albumin decreased

Total protein, 6.5–8.4 g/dL

Unchanged

Alkaline phosphatase

30–115 units/L Increased (+) Increased (++++)

Prothrombin time

INR1 of 1.0–1.4. After vitamin K, 10% increase in 24 hours 

Prolonged if damage severe and does not respond to parenteral vitamin K

Prolonged if obstruction marked, but responds to parenteral vitamin K

ALT, AST  

ALT, 5–35 units/L; AST, 5–40 units/L

Increased in hepatocellular damage, viral hepatitis

Minimally increased

Table 5. Causes of serum aminotransferase elevations. 4

Mild Elevations (< 5 x normal) 

Severe Elevations (> 15 x normal)

Hepatic: ALT-predominant Acute viral hepatitis (A-E, herpes)

  Chronic hepatitis B, C, D Medications/toxins

  Acute viral hepatitis (A-E, EBV, CMV) Ischemic hepatitis

  Steatosis/steatohepatitis Autoimmune hepatitis

  Hemochromatosis Wilson disease

  Medications/toxins Acute bile duct obstruction

  Autoimmune hepatitis Acute Budd–Chiari syndrome

Antitrypsin deficiency  Hepatic artery ligation

  Wilson disease  

  Celiac disease  

Hepatic: AST-predominant  

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Mild Elevations (< 5 x normal) 

Severe Elevations (> 15 x normal)

  Alcohol-related liver injury (AST:ALT > 2:1)  

  Cirrhosis  

Nonhepatic  

  Strenuous exercise  

  Hemolysis  

  Myopathy  

  Thyroid disease  

  Macro-AST  

Imaging

Demonstration of dilated bile ducts by ultrasonography (see ultrasound) or CT scan indicates biliary

obstruction (90–95% sensitivity). Ultrasonography, CT scan (see CT scan), and MRI may also

demonstrate hepatomegaly, intrahepatic tumors, and portal hypertension. Multiphasic helical or

multislice CT, CT arterial portography, in which imaging follows intravenous contrast infusion via a

catheter placed in the superior mesenteric artery, MRI with use of gadolinium or ferumoxides as

contrast agents, and intraoperative ultrasonography are the most sensitive techniques for detection of

individual small hepatic lesions in patients eligible for resection of metastases. Use of color Doppler

ultrasound or contrast agents that produce microbubbles increases the sensitivity of transcutaneous

ultrasound for detecting small neoplasms. MRI is the most accurate technique for identifying isolated

liver lesions such as hemangiomas, focal nodular hyperplasia, or focal fatty infiltration and for

detecting hepatic iron overload. Dynamic gadolinium-enhanced MRI and administration of

superparamagnetic iron oxide show promise in visualizing hepatic fibrosis.

Alcoholic Liver Disease

Essentials of Diagnosis

13

Chronic alcohol intake usually exceeds 80 g/d in men and 30–40 g/d in women with alcoholic

hepatitis or cirrhosis.

Fatty liver is often asymptomatic.

Fever, right upper quadrant pain, tender hepatomegaly, and jaundice characterize alcoholic

hepatitis, but the patient may be asymptomatic.

AST is usually elevated but rarely above 300 units/L; AST is greater than ALT, usually by a

factor of 2 or more.

Alcoholic hepatitis is often reversible but it is the most common precursor of cirrhosis in the

United States.7

General Considerations

Excessive alcohol intake can lead to fatty liver, hepatitis, and cirrhosis. Alcoholic hepatitis is

characterized by acute or chronic inflammation and parenchymal necrosis of the liver induced by

alcohol. Alcoholic hepatitis is often a reversible disease, is the most common precursor of cirrhosis in

the United States, and is associated with four to five times the number of hospitalizations and deaths

as hepatitis C, which is the second most common cause of cirrhosis.

