Liver injury associated with Acetaminophen: A Review
Ulfa Kholili1*, Yahya Haryo Nugroho2, Titong Sugihartono1, Iswan1,
Poernomo Boedi Setiawan1
1Gastroenterology-Hepatology Division, Department of Internal Medicine, Faculty of Medicine - Dr. Soetomo General Academic Hospital, Universitas Airlangga, Surabaya, 60131, Indonesia.
2Department of Internal Medicine, Faculty of Medicine - Dr. Soetomo General Academic Hospital, Universitas Airlangga, Surabaya, 60131, Indonesia.
The most widely prescribed pain and fever reliever in both the United States and Europe is acetaminophen, also referred to as paracetamol. It is included on the World Health Organization's List of Essential Medications, which includes the best and safest medications required in a healthcare system. Although acetaminophen overdose has been related to fatal and nonfatal hepatic necrosis since 1966, it is generally safe when used at standard therapeutic levels (up to 4000 mg per 24 hours). It involves fundamental metabolic pathways that actually occur on microsomes in hepatocytes, and overdosing on acetaminophen causes liver damage followed by liver failure. The typical acetaminophen overdose remedy is N-acetylcysteine (NAC), which is administered to all patients at high risk of liver toxicity. The standard of therapy is NAC medication, although for some people, liver transplantation may be a life-saving procedure. We shall explore the safety of acetaminophen in associated with liver injury in this review article, particularly in terms of epidemiology, pharmacokinetic, hepatotoxicity, clinical presentation, and the treatment.
Harmon Northrop Morse, an American chemist, produced paracetamol or also known as acetaminophen in 1878 by reducing p-nitrophenol with tin in glacial acetic acid; nevertheless, acetaminophen was not employed in medical therapy for approximately 15 years. In 1893, acetaminophen was discovered in the urine of phenacetin users, and it was concentrated into a white crystalline substance with a harsh taste. Although acetaminophen was found as an acetanilide metabolite in 1899, it was mostly overlooked at the time1. Beginning in the 1950s, acetaminophen replaced phenacetin (an antipyretic and analgesic widely used at the time, but was associated with hypertension, interstitial nephritis, and death)2. In some county such as, the United States, Indian, and the United Arab Emirates, acetaminophen is currently the most commonly used drug for fever and pain3–5.
According to the World Health Organization's List of Essential Medicine, acetaminophen is the safest and most effective medication required in the healthcare system6. Acetaminophen is available in a variety of forms, including liquid suspension, tablet, capsule, intramuscular, intravenous, suppository, and effervescent. It is frequently offered in conjunction with other drugs, such as numerous cold treatments7.
Since 1966, an acetaminophen overdose has been related to fatal and nonfatal liver necrosis when administered at normal therapeutic levels (up to 4000 mg per 24 hours)8. It is also hypothesized that in vulnerable people, such as alcoholics, repeated or slightly excessive therapeutic dosages might be hepatotoxic9–11. Acetaminophen is one of the drugs for which drug-induced liver damage is most frequently observed12,13. The most frequent cause of acute liver failure in the United States is acetaminophen, which accounts for about half of all reported cases and roughly a quarter of all liver transplant cases14,15.
In this paper, we will discuss We shall explore the safety of acetaminophen in associated with liver injury in this review article, particularly in terms of epidemiology, pharmacokinetic, hepatotoxicity, clinical presentation, and the treatment.
Epidemiology And Pharmacokinetics:
Acetaminophen is widely available and found in a wide range of goods, and its toxicity is often overlooked. The prevalence of acetaminophen-related Acute liver failure (ALF) has been rising since the 1990s. Acetaminophen overdoses were shown to be the cause of approximately 42% of ALF cases in the United States and Europe. ALF induced by acetaminophen overdose is responsible for roughly 300,000 hospitalizations in the United States16,17. Patients who ingested excessive acetaminophen consciously and subconsciously (52% vs. 48%) were both at risk of sudden liver failure, necessitating referral for liver transplantation13. Despite the fact that the majority of people experience minor side effects including hepatitis, cholestasis, or asymptomatic elevations in liver enzymes, approximately 48% develop acetaminophen hepatotoxicity and are diagnosed with acute heart failure13. Furthermore, investigations found that 29% of patients with acute liver failure due to acetaminophen toxicity required liver transplantation, with a 28% fatality rate12. A five-year retrospective study in Malaysia found that the risk of acetaminophen-induced hepatotoxicity was low (7.3%) in a multi-ethnic Asian community, with no death or morbidity rates at high acetaminophen dosages18.
Acetaminophen reaches peak plasma concentrations 10 to 60 minutes after oral dosing and is quickly absorbed from the gastrointestinal tract. The majority of bodily tissues absorb acetaminophen. After passing through the placenta, it is identified in breast milk. At typical therapeutic doses, plasma-protein binding is low, but it increases at greater concentrations. The elimination half-life of acetaminophen is 1 to 3 hours19,20. Acetaminophen is principally metabolized in the liver and eliminated in the urine as conjugates of glucuronide and sulphate. Only about 5% of the acetaminophen is excreted unchanged. A tiny hydroxylated metabolite identified as acetyl-p-benzoquinoneimine (NAPQI) is produced by cytochrome P450 isoenzymes, primarily CYP2E1 and CYP3A4, in the liver and kidney in very minute amounts. It is usually detoxified by conjugation with glutathione, but it can build up and cause tissue damage following a acetaminophen overdose19,20.
