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LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases; 2012-.
LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet].
Show detailsDescription. The clinical course of acute hepatic necrosis resembles an acute, toxic injury to the liver with sudden and precipitous onset, marked elevations in serum aminotransferase levels, and early signs of hepatic (or other organ) dysfunction or failure despite minimal or no jaundice. Rapid recovery after withdrawal of the agent is also typical. Other organ failure, such as lung, kidney or bone marrow, may also be present and may overshadow the hepatic injury. Acute hepatic necrosis is typically caused by a direct hepatotoxin and is usually dose dependent and “expected”, rather than idiosyncratic.
Latency to Onset. The time to onset of acute hepatic necrosis is typically short, 1 to 14 days.
Symptoms. Usually abrupt onset of nausea, weakness, fatigue and abdominal pain; somnolence and mental clouding may occur early. Itching is rare and jaundice appears later. Other organ failure (kidney, lung, bone marrow) may be prominent.
Serum Enzyme Elevations. ALT rising rapidly to above 800 IU/L (>20 times ULN), with alkaline phosphatase <2 times ULN (<230 U/L). As a result, the R ratio (ALT divided by Alk P, both expressed as multiples of the upper limit of normal) tends to be very high (>10). If measured, LDH levels are also elevated. Serum creatinine, BUN, INR and ammonia are also often raised, sometimes before hyperbilirubinemia (which is usually mild to moderate even at the height). Strikingly, the serum enzymes usually improve rapidly with stopping the medication, falling by 50% within 8 days.
Drugs. Typical causative agents include acetaminophen, aspirin, cocaine, niacin, high dose intravenous amiodarone, methotrexate, terbutaline, and direct toxins such as phosphorus or penny royal oil. In some instances, the hepatic injury is not a direct effect of the drug on the liver, but an indirect effect due to ischemic hepatic necrosis caused by sudden and severe heart failure, hypotension, shock, hyperthermia, or hypoxia.
Differential Diagnosis. The major diagnoses that should be excluded include ischemic hepatitis due to hypotension, hypoxia, or heat stroke. The episode of shock or hypoxia may have been unnoticed or poorly documented, even in the setting of inhospital observation. Ischemic hepatitis should be particularly suspected in patients with heart failure, arrhythmias, severe asthma or pulmonary disease, and status epilepticus. In some instances, the ischemic hepatitis is “drug induced”, such as after general anesthesia or propofol.
Criteria for Definition. Elements important in diagnosis of acute hepatic necrosis include:
- 1.
Latency of less than 14 days
- 2.
Abrupt onset of symptoms
- 3.
Alanine aminotransferase (ALT) levels above 800 U/L (>20 times ULN)
- 4.
Alkaline phosphatase (Alk P) levels that are normal or only modestly elevated (<2 times ULN).
- 5.
Bilirubin <10 mg/dL at time of diagnosis
- 6.
Acute injury and dysfunction of other organ systems (lungs, kidneys, bone marrow)
- 7.
If liver biopsy is obtained, changes of acute zone 3 coagulative necrosis with scant lobular lymphocytic infiltration, little or no fibrosis or cholestasis and no veno-occlusive changes.
A case might be considered “probable” if typical features are found, but ALT levels rise to only 400 to 800 U/L (between 10 and 20 times ULN). There may be some overlap between acute hepatic necrosis and drug induced acute hepatitis, but latency and recovery are typically longer with acute hepatitis. Acute hepatic necrosis can cause acute liver or multiorgan failure. Immunoallergic features (rash, fever, eosinophilia) may be present, but are usually not prominent. Autoantibodies are absent. Cirrhosis following acute hepatic necrosis is very rare, but isolated instances of residual inactive cirrhosis or advanced fibrosis have been reported.
Representative Cases
Case 1. Acute hepatic necrosis with jaundice due to high doses of niacin.