The frequency of alcoholic cirrhosis is estimated to be 10–15% among persons who consume over 50

g of alcohol (4 oz of 100-proof whiskey, 15 oz of wine, or four 12-oz cans of beer) daily for over 10

years (although the risk of cirrhosis may be lower for wine than for a comparable intake of beer or

spirits). The risk of cirrhosis is lower (5%) in the absence of other cofactors such as chronic viral

hepatitis and obesity. Genetic factors, including polymorphisms of the genes encoding for tumor

necrosis factor and cytochrome P450 2E1, may also account for differences in susceptibility. Women

appear to be more susceptible than men, in part because of lower gastric mucosal alcohol

dehydrogenase levels. Over 80% of patients with alcoholic hepatitis have been drinking 5 years or

more before symptoms that can be attributed to liver disease develop; the longer the duration of

drinking (10–15 or more years) and the larger the alcoholic consumption, the greater the probability

of developing alcoholic hepatitis and cirrhosis. In individuals who drink alcohol excessively, the rate

of ethanol metabolism can be sufficiently high to permit the consumption of large quantities without

raising the blood alcohol level over 80 mg/dL.

Deficiencies in vitamins and calories probably contribute to the development of alcoholic hepatitis or

its progression to cirrhosis. Many adverse effects of alcohol on the liver are thought to be mediated by

tumor necrosis factor and by the oxidative metabolite acetaldehyde, which contributes to lipid

14

peroxidation and induction of an immune response following covalent binding to proteins in the

liver.4

Clinical Findings

Symptoms and Signs

The clinical presentation of alcoholic liver disease can vary from an asymptomatic hepatomegaly to a

rapidly fatal acute illness or end-stage cirrhosis. A recent period of heavy drinking, complaints of

anorexia and nausea, and the demonstration of hepatomegaly and jaundice (see photograph) strongly

suggest the diagnosis. Abdominal pain and tenderness, splenomegaly, ascites (see photograph), fever,

and encephalopathy may be present.

Laboratory Findings

In patients with steatosis, mild liver enzyme elevations may be the only laboratory abnormality.

Anemia (usually macrocytic) may be present. Leukocytosis with shift to the left is common in patients

with severe alcoholic hepatitis. Leukopenia is occasionally seen and resolves after cessation of

drinking. About 10% of patients have thrombocytopenia related to a direct toxic effect of alcohol on

megakaryocyte production or to hypersplenism.

AST is usually elevated but rarely above 300 units/L. AST is greater than ALT, usually by a factor of

2 or more. Serum alkaline phosphatase is generally elevated, but seldom more than three times the

normal value. Serum bilirubin is increased in 60–90% of patients with alcoholic hepatitis. Serum

bilirubin levels greater than 10 mg/dL and marked prolongation of the prothrombin time (6 seconds

above control) indicate severe alcoholic hepatitis with a mortality rate as high as 50%. The serum

albumin is depressed, and the globulin level is elevated in 50–75% of individuals, even in the absence

of cirrhosis. Increased transferrin saturation, hepatic iron stores, and sideroblastic anemia are found in

many alcoholic patients. Folic acid deficiency may coexist.

Liver Biopsy

Liver biopsy, if done, demonstrates macrovesicular fat and, in patients with alcoholic hepatitis,

polymorphonuclear infiltration with hepatic necrosis, Mallory bodies (alcoholic hyaline), and

perivenular and perisinusoidal fibrosis (see micrograph). Micronodular cirrhosis may be present as

well. The findings are identical to those of nonalcoholic steatohepatitis.

Other Studies

15

Imaging studies are used to exclude other diagnoses; they can detect moderate to severe hepatic

steatosis reliably but not inflammation or fibrosis. Ultrasound helps exclude biliary obstruction and

identifies subclinical ascites. CT scanning with intravenous contrast or MRI may be indicated in

selected cases to evaluate patients for collateral vessels, space-occupying lesions of the liver, or

concomitant disease of the pancreas.

Differential Diagnosis

Alcoholic hepatitis may be closely mimicked by cholecystitis and cholelithiasis and by drug toxicity.

Other causes of hepatitis or chronic liver disease may be excluded by serologic or biochemical testing,

by imaging studies, or by liver biopsy. A formula based on the AST/ALT ratio, body mass index,

mean corpuscular volume, and gender has been reported to reliably distinguish alcoholic liver disease

from nonalcoholic fatty liver disease (NAFLD).

