TREATMENT

• Acute hepatitis B: Patients can usually be treated supportively on an outpatient basis.
  
• Chronic hepatitis B
  
  
  
  • Current indications for treatment include patients with chronic hepatitis B (e antigen positive and negative) with HBV DNA >2,000 IU/mL and/or elevated ALT with necroinflammation and fibrosis on liver biopsy. Patients with cirrhosis, both compensated and decompensated, should be treated even with normal ALT levels or HBV DNA <2,000 IU/mL.⁴
    
  • Entecavir, tenofovir, and pIFN-α are first-line treatment agents.⁵ The goal of treatment is viral suppression or eradication to prevent progression to cirrhosis and HCC. Treatment end points include clearance of HBV DNA, hepatitis B e antigen and hepatitis B surface antigen seroconversion (loss of antigen and production of antibody), and normalization of liver enzymes and histology.

Hepatitis C

GENERAL PRINCIPLES

• The hepatitis C virus (HCV) is an RNA virus of the Flavivirus family. There are six genotypes (1 to 6) and multiple subtypes (a, b, c, etc.). Genotype 1 is the most common in the United States (75%).
  
• HCV is a common blood-borne infection that is often transmitted by intravenous and intranasal drug use.
  
• HCV can cause both acute and chronic hepatitis.
  
• There are approximately 180 million HCV carriers worldwide. In the United States, about 4 million people are infected with HCV and 50% to 75% are unaware of their infection.⁶
  
• In industrialized countries, HCV accounts for 20% of cases of acute hepatitis, 70% of chronic hepatitis, 40% of cirrhosis, 60% of HCC, and 40% to 50% of liver transplantations.
  
• Male gender, older age at the time of infection, duration of infection, hepatic steatosis, heavy alcohol consumption, daily marijuana use, and coinfection with HIV have been identified as risk factors for fibrosis progression.
  
• Patients with cirrhosis due to hepatitis C develop HCC at a rate of approximately 1% to 4% per year.⁷

DIAGNOSIS

• Acute hepatitis can be asymptomatic, especially in children and young adults. Symptoms vary from mild illness to acute liver failure. Malaise, fatigue, pruritus, headache, abdominal pain, myalgias, arthralgias, nausea, vomiting, anorexia, and fever are common but nonspecific presentations.
  
• Chronic hepatitis C runs an indolent course, sometimes for decades, and its diagnosis requires a high index of suspicion. Fatigue is a common symptom. The disease may only become clinically apparent late in the natural course, when advanced liver disease develops. Patients with risk factors for HCV infection should be tested. In addition, the CDC recommends one-time screening for hepatitis C for all those born in the decades from 1945 through 1965.⁸
  
• Extrahepatic, unusual presentations include mixed cryoglobulinemia (10% to 25% of patients with HCV), glomerulonephritis, porphyria cutanea tarda, vasculitis, lymphoma, diabetes mellitus, and lichen planus.⁹
  
• The diagnosis of hepatitis C is based on a combination of liver chemistries, serologies, molecular studies, and histology.
  
• Antibodies against HCV (anti-HCV) may be undetectable for the first 8 weeks after infection. Antibodies do not confer immunity. The test has a sensitivity of 95% to 99% and a lower specificity. A false-positive test (anti-HCV positive with HCV RNA negative) may occur in the setting of autoimmune hepatitis (AIH) or hypergammaglobulinemia. A false-negative test (anti-HCV negative with HCV RNA positive) may be seen in immunosuppressed individuals and in patients on hemodialysis.
  
• HCV RNA can be detected by PCR in serum as early as 1 to 2 weeks after infection (qualitative and quantitative assays). HCV RNA determination is useful for both diagnosis and treatment purposes.
  
• HCV genotype influences the duration, dosage, and response to treatment.
  
• Liver biopsy is useful to score the degree of inflammation (grade) and fibrosis (stage) in the liver of chronically infected patients. It also allows for assessment of the amount of liver steatosis and guides treatment decisions.