[Modified from: Patterson DJ, Dew EW, Gyorkey F, Graham DY. Niacin hepatitis. South Med J 1983; 76: 239-41. PubMed Citation]
A 41 year old man with history of taking 4.5 grams of niacin daily for 5 months presented with nausea, anorexia, weakness and abdominal pain followed by jaundice. He was icteric, but had no fever or rash. Blood tests showed marked elevations in serum aminotransferase levels and jaundice (Table). Tests for hepatitis B and autoantibodies were negative. An initial prothrombin time was 28.5 seconds (normal <14 seconds), but it corrected within 3 days of stopping niacin. A liver biopsy showed submassive lobular collapse, marked cholestasis, ballooned hepatocytes and mild fibrosis. Once niacin was stopped, he improved rapidly and serum enzymes fell to normal within a month. Review of this history revealed that he had developed jaundice while taking niacin in the past, had recovered on stopping, but nevertheless began taking it again.
Key Points
| Medication: | Niacin 4.5 grams daily |
|---|---|
| Pattern: | Hepatocellular (R=24) |
| Severity: | 3+ (jaundice, hospitalization) |
| Latency: | 6 months |
| Recovery: | 4 days for symptoms, 49 days for ALT |
| Other medications: | None |
Laboratory Values
| Time After Starting | Time After Stopping | ALT (U/L) | Alk P (U/L) | Bilirubin (mg/dL) | Other |
|---|---|---|---|---|---|
| 0 | Niacin started, increasing to 4.5 grams/day | ||||
| 20 weeks | Admission: niacin stopped | Nausea, vomiting and jaundice | |||
| 20 weeks | 0 | 3300 | 379 | 7.2 | Protime 28.5 sec |
| 2 days | 2155 | 343 | 8.0 | ||
| 4 days | 1212 | 299 | 6.6 | Protime 12.5 sec | |
| 21 weeks | 9 days | 237 | 193 | 2.2 | Discharged |
| 27 weeks | 7 weeks | 35 | 78 | 0.7 | |
| 30 weeks | 10 weeks | 26 | 57 | 0.3 | |
| Normal Values | <41 | <115 | <1.2 | ||
Comment
A typical example of hepatotoxicity from high doses of niacin. The latency probably related to the gradual increase in dose of niacin and the hepatic injury triggered by reaching toxic levels. Serum aminotransferases were markedly elevated, and there was a prompt improvement with stopping therapy, levels falling by more than 50% within 3 days. The cellular injury in acute hepatic necrosis is more typical of “necrosis” as opposed to “apoptosis”, which is the major form of hepatocellular injury in viral hepatitis. The prolongation of the prothrombin time indicated the severity of the injury and biopsy showed submassive necrosis and collapse. Multiple such episodes might lead to posthepatic cirrhosis.
Case 2. Acute hepatic necrosis from high dose intravenous amiodarone therapy.
[Modified from patient 1 in: Pye E, Northcote RJ, Cobbe SM. Acute hepatitis after parenteral amiodarone administration. Br Heart J 1988; 59: 690-1. PubMed Citation]
A 48 year old woman with valvular heart disease and atrial fibrillation was treated with intravenous amiodarone and developed acute elevations in serum aminotransferase levels and mild jaundice that reversed rapidly. She had undergone both mitral and aortic valve replacement in the past and had chronic congestive heart failure that was worsened by the onset of rapid atrial fibrillation. After several days of monitoring, she was given amiodarone using a bolus dose of 300 mg and then 900 mg daily. Discontinuation of amiodarone was followed by rapid fall of serum aminotransferase levels to pretreatment values.
Key Points
| Medication: | Amiodarone |
|---|---|
| Pattern: | Hepatocellular (R=13.1) |
| Severity: | 3+ (ALT elevations with jaundice and prolongation of hospitalization) |
| Latency: | 1 day |
| Recovery: | One to two weeks |
| Other medications: | Digoxin, verapamil, others not given |
Laboratory Values
| Time After Starting | Time After Stopping | ALT ( U/L) | Alk P (U/L) | Bilirubin* (mg/dL) | Other | |
|---|---|---|---|---|---|---|
| -3 days | 45 | 145 | 2.0 | |||
| -1 days | 22 | 150 | 1.8 | |||
| 0 | 28 | 185 | 1.8 | Amiodarone started | ||
| 1 day | 580 | 150 | 3.8 | |||
| 2 days | 0 | 1770 | 140 | 9.1 | Amiodarone stopped | |
| 3 days | 1 day | 1450 | 140 | 8.5 | ||
| 4 days | 2 days | 740 | 160 | 5.9 | ||
| 5 days | 3 days | 700 | 156 | 4.7 | ||
| 1 week | 5 days | 320 | 170 | 3.2 | ||
| 2 weeks | 10 days | 50 | 120 | 1.5 | ||
| Normal Values | <55 | <280 | <1.2 | |||
- *
Converted from μmol.