Treatment

General Measures

Abstinence from alcohol is essential. Fatty liver is quickly reversible with abstinence. Every effort

should be made to provide sufficient amounts of carbohydrates and calories in anorectic patients to

reduce endogenous protein catabolism, promote gluconeogenesis, and prevent hypoglycemia.

Nutritional support (40 kcal/kg with 1.5–2 g/kg as protein) improves survival in patients with

malnutrition. Use of liquid formulas rich in branched-chain amino acids does not improve survival

beyond that achieved with less expensive caloric supplementation. The administration of vitamins,

particularly folic acid and thiamine, is indicated, especially when deficiencies are noted; glucose

administration increases the vitamin B1 requirement and can precipitate Wernicke–Korsakoff

syndrome if thiamine is not coadministered.

Pharmacologic Measures

Methylprednisolone, 32 mg/d orally or the equivalent for 1 month, may reduce short-term mortality in

patients with alcoholic hepatitis and either encephalopathy or a discriminant function (defined by the

patient's prothrombin time minus the control prothrombin time times 4.6 plus the total bilirubin in

mg/d is > 32). Failure of the serum bilirubin level to decline after 7 days of treatment predicts

nonresponse and poor long-term survival, as does a model that includes age, renal failure, serum

albumin, prothrombin time, serum bilirubin on admission, and serum bilirubin on day 7. No benefit

has been demonstrated in patients with concomitant gastrointestinal bleeding.

16

Pentoxifylline—an inhibitor of tumor necrosis factor—400 mg orally three times daily for 4 weeks,

may reduce 1-month mortality rates in patients with severe alcoholic hepatitis, primarily by

decreasing the risk of hepatorenal syndrome. Other experimental therapies include propylthiouracil,

oxandrolone, S-adenosyl-L-methionine, infliximab, antioxidants, and extracorporeal liver support.

Colchicine does not reduce mortality in patients with alcoholic cirrhosis.

Prognosis

Short-Term

When the prothrombin time is short enough to permit liver biopsy (< 3 seconds above control), the 1-

year mortality rate is 7%, rising to 20% if there is progressive prolongation of the prothrombin time

during hospitalization. Individuals in whom the prothrombin time prohibits liver biopsy have a 42%

mortality rate at 1 year. Other unfavorable prognostic factors are a serum bilirubin greater than 10

mg/dL, hepatic encephalopathy, azotemia, leukocytosis, lack of response to corticosteroid therapy,

and possibly little steatosis on a liver biopsy specimen and reversal of portal blood flow by Doppler

ultrasound. In addition to the discriminant function discussed above, the MELD score used for

cirrhosis (see later) and the Glasgow alcoholic hepatitis score (based on age, white blood cell count,

blood urea nitrogen, prothrombin time ratio, and bilirubin level) correlate with mortality from

alcoholic hepatitis and have higher specificities.

Long-Term

In the United States, the 3-year mortality rate of persons who recover from acute alcoholic hepatitis is

ten times greater than that of control individuals of comparable age. Histologically severe disease is

associated with continued excessive mortality rates after 3 years, whereas the death rate is not

increased after the same period in those whose liver biopsies show only mild alcoholic hepatitis.

Complications of portal hypertension (ascites, variceal bleeding, hepatorenal syndrome),

coagulopathy, and severe jaundice following recovery from acute alcoholic hepatitis also suggest a

poor long-term prognosis. Alcoholic cirrhosis is a risk factor for hepatocellular carcinoma, and the

risk is highest in carriers of the C282Y mutation for hemochromatosis or with increased hepatic iron.

The most important prognostic consideration is continued excessive drinking. A 6-month period of

abstinence is generally required before liver transplantation is considered, although this requirement

has been questioned.4

17

Drug- & Toxin-Induced Liver Disease

Most cases of drug-induced liver disease present as acute hepatitis, although some present as

cholestasis or other patterns. The incidence of drug-induced hepatitis has been rising; acetaminophen

is now the most common cause of fulminant hepatitis in the United States and the United Kingdom.