TREATMENT

• Acute hepatitis C: IFN-α (standard or pegylated) for 6 months has been associated with a high rate (98%) of sustained HCV RNA clearance.¹⁰
  
• Chronic hepatitis C: Treatment varies according to genotype. In patients with genotype 1, the standard of care is to use triple therapy including pegylated interferon (pIFN-α), ribavirin, and a protease inhibitor (PI). Boceprevir and telaprevir are the only two currently approved PIs (only for genotype 1 patients). In patients with genotype 2 or 3, a combination of pIFN-α and ribavirin is administered for 6 to 12 months.
  
• Multiple side effects are associated with these regimens. pIFN-α is associated with flu-like symptoms, neuropsychiatric disorders, and bone marrow suppression. Ribavirin is associated with hemolytic anemia and pulmonary symptoms. PIs are associated with anemia, rash, dysgeusia, diarrhea, and anal discomfort.
  
• pIFN-α should not be used in patients with decompensated cirrhosis or in patients with autoimmune conditions. Ribavirin is teratogenic and should not be used in pregnancy, in women of childbearing age who are not using birth control, in patients with chronic renal insufficiency, or in those who cannot tolerate anemia. PIs inhibit the hepatic cytochrome P450 enzymes and have extensive drug-drug interactions.

IMMUNE-MEDIATED LIVER DISEASE

Autoimmune Hepatitis

GENERAL PRINCIPLES

• AIH is a chronic disorder characterized by inflammation of the liver associated with circulating autoantibodies and hypergammaglobulinemia.
  
• There are two types of AIH. Type 1 is the most common form (80%). It is associated with ANA (antinuclear antibodies) and/or ASMA (anti–smooth muscle antibodies). Type 2, predominately seen in children and young adults, is associated with antibodies to liver/kidney/microsome type 1 (ALKM-1) and/or antibodies to cytosol type 1 (ALC-1).
  
• AIH affects all ethnic groups and occurs worldwide. In Norway and Sweden, for example, its prevalence is 11 to 17 per 100,000.¹¹
  
• Women are affected more than men (gender ratio 3.6:1).

DIAGNOSIS

• An acute presentation, clinically similar to acute viral hepatitis, is observed in 30% to 40% of patients.
  
• Extrahepatic manifestations may be found in 30% to 50% and include synovitis, celiac disease, Coombs-positive hemolytic anemia, autoimmune thyroiditis, Graves disease, rheumatoid arthritis, ulcerative colitis, uveitis, and other autoimmune-mediated processes.
  
• The most common symptoms at presentation include fatigue, jaundice, myalgia, anorexia, diarrhea, acne, and right upper quadrant abdominal tenderness.
  
• Diagnostic criteria are based on autoantibodies, IgG levels, histologic changes, and the exclusion of viral hepatitis and other liver conditions.¹²
  
• Liver biopsy is essential for the diagnosis.

TREATMENT

• Goals of treatment include biochemical normalization and histologic remission.
  
• Treatment should be started in patients with elevated serum aminotransferase levels and hypergammaglobulinemia (aminotransferases >10 times upper limit of normal [ULN] or aminotransferases >5 times ULN and immunoglobulins ≥2 times ULN) or those with biopsy findings of interface hepatitis, bridging necrosis, or multiacinar necrosis.
  
• Therapy is initiated with either prednisone monotherapy (40 to 60 mg/day) or a combination of prednisone and azathioprine (30 mg/day and 1 to 2 mg/kg/day, respectively).¹¹
  
• Prednisone is tapered with biochemical and clinical improvement. Some patients require lifelong low-dose therapy.
  
• Liver transplantation should be considered in patients with decompensated cirrhosis and those with AIH-mediated acute liver failure.
  
• Most adults (90%) have clinical and biochemical improvement within 2 weeks of beginning treatment. Remission is achieved in 80% of patients at 3 years.
  
• Relapses occur in at least 20% to 50% of patients after treatment discontinuation. Those patients require retreatment.

Primary Biliary Cirrhosis

GENERAL PRINCIPLES

• Primary biliary cirrhosis (PBC) is a cholestatic disorder with autoimmune features and unknown etiology.
  
• It is more commonly seen in women (90% to 95%) and in Caucasians.
  