Comment
The patient experienced a marked rise in serum aminotransferase levels and jaundice within a day of starting intravenous amiodarone for atrial fibrillation. This patient probably had underlying congestive liver disease from chronic right heart failure as shown by the slight elevations in bilirubin and ALT levels before amiodarone therapy. Thus, amiodarone acute hepatic injury may occur predominantly in patients with an underlying degree of liver injury from heart failure and ischemia. The form of injury is acute hepatic necrosis with rapid rise and rapid fall in enzyme levels.
Case 3. Acute hepatic necrosis after methylenedioxymetamphetamine (Ecstasy) use.
[Modified from: Brown C, Osterloh J. Multiple severe complications from recreational ingestion of MDMA ('Ecstasy'). JAMA 1987; 258: 780-1. PubMed Citation]
A 32 year old woman developed hallucinations and confusion a few hours after ingesting 100 to 150 mg of methylenedioxymetamphetamine (MDMA) and was brought to the emergency room with agitation, disorientation and high fever. On examination, she had tachycardia (150/min), hypotension (90/50 mm Hg), tachypnea (36/min) and fever (41.6 oC). She had dilated pupils, nystagmus and hyperreflexia. Laboratory tests showed normal blood counts and liver tests with mild dehydration (creatinine 1.9 mg/dL), and serious hypoxemia (pO2 44 mm). She was admitted to an intensive care unit for ventilator support for 24 hours. Thereafter, she had weakness, anorexia and nausea, but improved over the next week and was discharged 10 days after admission. She had no previous history of liver disease or jaundice and took no other medications. She had used MDMA previously without complications. She denied injection drug use. During the course of her hospitalization, she developed elevations in serum enzymes and jaundice (Table). The prothrombin time became abnormal, but she remained stable and liver test abnormalities were markedly improved over the 10 day hospitalization. Analysis of the recovered powder that was taken demonstrated that it was 99% pure MDMA.
Key Points
| Medication: | Methylenedioxymetamphetamine (MDMA: "Ecstasy”) |
|---|---|
| Pattern: | Hepatocellular (R=~100) |
| Severity: | 3+ (jaundice, hospitalization) |
| Latency: | 3 days to jaundice |
| Recovery: | Rapid, not completely documented |
| Other medications: | None mentioned |
Laboratory Values
| Time After Stopping | AST (U/L) | Alk P (U/L) | Protime (seconds) | Bilirubin (mg/dL) | Other |
|---|---|---|---|---|---|
| Single ingestion of MDMA | |||||
| 0 | 30 | 50 | 13.6 | 0.4 | Admission |
| 1 day | 385 | 65 | 33.2 | 1.2 | Extubation |
| 2 days | 37.9 | ||||
| 3 days | 1820 | 107 | 18.9 | 6.8 | |
| 4 days | 1435 | 90 | 13.8 | 7.6 | |
| 5 days | 1680 | 145 | 12.8 | 5.6 | |
| 10 days | 237 | 68 | 1.6 | ||
| Normal Values | <42 | <115 | <14.5 | <1.2 | |
Comment
Abuse of MDMA, an amphetamine derivative used orally as a “social” drug, often during “rave” parties, has been associated with severe toxic reactions with severe hyperthermia, shock, respiratory failure and hepatitis. This case demonstrates “hyperacute” hepatic failure that can occur with MDMA use. The liver injury arises 1 to 3 days after the initial presentation with hyperthermia, hypotension and hypoxia, the prothrombin time becoming abnormal immediately followed by rise in ALT and AST and jaundice. The clinical pattern is “acute hepatic necrosis” as occurs with toxic reactions, most typically with acetaminophen overdose. The cause of the hyperacute hepatic failure due to MDMA may actually be the effects of hypotension, hypoxia and hyperthermia on the liver, as the early hepatic histology resembles hyperthermia induced liver injury (fat accumulation and central coagulative necrosis). Why a person who has been regularly abusing MDMA should suddenly have such an overwhelming toxic reaction is unclear, but it probably represents drug overdose and administration of more than claimed dose of the illegally (and unreliably) prepared substance or else an underlying change in susceptibility (perhaps dehydration from participation in a “rave” or a concurrent illness).