Hepatic toxins can be further subdivided into those for which hepatic toxicity is predictable and dose

dependent for most individuals (eg, acetaminophen) and those that cause unpredictable (idiosyncratic)

reactions without relationship to dose. Idiosyncratic reactions to drugs may be due to genetic

predisposition in susceptible individuals to certain pathways of drug metabolism that generate toxic

intermediates. Prominent examples of drugs causing acute liver failure that have been withdrawn from

the U.S. market include bromfenac, a nonsteroidal anti-inflammatory drug (NSAID), and troglitazone

sulfate, a thiazolidinedione used as an insulin-sensitizing agent in diabetes mellitus. Other

thiazolidinediones such as rosiglitazone and pioglitazone do not seem to have the same complication,

although routine testing of transaminases has been recommended for those taking the drugs. HMG-

CoA reductase inhibitors such as atorvastatin, lovastatin, and others are associated with elevated

levels of transaminases in less than 3% of patients and with few cases of acute liver failure.4

Essentials of Diagnosis

Drug-induced liver disease can mimic viral hepatitis, biliary tract obstruction, or other types

of liver disease.

Clinicians must inquire about the use of many widely used therapeutic agents, including over-

the-counter "natural" and "herbal" products, in any patient with liver disease.1

General Considerations

Many therapeutic agents may cause hepatic injury. The medications most commonly implicated are

nonsteroidal anti-inflammatory drugs and antibiotics because of their widespread use. Drug-induced

liver disease can mimic viral hepatitis, biliary tract obstruction, or other types of liver disease. In any

patient with liver disease, the clinician must inquire carefully about the use of potentially hepatotoxic

drugs or exposure to hepatotoxins, including over-the-counter "natural" and herbal products. In some

cases, coadministration of a second agent may increase the toxicity of the first (eg, isoniazid and

rifampin, acetaminophen and alcohol). Drug toxicity may be categorized on the basis of pathogenesis

or histologic appearance.

18

Direct Hepatotoxic Group

The liver lesion caused by this group of drugs is characterized by (1) dose-related severity, (2) a latent

period following exposure, and (3) susceptibility in all individuals. Examples include acetaminophen

(toxicity is enhanced by fasting and chronic alcohol use because of depletion of glutathione and

induction of cytochrome P450 2E1), alcohol, carbon tetrachloride, chloroform, heavy metals,

mercaptopurine, niacin, plant alkaloids, phosphorus, tetracyclines, tipranavir, valproic acid, and

vitamin A. Statins, like all cholesterol-lowering agents, may cause serum aminotransferase elevations

but rarely cause true hepatitis and are no longer considered contraindicated in patients with liver

disease.

Idiosyncratic Reactions

Except for acetaminophen, most severe hepatotoxicity is idiosyncratic. Reactions of this type are (1)

sporadic, (2) not related to dose, and (3) occasionally associated with features suggesting an allergic

reaction, such as fever and eosinophilia, which may be associated with a favorable outcome. In some

patients, toxicity results directly from a metabolite that is produced only in certain individuals on a

genetic basis. Toxicity may be observed only on post-marketing surveillance and not during

preclinical trials. Examples include amiodarone, aspirin, carbamazepine, chloramphenicol, diclofenac,

disulfiram, duloxetine, ezetimibe, flutamide, halothane, isoniazid, ketoconazole, lamotrigine,

methyldopa, nevirapine, oxacillin, phenytoin, pyrazinamide, quinidine, streptomycin, rofecoxib and

troglitazone (both withdrawn from the market in the United States), and less commonly other

thiazolidinediones, and perhaps tacrine.

Table 6. Principal Alterations of Hepatic Morphology Produced by Some Commonly Used Drugs and Chemicals.7