• PBC is an indolent disease that progresses from laboratory abnormalities to increasing histologic damage, leading to fibrosis, cirrhosis, and liver failure.

DIAGNOSIS

• The clinical course is highly variable, with up to 50% to 60% of patients asymptomatic at the time of diagnosis. Fatigue, jaundice, and pruritus are often the most troublesome symptoms. While there are no exam findings that are specific for PBC, xanthomata and xanthelasma can be manifestations of underlying cholestasis.
  
• Extrahepatic manifestations include keratoconjunctivitis sicca (Sjögren syndrome), renal tubular acidosis, gallstones, thyroid disease, scleroderma, Raynaud phenomenon, CREST syndrome, and celiac disease.
  
• Antimitochondrial antibodies are present in >90% of patients with PBC. Typical biochemical features include elevated levels of alkaline phosphatase, total bilirubin, and cholesterol as well as elevations of IgM.
  
• Liver biopsy is helpful for both diagnosis and staging.

TREATMENT

• No curative therapy is available, but ursodeoxycholic acid (13 to 15 mg/kg/day) has been shown to improve laboratory abnormalities as well as survival.¹³
  
• Symptom-specific therapy for pruritus, steatorrhea, and malabsorption may be needed.
  
• Liver transplantation is an alternative in advanced liver disease.

Primary Sclerosing Cholangitis

GENERAL PRINCIPLES

• Primary sclerosing cholangitis (PSC) is a cholestatic liver disease characterized by inflammation, fibrosis, and progressive obliteration of the extrahepatic and intrahepatic biliary tree.
  
• PSC can be subdivided into those with small duct and large duct involvement. Small duct disease has typical histologic features of PSC with a normal cholangiogram. Large duct, or classic, PSC has characteristic strictures of the biliary ducts that can be detected by cholangiography.
  
• Most patients have involvement of both intrahepatic and extrahepatic ducts, with <25% having only intrahepatic involvement and <5% only extrahepatic disease.¹⁴
  
• Male to female ratio is 2:1, and peak incidence is approximately age 40.
  
• The clinical progression of PSC is unpredictable, but most patients have insidious progression to cirrhosis.
  
• Cholangiocarcinoma has a poor prognosis; however, perihilar cholangiocarcinoma may be an indication for liver transplantation in selected patients.

DIAGNOSIS

• Clinical manifestations include intermittent episodes of jaundice, hepatomegaly, pruritus, weight loss, and fatigue. Acute cholangitis is a frequent complication in patients with severe biliary strictures.
  
• Patients are at increased risk for cholangiocarcinoma, which develops in 10% to 30%.¹⁵
  
• In 70% of patients with PSC, ulcerative colitis is an associated condition. Crohn disease is less commonly associated with PSC.
  
• pANCA (perinuclear antineutrophil cytoplasmic antibody) is positive in 80% of cases. In contrast, ANA is only seen in 50% of patients.
  
• Imaging studies useful in the diagnosis of PSC include liver ultrasound, MRCP (magnetic resonance cholangiopancreatography), and ERCP (endoscopic retrograde cholangiopancreatography). Those studies typically show ductal dilation, strictures, or irregularities of the intrahepatic or extrahepatic bile ducts. ERCP is also useful to obtain brushings to evaluate for associated malignancy.
  
• While liver biopsy is not the gold standard for the diagnosis of PSC, it is helpful to exclude other diseases and for staging.

TREATMENT

• No specific drug treatments have been shown to alter disease progression. Ursodeoxycholic acid is not currently recommended for therapy.¹⁴
  
• Acute cholangitis should be managed with antibiotics and endoscopic therapy (dilation and stenting of dominant strictures).
  
• Symptom-specific therapy for pruritus, steatorrhea, and malabsorption may be needed.
  
• Liver transplantation is an alternative in advanced liver disease.