Case 4. Severe acute acetaminophen hepatotoxicity after an intentional overdose.
[Acute Liver Failure Study Group Patient #2281]
A 27 year old woman took an overdose of acetaminophen (30 tablets of 325 mg each) in a suicide attempt, because of a failed romantic relationship. The following day she was nauseated and vomited several times, but she waited another day before presenting to an emergency room, approximately 48 hours after the ingestion. She had no other significant medical problems and denied a history of liver disease, alcohol abuse or risk factors for viral hepatitis. On presentation, she was oriented but drowsy. Her vital signs included pulse of 125/min, BP 100/65, respirations 25/min and temperature 37 °C. She was mildly jaundiced, but had no rash or signs of chronic liver disease. The total serum bilirubin level was 4.4 mg/dL, ALT 3,570 U/L, AST 7,377 U/L, and alkaline phosphatase 109 U/L (Table). A urine toxicology screen was positive for benzodiazepines and cocaine. Serum acetaminophen level was 31 mcg/mL, and serum acetaminophen adducts were positive (23.8 nmol/mL). She was admitted to the intensive care unit and given intravenous N-acetylcysteine. Tests for hepatitis A, B and C were negative as were autoantibodies. Abdominal ultrasound showed no evidence of biliary obstruction. Over the next few days she had mild hepatic encephalopathy. She was placed on a liver transplantation waiting list, but began to improve spontaneously, and was transferred to a psychiatric service after a week in the hospital. When finally discharged several weeks later, all liver tests had returned to normal.
Key Points
| Medication: | Acetaminophen (~10 grams as a single overdose) |
|---|---|
| Pattern: | Hepatocellular (R=~100) |
| Severity: | Severe (jaundice, encephalopathy and INR prolongation) |
| Latency: | 2 days |
| Recovery: | ~2 weeks |
| Other medications: | Possibly cocaine and benzodiazepines |
Laboratory Values
| Time After Ingestion | ALT (U/L) | Bilirubin (mg/dL) | INR | Other |
|---|---|---|---|---|
| 2 days | 3570 | 4.4 | 6.9 | Admission |
| 3 days | 7372 | 4.2 | 6.6 | Encephalopathy |
| 4 days | 5139 | 4.7 | 4.0 | |
| 5 days | 2852 | 5.6 | 3.7 | |
| 6 days | 1764 | 6.3 | 3.0 | |
| 7 days | 1478 | 8.0 | 3.2 | |
| 8 days | 828 | 9.9 | 2.1 | Transferred from ICU |
| 2 weeks | Normal | Normal | Normal | Discharged |
| Normal Values | <42 | <1.2 | <1.2 |
Comment
Acetaminophen hepatotoxicity typically presents within 2 to 5 days of an intentional overdose with a pattern of acute hepatocellular necrosis with striking elevations of aminotransferase levels (often above 2000 U/L and higher than typically seen with acute viral hepatitis). Jaundice typically worsens over the first few days, while signs of hepatic failure may improve (encephalopathy and coagulopathy). Patients may also have renal insufficiency. This is the classical pattern of acute hepatic necrosis and is typically the result of exposure to a direct toxin rather than an idiosyncratic reaction to a medication. Late presentation (>48 hours) after a suicidal overdose is associated with severe toxicity while early presentation (<12 to 24 hours) is associated with milder degrees or no liver injury provided the antidote, N-acetylcysteine, is given promptly on arrival.
Hepatic Histology of Acute Hepatic Necrosis
Pure cases of acute hepatic necrosis (those without preexisting liver disease) have a simple histological appearance. There is zonal coagulative necrosis that may vary in intensity from involvement of a fraction of one acinar zone to necrosis of the entire acinus. Early in the injury, hepatocyte ghost cells will be seen in the areas of necrosis, but if the patient survives the initial insult, neutrophils and macrophages will begin to migrate in to the necrotic zone, beginning at the edges. Eventually all of the necrotic hepatocytes will be removed, leaving behind an area of necrotic collapse filled with pigmented macrophages. This process will begin within 12 to 24 hours of injury and may be completely resolved within one to two weeks, depending on the degree of necrosis. At the edges of the necrotic zone, hepatocyte apoptosis may be seen. The remaining hepatocytes may show steatosis. This latter finding is characteristic of acetaminophen injury as well as other causes of acute hepatic necrosis. Zone 3 is usually the zone affected, but zone 1 coagulative necrosis occurs with some types of direct hepatotoxins. There is usually little lymphocytic infiltrate associated with the necrosis and the presence of significant inflammation should suggest other patterns of liver injury.