Principal Morphologic Change

Class of Agent Example 

Cholestasis Anabolic steroid Methyltestosterone

  Antithyroid Methimazole

  Antibiotic Erythromycin estolate

    Nitrofurantoin

  Oral contraceptive Norethynodrel with mestranol

19

Principal Morphologic Change

Class of Agent Example 

  Oral hypoglycemic Chlorpropamide

  Tranquilizer Chlorpromazine\ 

  Oncotherapeutic Anabolic steroids

    Busulfan

    Tamoxifen

  Immunosuppressive Cyclosporine

  Anticonvulsant Carbamazepine

  Calcium channel blocker

Diltiazem

    Nifedipine

    Verapamil

  Angiotensin-converting enzyme inhibitor

Captopril

    Enalapril

  Antidepressant Trazadone

Fatty liver Antibiotic Tetracycline

  Anticonvulsant Sodium valproate

  Antiarrhythmic Amiodarone

  Oncotherapeutic Asparaginase

    Methotrexate

Hepatitis Anesthetic Halothane

  Anticonvulsant Phenytoin

    Carbamazepine

    Lamotrigine

20

Principal Morphologic Change

Class of Agent Example 

    Felbamate

  Antihypertensive Methyldopa

    Captopril

    Enalapril

  Antibiotic Isoniazid

    Rifampin

    Nitrofurantoin

  Diuretic Chlorothiazide

  Laxative Oxyphenisatin

  Antidepressant Amitriptyline

    Imipramine

    Nefazodone

    Venlafaxine

  Anti-inflammatory Ibuprofen

    Indomethacin

  Antifungal Ketoconazole

    Fluconazole

  Antiviral Ritonavir

    Efavirenz

    Nevirapine

    Zidovudine

    Dideoxyinosine

  Calcium channel Nifedipine

21

Principal Morphologic Change

Class of Agent Example 

blocker

    Verapamil

    Diltiazem

  Leukotriene receptor antagonist

Zafirlukast

  Antipsychotic Clozapine

Mixed hepatitis and cholestasis

Immunosuppressive Azathioprine

  Lipid lowering Nicotinic acid

    Lovastatin, atorvastatin, other HMG-CoA reductase inhibitors

Toxic (necrosis) Hydrocarbon Carbon tetrachloride

  Metal Yellow phosphorus

  Mushroom Amanita phalloides 

  Analgesic Acetaminophen

  Solvent Dimethylformamide

Granulomas Anti-inflammatory Phenylbutazone

  Antibiotic Sulfonamides

  Xanthine oxidase inhibitor

Allopurinol

  Antiarrhythmic Quinidine

  Anticonvulsant Carbamazepine

Cholestatic Reactions

Noninflammatory

22

Drug-induced cholestasis results from inhibition or genetic deficiency of various hepatobiliary

transporter systems. The following drugs cause cholestasis: anabolic steroids containing an alkyl or

ethinyl group at carbon 17, azathioprine, indinavir (increased risk of indirect hyperbilirubinemia in

patients with Gilbert syndrome), cyclosporine, estrogens, mercaptopurine, methyltestosterone, and

ticlopidine.

Inflammatory

The following drugs cause inflammation of portal areas with bile duct injury (cholangitis), often with

allergic features such as eosinophilia: amoxicillin-clavulanic acid (among most common causes of

drug-induced liver injury), azathioprine, azithromycin, captopril, cephalosporins, chlorothiazide,

chlorpromazine, chlorpropamide, erythromycin, mercaptopurine, penicillamine, prochlorperazine,

semisynthetic penicillins (eg, cloxacillin), and sulfadiazine. Cholestatic and mixed cholestatic

hepatocellular toxicity is more likely than pure hepatocellular to

xicity to lead to chronic liver disease.

Table 7. Idiosyncratic Drug Reactions and the Cells That Are Affected.4

Type of Reaction

Effect on Cells Examples of Drugs

Hepatocellular Direct effect or production by enzyme–drug adduct leads to cell dysfunction, membrane dysfunction, cytotoxic T-cell response

Isoniazid, trazodone, diclofenac, nefazodone, venlafaxine, lovastatin

Cholestasis Injury to canalicular membrane and transporters

Chlorpromazine, estrogen, erythromycin and its derivatives

Immunoallergic Enzyme–drug adducts on cell surface induce IgE response

Halothane, phenytoin, sulfamethoxazole

Granulomatous Macrophages, lymphocytes infiltrate hepatic lobule

Diltiazem, sulfa drugs, quinidine

Microvesicular fat

Altered mitochondrial respiration, oxidation leads to lactic acidosis and triglyceride accumulation