METABOLIC LIVER DISEASE

Nonalcoholic Fatty Liver Disease

• Nonalcoholic fatty liver disease (NAFLD) is an increasingly common metabolic disorder of the liver strongly associated with diabetes mellitus type 2, the metabolic syndrome, obesity, and dyslipidemia.¹⁶
  
• The disorder can range from the benign accumulation of triglyceride in hepatocytes (simple steatosis) to the nonalcoholic steatohepatitis (NASH) characterized by steatosis with hepatocellular ballooning plus lobular inflammation. The proportion of patients with NAFLD who will progress to NASH is unknown. For patients with NASH, progression to cirrhosis occurs in approximately 11% over a 15-year period.¹⁷
  
• NAFLD has an estimated prevalence of 6% to 14% in the general population in the US.¹⁸
  
• NAFLD should be considered in the differential diagnosis of patients with elevated liver enzymes, particularly those with the metabolic syndrome.
  
• Imaging studies, including ultrasound, CT, and MRI, may show steatosis, but the presence of inflammation can only be determined by liver biopsy.
  
• Weight loss improves liver histology, and bariatric surgery can be considered in morbidly obese patients.¹⁶ Discontinuation of medications associated with NAFLD (e.g., amiodarone, corticosteroids, and total parenteral nutrition) should also be considered.

Alpha-1 Antitrypsin Deficiency

• Alpha-1 antitrypsin (α1AT) is a PI. α1AT deficiency is an autosomal recessive disorder that damages the liver through the accumulation of misfolded α1AT in hepatocytes and damages the lungs through uninhibited proteolysis, resulting in cirrhosis and emphysema.
  
• Patients with low serum α1AT levels (<10% to 15% of normal) should undergo α1AT genotype testing. The M allele gives rise to the normal PI, while S and Z are the most common deficiency alleles. The genotypes associated with liver disease are SZ, ZZ, and possibly MZ.¹⁹ Patients who are homozygous for the Z allele may develop chronic hepatitis, cirrhosis, or HCC at a rate of 10% to 15% in the first 20 years of life.
  
• Diagnosis requires liver biopsy showing periportal hepatocytes with intracellular globules.
  
• No specific drug therapy exists for α1AT-associated liver disease.
  
• Liver transplantation in patients with decompensated cirrhosis normalizes α1AT production.

Hereditary Hemochromatosis

GENERAL PRINCIPLES

• Hereditary hemochromatosis is characterized by increased iron absorption and toxic deposition of iron into parenchymal cells of various tissues. It can be caused by mutations that affect any of the proteins that limit the entry of iron into the blood.
  
• Ninety percent of individuals with hereditary hemochromatosis are homozygous for the mutation C282Y in the HFE gene on chromosome 6. However, not all patients with the mutation develop iron overload.²⁰ There are other conditions, not linked to the C282Y mutation, associated with iron overload or high ferritin, suggesting that other proteins in the iron metabolism process are defective.
  
• Patients with a family history of hemochromatosis in a first-degree relative due to an HFE gene mutation should be screened for hemochromatosis.²¹
  
• Noncirrhotic patients appropriately treated for hereditary hemochromatosis have an excellent prognosis. The survival rate in appropriately treated noncirrhotic patients is identical to that of the general population.
  
• Patients with cirrhosis or advanced fibrosis are at increased risk for the development of HCC despite therapy and should be routinely screened for HCC.

DIAGNOSIS

• Patients with hereditary hemochromatosis may be asymptomatic or may develop hepatic dysfunction (including cirrhosis), bronzing of the skin, diabetes, cardiomyopathy, arthritis, and hypogonadism.
  
• Transferrin saturation (serum iron divided by the total iron-binding capacity) ≥45% and/or elevated ferritin are suggestive of hemochromatosis and should be further investigated with HFE mutation analysis.²¹
  
• Indications for liver biopsy in patients with an HFE gene mutation include ferritin >1,000 μg/L and elevated transaminases.
  
• MRI is the modality of choice for noninvasive quantification of iron storage in the liver.

TREATMENT

• Treatment consists of phlebotomy (500 mL blood) every 1 to 2 weeks until the ferritin is 50 to100 μg/L. The need for maintenance phlebotomy varies.²¹
  
• For patients who cannot tolerate phlebotomy, iron chelation with deferoxamine may be an alternative. Side effects include gastrointestinal distress, visual and auditory impairments, and muscle cramps. Deferoxamine is only given IV, IM, or SC. Deferasirox is another alternative in the treatment of iron overload and is given orally.²²

Wilson Disease

GENERAL PRINCIPLES

• Wilson disease is an autosomal recessive disorder (ATP7B gene on chromosome 13) leading to progressive copper overload. Incidence is 1 in 30,000 with a female to male ratio of 2:1 and an age at presentation ranging from 6 to 20 years.
  