The histological differential diagnosis mainly consists of causes of hypoxic-ischemic injury. Such injury may be seen secondary to shock from any cause as well as from sinusoidal obstruction syndrome (SOS). Some forms of SOS will have little inflammation and prominent zone 3 coagulative necrosis, mimicking the pattern of acute hepatic necrosis. The central veins should be carefully inspected for the characteristic veno-occlusive lesions. Zone 3 necrosis may be seen as a component of acute or chronic hepatitis, particularly hepatitis due to autoimmune hepatitis. In such cases, there will be significant inflammatory infiltrate in the necrotic areas, often with plasma cells or eosinophils.
Histologic Images
Photomicrographs
David E. Kleiner, MD, PhD
Laboratory of Pathology
National Cancer Institute
Case A. Acetaminophen Toxicity
Photomicrographs from an explant, probably from a child.
Case contributed by Dr. Linda Ferrell, UCSF, Department of Pathology.
Histologic Features to Note:
Acute Hepatic Necrosis – Case A – At low magnification there is zonal necrosis present, seen as areas of darker pink (arrows) against the viable hepatocytes which are pale due to steatosis and ballooning injury.
Case A. Acetaminophen Toxicity
Histologic Features to Note:
Acute Hepatic Necrosis – Case A – Here the zonal necrosis is present around three central veins (V), while hepatocytes near portal areas (P) remain viable.
Case A. Acetaminophen Toxicity
Histologic Features to Note:
Acute Hepatic Necrosis – Case A – A few viable hepatocytes are left near the vein, but most are present as hepatocyte ghosts. Macrophages (arrows) have infiltrated into the necrotic zone. Hepatocytes around the edges of the necrosis show ballooning injury and steatosis.
Case A. Acetaminophen Toxicity
Histologic Features to Note:
Acute Hepatic Necrosis – Case A – The hepatocytes near the portal area are viable, but show ballooning injury and steatosis. There is no inflammation.
Case B. Acetaminophen Toxicity
This section is also from an explant, probably from an adult. The history included alcohol abuse, which may account for the striking degree of steatosis as well as the inflammation in some of the portal areas.
Case contributed by Dr. Linda Ferrell, UCSF Department of Pathology.
Histologic Features to Note:
Acute Hepatic Necrosis – Case B – At low magnification there is marked steatosis involving zones 2 and 3, but the coagulative necrosis is not yet evident. There is some inflammation, seen here as patches of purple cells (arrows) in the portal areas.
Case B. Acetaminophen Toxicity
Histologic Features to Note:
Acute Hepatic Necrosis – Case B – In zone 3, many of the hepatocytes are necrotic and some lipid vacuoles have merges to form lipid lakes. Most of the nuclei that can be seen belong to sinusoidal cells such as endothelial cells and macrophages.
Case B. Acetaminophen Toxicity
Histologic Features to Note:
Acute Hepatic Necrosis – Case B – The portal areas show inflammation, most likely related to preexisting alcoholic liver disease. The hepatocytes are mostly viable, but an edge the necrotic zone is apparent (arrows).
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- Review The Pathology of Acute Liver Failure.[Clin Liver Dis. 2018]Review The Pathology of Acute Liver Failure.Fyfe B, Zaldana F, Liu C. Clin Liver Dis. 2018 May; 22(2):257-268.
- Review Primary angioembolization in liver trauma: major hepatic necrosis as a severe complication of a minimally invasive treatment-a narrative review.[Updates Surg. 2022]Review Primary angioembolization in liver trauma: major hepatic necrosis as a severe complication of a minimally invasive treatment-a narrative review.Segalini E, Morello A, Leati G, Di Saverio S, Aseni P. Updates Surg. 2022 Oct; 74(5):1511-1519. Epub 2022 Sep 4.
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