Didanosine, tetracycline, acetylsalicylic acid, valproic acid

Steatohepatitis Multifactorial Amiodarone, tamoxifen

23

Type of Reaction

Effect on Cells Examples of Drugs

Autoimmune Cytotoxic lymphocyte response directed at hepatocyte membrane components

Nitrofurantoin, methyldopa, lovastatin, minocycline

Fibrosis Activation of stellate cells Methotrexate, excess vitamin A

Vascular collapse

Causes ischemic or hypoxic injury Nicotinic acid, cocaine, methylenedioxymethamphetamine

Oncogenesis Encourages tumor formation Oral contraceptives, androgens

Mixed Cytoplasmic and canalicular injury, direct damage to bile ducts

Amoxicillin-clavulanate, carbamazepine, herbs, cyclosporine, methimazole, troglitazone

Table 8. Postulated Mechanisms of Drug-Induced Liver Disease.4

Effect Example

Alteration of the physical properties of membranes Estrogens

Inhibition of membrane enzymes (eg, Na+-K+ ATPase) 

Chlorpromazine metabolites

Interference with hepatic uptake processes Rifampin

Impairment of cytoskeletal function Chlorpromazine metabolites

Formation of insoluble complexes in bile Chlorpromazine

Conversion to reactive intermediates  

  Electrophils producing covalent modifications of tissue macro-molecules

Acetaminophen

  Free radicals producing lipid peroxidation Carbon tetrachloride

  Redox cycling with production of oxygen radicals Nitrofurantoin

24

Acute or Chronic Hepatitis

Medications that may result in acute or chronic hepatitis that is histologically—and in some cases

clinically—indistinguishable from autoimmune hepatitis include aspirin, isoniazid (increased risk in

HBV and HCV carriers), methyldopa, minocycline, nitrofurantoin, nonsteroidal anti-inflammatory

drugs, and propylthiouracil. Hepatitis also can occur in patients taking cocaine,

methylenedioxymethamphetamine (MDMA; Ecstasy), efavirenz, imatinib mesylate, nevirapine

(increased risk in HBV and HCV carriers), ritonavir (greater rate than other protease inhibitors),

sulfonamides, telithromycin, troglitazone (withdrawn from the market in the United States), and

zafirlukast as well as a variety of alternative remedies (eg, chaparral, germander, jin bu huan, kava,

skullcap). In patients with jaundice due to drug-induced hepatitis, the mortality rate without liver

transplantation is at least 10%.

Other Reactions

Fatty Liver

Macrovesicular

This type of liver injury may be produced by alcohol, amiodarone, corticosteroids, methotrexate,

irinotecan, zalcitabine, and possibly oxaliplatin.

Microvesicular

Often resulting from mitochondrial injury, this condition is associated with didanosine, stavudine,

tetracyclines, valproic acid, and zidovudine.

Granulomas

Allopurinol, quinidine, quinine, phenylbutazone, and phenytoin can lead to granulomas.

Fibrosis and Cirrhosis

Methotrexate, and vitamin A are associated with fibrosis and cirrhosis.

Sinusoidal Obstruction Syndrome (Veno-Occlusive Disease)

This disorder may result from treatment with antineoplastic agents (eg, pre-bone marrow transplant,

oxaliplatin), and pyrrolizidine alkaloids (eg, Comfrey).

Peliosis Hepatis (Blood-Filled Cavities)

25

Peliosis hepatitis may be caused by anabolic steroids and oral contraceptive steroids as well as

azathioprine and mercaptopurine, which may also cause nodular regenerative hyperplasia.

Neoplasms

Neoplasms may result from therapy with oral contraceptive steroids, including estrogens (hepatic

adenoma but not focal nodular hyperplasia); and vinyl chloride (angiosarcoma).7

Diagnosis

When a single agent is involved, the diagnosis may be relatively simple, but with multiple agents,

implicating a specific agent as the cause is difficult. To facilitate the diagnosis of drug-induced

hepatic injury, several clinical tools for causality assessment have been developed to assist the

clinician.

History: History must include dose, route of administration, duration, previous administration,

and use of any concomitant drugs, including over-the-counter medications and herbs.