• The gene mutation in Wilson disease results in accumulation of copper in the liver and ultimately liver injury. In addition, copper is also deposited in other organs, notably the brain, kidneys, and cornea.
  
• First-degree relatives of patients diagnosed with Wilson disease should be screened for this condition.

DIAGNOSIS

• Presentation of liver disease in Wilson disease ranges from asymptomatic to acute liver failure.
  
• Extrahepatic manifestations include neuropsychiatric symptoms, gold-brown rings at the periphery of the cornea on slit-lamp examination (Kayser-Fleischer rings), Coombs-negative hemolytic anemia, renal tubular acidosis, arthritis, and osteopenia.
  
• Low serum ceruloplasmin of <20 mg/dL (seen in 85% of patients) and elevated 24-hour urine copper level of >100 mcg/24 hours suggest the diagnosis.²³
  
• Liver biopsy with a copper level >250 mcg/g (dry weight) is consistent with Wilson disease.

TREATMENT

• Copper-chelating agents (including D–penicillamine, trientine, and zinc salts) block the intestinal absorption of copper and are used to treat Wilson disease.²³ While zinc and trientine are well tolerated, D-penicillamine is associated with several side effects including hypersensitivity, bone marrow suppression, proteinuria, systemic lupus erythematosus, and Goodpasture syndrome.
  
• Patients presenting with fulminant liver failure should be considered for liver transplant.
  
• Liver transplant in patients with Wilson disease without neurologic symptoms carries an excellent prognosis.

ALCOHOLIC AND DRUG-INDUCED LIVER DISEASE

Alcohol-Induced Liver Disease

GENERAL PRINCIPLES

• Alcohol is, when used in excess, a hepatotoxin capable of inducing a spectrum of diseases including fatty liver, alcoholic hepatitis, and alcoholic cirrhosis. In the US, excessive alcohol consumption is the third leading preventable cause of death and 50% of all cases of cirrhosis are due to alcohol abuse.
  
• Patients with fatty liver are generally asymptomatic and may have hepatomegaly and mild transaminase elevations (typically with an AST:ALT ratio >2:1).
  
• Alcoholic hepatitis ranges from asymptomatic to quite severe, with fever, abdominal pain, jaundice, complications of portal hypertension and, in some cases, liver failure and death.
  
• Alcoholic cirrhosis is typically micronodular and results from chronic alcohol consumption. The sensitivity of the liver to damage from alcohol varies widely. Among patients with heavy alcohol consumption, only 6% to 41% progress to cirrhosis.²⁴

DIAGNOSIS

• A thorough history is essential; self-reports of alcohol consumption may be underestimates.
  
• Patients with suspected alcoholic liver disease should be evaluated for coexisting causes of liver injury. Liver biopsy may be helpful if alternative diagnoses are being considered.
  
• Severity of alcoholic hepatitis can be estimated by using a discriminant function.²⁵

• A DF of >32 defines a severe alcoholic hepatitis and is associated with a high 30-day mortality.
  
• In-hospital mortality of severe alcoholic hepatitis is approximately 50%.

TREATMENT

• The cornerstone of treatment is abstinence from alcohol. Abstinence from alcohol may reverse fatty liver and lead to biochemical improvement in patients with alcoholic cirrhosis.
  
• In alcoholic hepatitis, medical therapies include corticosteroids and pentoxifylline. Corticosteroids (prednisolone 40 mg daily for 4 weeks) should be considered in subjects with alcoholic hepatitis and a DF of ≥32 or encephalopathy. Potential contraindications to steroids include infection, gastrointestinal bleeding, and pancreatitis.²⁶ Pentoxifylline (400 mg tid for 4 weeks) decreases cytokine production and is an alternative for patients in whom steroids are contraindicated.²⁷ In addition, good nutrition is an essential component of treatment.
  