Knowing whether the patient was exposed to the same drug before may be helpful. The

latency period of idiosyncratic drug reactions is highly variable; hence, obtaining a history of

every drug ingested in the past 3 months is essential.

o Onset: The onset is usually within 5-90 days of starting the drug.

o Exclusion of other causes of liver injury/cholestasis: Excluding other causes of liver

injury is essential.

Dechallenge: A positive dechallenge is a 50% fall in serum transaminase levels within 8 days

of stopping the drug. A positive dechallenge is very helpful in cases of use of multiple

medications.

Track record of the drug: Previously documented reactions to a drug aid in diagnosis.

Rechallenge: Deliberate rechallenge in clinical situations is unethical and should not be

attempted; however, inadvertent rechallenge in the past has provided valuable evidence that

the drug was indeed hepatotoxic.

Differential diagnoses

Acute viral hepatitis

Autoimmune hepatitis

26

Shock liver

Cholecystitis

Cholangitis

Budd-Chiari syndrome

Alcoholic liver disease

Cholestatic liver disease

Pregnancy-related conditions of liver

Malignancy

Wilson disease

Hemochromatosis

Coagulation disorders

Laboratory studies

Performing laboratory tests to assess and diagnose the effects of the suspected medication is essential.

These include complete blood cell count, basic metabolic profile, and urinalysis. Patients with a

hepatocellular process generally have a disproportionate elevation in serum aminotransferase levels

compared with alkaline phosphatase levels, while those with cholestasis have the opposite findings.

Hepatitis B serology (hepatitis B surface antigen, anti–hepatitis B surface antibody, anti–hepatitis B

core antibody, hepatitis C serology) and hepatitis A serology (anti–hepatitis A virus antibody) should

be performed to exclude an infectious etiology.

ANA testing may help in cases of possible autoimmune hepatitis. Positive ANA and ASMA findings

may add to the diagnostic evaluation but are usually confusing and hence not used. The presence of

antibodies to specific forms of CYP has been associated with hypersensitivity to some drugs. For

example, some antibodies and the associated drugs involved are as follows: CYP 1A2, dihydralazine;

CYP 3A1, anticonvulsants; and CPY 2E1, halothane. Their role in pathophysiology is uncertain but

may help in diagnosis. Lymphocyte transformation to test drugs may be observed for drugs acting

through immunologic reactions, but this is not commonly used.

Hepatic function tests and their interpretations are as follows:

Bilirubin (total) - To diagnose jaundice and assess severity

Bilirubin (unconjugated) - To assess for hemolysis

Alkaline phosphatase - To diagnose cholestasis and infiltrative disease

27

AST/serum glutamic oxaloacetic transaminase (SGOT) - To diagnose hepatocellular disease

and assess progression of disease

ALT/serum glutamate pyruvate transaminase (SGPT) - ALT relatively lower than AST in

persons with alcoholism

Albumin - To assess severity of liver injury (HIV infection and malnutrition may confound

this.)

Gamma globulin - Large elevations suggestive of autoimmune hepatitis, other typical increase

observed in persons with cirrhosis

Prothrombin time after vitamin K - To assess severity of liver disease

Antimitochondrial antibody - To diagnose primary biliary cirrhosis

ASMA - To diagnose primary sclerosing cholangitis

Imaging studies

Imaging studies are used to exclude causes of liver pathology, after which a diagnosis can be made.

Ultrasonography: Ultrasonography is inexpensive compared with CT scanning and MRI and

is performed in only a few minutes. Ultrasonography is effective to evaluate the gall bladder,

bile ducts, and hepatic tumors.

CT scanning: CT scanning can help detect focal hepatic lesions 1 cm or larger and some

diffuse conditions. It can also be used to visualize adjacent structures in the abdomen.

MRI: MRI provides excellent contrast resolution. It can be used to detect cysts,

hemangiomas, and primary and secondary tumors. The portal vein, hepatic veins, and biliary

tract can be visualized without contrast injections.

Procedures 

Liver biopsy: Histopathologic evaluation remains an important tool in diagnosis. A liver

biopsy is not essential in every case, but a morphologic pattern consistent with the expected

pattern provides supportive evidence.