• Patients with decompensated alcoholic cirrhosis may be considered for transplant when they have demonstrated sustained abstinence from alcohol (>6 months) and enrollment in a rehabilitation program.

DRUG-INDUCED LIVER INJURY

GENERAL PRINCIPLES

• Drug-induced liver injury (DILI) may be intrinsic or idiosyncratic. Intrinsic hepatotoxicity is a direct, dose-dependent drug effect. Idiosyncratic hepatotoxicity includes hypersensitivity reactions and altered drug metabolism, which are variable and not predictable.
  
• Incidence of DILI is estimated to be between 1 in 10,000 and 1 in 100,000. A searchable database of medications and supplements associated with liver injury is available online (http://livertox.nih.gov, last accessed April 18, 2014). DILI accounts for up to 10% of all adverse drug reactions and represents 10% of hepatology consultations.
  
• DILI is a frequent cause of acute jaundice, and it is the most common cause of acute liver failure in the US. Jaundice in DILI is a poor prognostic indicator, with a case fatality rate of 10% to 50%.²⁸
  
• Use of herbal and dietary supplements is common in the US. Like other pharmaceuticals, these supplements may exhibit hepatotoxicity, manifested as transient abnormalities of liver enzymes or acute or chronic hepatitis.

DIAGNOSIS

• Clinical presentation of DILI ranges from asymptomatic elevation of liver enzymes to fulminant hepatic failure.
  
• A high index of suspicion is essential to suspect DILI. A thorough interview with the patient and his/her relatives and a review of pharmacy records are essential to define the drugs, herbs, or dietary supplements involved in the liver injury.
  
• Diagnostic criteria include clinical suspicion, temporal relationship between drug exposure and liver injury, and resolution of injury after discontinuing the offending agent.
  
• Patterns of liver biochemistry abnormalities in DILI include hepatocellular (AST and ALT >2× ULN), cholestatic (alkaline phosphatase and conjugated bilirubin >2× ULN), and mixed (hepatocellular and cholestatic).

TREATMENT

Treatment involves stopping the offending agent, instituting supportive measures and, when applicable (e.g., acetaminophen), use of drug-specific therapy.²⁸

Acetaminophen Hepatotoxicity

GENERAL PRINCIPLES

• Acetaminophen is a safe and effective analgesic and antipyretic if consumed at the recommended dose of <4 g/day. However, it is the most common cause of acute liver failure in the US (suicide attempts or therapeutic misadventures).²⁹
  
• The toxicity of acetaminophen is dose dependent. Overdose is defined as >150 mg/kg in children and >10 to 15 g in adults. Toxicity can actually occur at doses <10 g.
  
• Toxicity is due to the metabolism of acetaminophen to toxic N-acetyl-p-benzoquinone imine (NAPQI). At usual doses, NAPQI is quickly detoxified by conjugation with glutathione.
  
• Hepatotoxicity is not increased in the setting of nonalcoholic chronic liver disease. In chronic ethanol abusers, the repetitive use of supratherapeutic doses of acetaminophen is linked to liver toxicity.
  
• Drugs that induce CYP2E1 enzymes (carbamazepine, phenytoin, phenobarbital, isoniazid, and rifampin) can produce liver injury in the absence of acetaminophen overdose.

DIAGNOSIS

• Patients may present asymptomatically; symptoms of toxicity may not develop until 1 to 2 days after ingestion. Initial symptoms are nonspecific and include anorexia, malaise, nausea, and vomiting, followed by right upper quadrant pain.
  
• Subsequently, hepatic failure develops, including jaundice, encephalopathy (cerebral edema), and coagulopathy. Renal failure can also develop at this point, due to drug-induced acute tubular necrosis and dehydration.
  
• Differential diagnosis includes gastroenteritis, acute cholecystitis, pancreatitis, alcoholic hepatitis, viral hepatitis, Reye syndrome, shock liver, and other forms of drug/herb hepatotoxicity.
  
• The Rumack-Matthew nomogram is used to predict the likelihood of hepatotoxicity given the serum acetaminophen level obtained and the time since consumption.²⁹
  
• Serum aminotransferases begin to rise sharply about 12 hours after ingestion. Peak levels occur at about 72 hours and are frequently >3,000 IU/L.
  