28

Treatment

Early recognition of drug-induced liver reactions is essential to minimizing injury. Monitoring hepatic

enzyme levels is appropriate and necessary with a number of agents, especially with those that lead to

overt injury. For drugs that produce liver injury unpredictably, biochemical monitoring is less useful.

ALT values are more specific than AST values. ALT values that are within the reference range at

baseline and rise 2- to 3-fold should lead to enhanced vigilance in terms of more frequent monitoring.

ALT values 4-5 times higher than the reference range should lead to prompt discontinuation of the

drug.

No specific treatment is indicated for drug-induced hepatic disease. Treatment is largely supportive

and based on symptomatology. The first step is to discontinue the suspected drug. Specific therapy

against drug-induced liver injury is limited to the use of N -acetylcysteine in the early phases of

acetaminophen toxicity. L-carnitine is potentially valuable in cases of valproate toxicity. In general,

corticosteroids have no definitive role in treatment. They may suppress the systemic features

associated with hypersensitivity or allergic reactions. Management of protracted drug-induced

cholestasis is similar to that for primary biliary cirrhosis. Cholestyramine may be used for alleviation

of pruritus. Ursodeoxycholic acid may be used. Lastly, consulting a hepatologist is also helpful.

Referral to liver transplantation center/surgical care

No specific antidote is available for the vast majority of hepatotoxic agents. Emergency liver

transplantation has increasing utility in the setting of drug-induced fulminant hepatic injury.

Considering early liver transplantation is important. The Model for End-Stage Liver Disease score can

be used to evaluate short-term survival in an adult with end-stage liver disease. This can help stratify

candidates for liver transplantation. The parameters used are serum creatinine, total bilirubin,

international normalized ratio, and the cause of the cirrhosis. Another criterion commonly used for

liver transplantation is the Kings College criteria.

Kings College criteria for liver transplantation in cases of acetaminophen toxicity are as

follows:

o pH less than 7.3 (irrespective of grade of encephalopathy)

o Prothrombin time (PT) greater than 100 seconds or international normalized ratio

greater than 7.7

29

o Serum creatinine level greater than 3.4 mg/dL in patients with grade III or IV

encephalopathy

Measurement of lactate levels at 4 and 12 hours also helps in early identification of patients

who require liver transplantation.

Kings College criteria for liver transplantation in other cases of drug-induced liver failure are

as follows:

o PT greater than 100 seconds (irrespective of grade of encephalopathy) or

o Any 3 of the following criteria:

Age younger than 10 years or older than 40 years

Etiology of non-A/non-B hepatitis, halothane hepatitis, or idiosyncratic drug

reactions

Duration of jaundice of more than 7 days before onset of encephalopathy

PT greater than 50 seconds

Serum bilirubin level greater than 17 mg/dL

Prognosis

The prognosis is highly variable depending on the patient's presentation and stage of liver damage. In

a prospective study conducted in the United States from 1998-2001, the overall survival rate of

patients (including those who received a liver transplant) was 72%. The outcome of acute liver failure

is determined by etiology, the degree of hepatic encephalopathy present upon admission, and

complications such as infections.2

30

References

1. Anthony SF, Eugene B, Dennis LK, et al. Harrison’s Manual of Medicine. McGraw-Hill

Professional. 2009; 11:757-72

2. Drug Induced Hepatitis. Saved from emedicine.medscape.com. June 2010

3. DeLeve LD, Kaplowitz N. Drug-Induced Liver Disease. Informa Health Care, 2007; 26:547-

66

4. Ganong WF, McPhee SJ. Pathophysiology of Disease. McGraw-Hill Professional. 2005; 13

5. Haist SA, Robbins JB, Gomella LG. Internal Medicine on Call, Lange Medical Book.

McGraw-Hill Professional. 2005; 255-9

6. Martin KJ, Schmitz PG. Internal Medicine : Just the Facts. McGraw-Hill Professional. 2008;

338-42

7. Papadakis MA, McPhee SJ. Current Medical Diagnosis and Treatment. McGraw-Hill

Professional. 2009; 16

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