• Hepatic synthetic function declines as hepatotoxicity progresses (e.g., prolonged PT, hyperbilirubinemia, hypoalbuminemia, and hypoglycemia). Acidosis, azotemia, and electrolyte disturbances may occur.

TREATMENT

• Treatment involves the prompt administration of N-acetylcysteine (NAC) (a glutathione precursor) to protect the liver against the toxic metabolites of acetaminophen.²⁹ If the patient presents with acute liver failure, treatment should be administered in intensive care units of hospitals with liver transplant programs.
  
• Treatment should begin ideally within 8 to 10 hours postingestion, but may be beneficial up to 24 hours.
  
• NAC is given orally or intravenously.
  
  
  
  • Oral: Loading dose of 140 mg/kg followed by a maintenance dose of 70 mg/kg every 4 hours for a total of 17 doses over 72 hours.
    
  • Intravenous: Loading dose of 150 mg/kg IV over 15 minutes followed by a maintenance dose of 50 mg/kg over 4 hours followed by 100 mg/kg over 16 hours. Other IV dosage regimens have also been suggested.
  
  
• Patients who present late (>10 hours after ingestion) may benefit from longer treatment durations than those described above.
  
• Prompt administration of N-acetylcysteine is associated with a good outcome. Unfortunately, many patients present for medical care late, once the toxic effects are established and the acute liver failure is too advanced to be reversed by simple administration of NAC.
  
• Careful attention should be paid to detecting cerebral edema and correcting fluid, electrolyte, and acid-base abnormalities.
  
• Liver transplantation should be considered in patients with liver failure that continues to progress despite adequate treatment.²⁹

TUMORS OF THE LIVER

Adenoma

• Hepatic adenomas are rare, benign epithelial liver tumors commonly associated with a history of oral contraceptive (OC) use and androgen steroid therapy. Usually located in the right hepatic lobe, roughly three-fourths of adenomas are solitary.³⁰
  
• The incidence of liver adenomas is estimated to be 0.1 per year per 100,000 and has grown to be 3 to 4 per 100,000 in long-term OC users.³¹
  
• Hepatic adenomas, especially those that are larger, may present with upper abdominal pain. Adenomas >5 cm in diameter have an increased risk of spontaneous bleeding. Hepatic adenomas have a risk of malignant transformation that has been calculated at 4% to 10%.³²
  
• Diagnosis is usually based on the clinical setting with the assistance of imaging studies. In particular, contrast CT scans may show early-phase peripheral enhancement followed by centripetal flow during the portal venous phase.³³
  
• OC cessation may lead to regression and even complete resolution of hepatic adenomas.³⁴
  
• Because of the risk of hemorrhage, rupture, and malignant transformation, surgical resection is typically recommended for adenomas >5 cm in diameter.³⁵

Hemangioma

• Hepatic hemangiomas, the most common benign liver tumors, are nonepithelial lesions usually discovered incidentally.³⁶
  
• Approximately three-fourths are found in females. Female sex hormones (endogenous or exogenous) may exert influence over the growth of hemangiomas, but significant enlargement still only occurs in a minority of patients.³⁷
  
• Although typically of minimal clinical concern, hemangiomas measuring >10 cm in diameter may be symptomatic (right upper quadrant abdominal pain, nausea, or early satiety).
  
• Giant hepatic hemangiomas may be associated with the Kasabach-Merritt syndrome, which is characterized by fibrinolysis, thrombocytopenia, coagulopathy, and a fatal outcome in up to 30% of patients and often represents an indication for liver transplantation.
  
• Diagnosis of liver hemangiomas is made on imaging.
  
• As most hemangiomas remain stable in size, surgical indications are typically limited to symptomatic patients with giant hemangiomas.³⁸

Focal Nodular Hyperplasia

• Focal nodular hyperplasia (FNH) is a benign liver tumor that is usually solitary (but may be multiple in 20% of cases) and <5 cm in diameter. FNH is the second most common benign liver tumor after hemangiomas and is found predominantly in females in a roughly 10:1 ratio.³⁹
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