Dosage and factors Affecting acetaminophen Hepatotoxicity
A single dose of acetaminophen of less than 7.5 to 10 g for an adult or 150 mg/kg for a child is unlikely to cause toxicity21. A single dose of more than 250mg/kg or more than 12 g in a 24-hour period might cause toxicity22. Nearly all patients who receive doses greater than 350 mg/kg suffer from significant liver damage (defined as a peak level of aspartate aminotransferase (AST) or alanine aminotransferase (ALT) greater than 1000 IU/L) if they are not appropriately treated22–24.
Acetaminophen overuse is the most significant factor that can lead to acetaminophen hepatotoxicity, followed by delayed N-acetylcysteine (NAC) therapy, increased cytochrome P450 activity, decreased capacity for glucuronidation or sulfation, and depletion of glutathione reserves. Acetaminophen's propensity to cause hepatotoxicity can be influenced by a number of variables, including advanced age, nutritional state, genetic make-up, concurrent alcohol or drug use, and comorbidities11,25–27.
Pathogenesis of Acetaminophen Hepatotoxicity
Acetaminophen does not cause hepatotoxicity. On the other hand, its active metabolite NAPQI is the main culprit. 85-90 % of acetaminophen is metabolized and removed in the urine by glucuronidation or sulfation when taken in the recommended dose. Overdosing on this metabolite overwhelms glutathione's reducing ability, resulting in covalent alteration of multiple intracellular structures by NAPQI, resulting in zone 3, centrilobular hepatocyte necrosis (Figure 1)28–30. The cytochrome p450 system, primarily CYP2E1, converts approximately 10% of this compound into the reactive metabolite N-acetyl-p-benzoquinone imine (NAPQI), even though only 2% is eliminated intact in the urine. NAPQI is readily converted to innocuous metabolites by glutathione in normal conditions (GSH). In cases of GSH depletion, such as acetaminophen overdose, malnutrition, and prolonged alcohol consumption, NAPQI persists and causes liver injury31. The production of protein adducts by interacting with sulfhydryl groups, which leads to mitochondrial failure and cell death, as well as modulation of the liver's innate immune system, are two primary mechanisms by which NAPQI causes liver injury (Figure 2)31,32.
NAPQI causes hepatocyte necrosis and mitochondrial malfunction by creating adducts with mitochondrial proteins. However, the specific target protein that causes NAPQI has yet to be discovered. Hepatotoxicity is triggered by adduct formation leading to mitochondrial injury, which causes adenosine triphosphate (ATP) depletion due to the halt of its production, mitochondrial membrane potential damage under redox circumstances, and adduct formation leading to mitochondrial injury33. There's also an early translocation of the membrane Bcl-2-associated X protein (BAX), which interacts with BAX in the outer mitochondrial membrane to create holes, allowing inter-membrane proteins like cytochrome c to get through. Finally, cell death occurs as a result of the release of mitochondrial proteins and the halting of ATP synthesis (Figure 2)30.
Figure 1. Zone 3 (perivenular) coagulative necrosis is a symptom of acetaminophen intoxication (asterisks). Surviving hepatocytes are seen in zone 1 near portal tracts in the absence of inflammation (hematoxylin and eosin, original magnification) (arrows)28,29.
Figure 2. Acetaminophen (APAP) metabolism and probable factors determining its toxicity12.
Ultrastructural changes of the liver in acetaminophen hepatotoxicity:
Dixon et al. looked examined lesions for up to 28 days following an acetaminophen overdose and found macrophage infiltration, hydropic vacuolization, centrilobular necrosis, and regenerative activity with a quick recovery to normal structur34. In non-viral fatal cases, acetaminophen induced more severe light and electron microscopic changes35. According to Manov et al., findings in advanced stages of necrosis are difficult to interpret since necrosis occurs when the centrilobular and midzonal cells are involved and, in certain cases, manifests as severe coagulative necrosis. The ultrastructure of human liver cancer cell lines, HepG2 and Hep3B hepatoma-derived cells, exposed to acetaminophen over varied time periods and doses, was investigated for hepatotoxicity. The fraction of solid granule positive mitochondria reduced considerably after acetaminophen therapy. Apoptotic bodies, cell shrinkage, chromatin condensation and margination, and other morphological changes indicative of apoptosis were found in the liver after the operation (Figure 3)36.
Figure 3. In cultivated hepatoma cells, the ultrastructure of acetaminophen toxicity. (A) A set of control HepG2 cells with a normal nucleus and heterochromatin in lipid droplets in the cytoplasm. (B) Higher magnification of control HepG2 cells. (C) HepG2 cells treated to acetaminophen. (D) Hep3B cells in apoptosis with acetaminophen, fat droplets, and no microvilli. (E) Hep3B cells at the necrapoptotic stage after exposure to acetaminophen: The nuclear membrane has been damaged, the nucleolus and nucleoplasm have undergone significant alterations, and the nucleus has clumping marginal chromatin. (F) Membrane bodies (arrows; autophagolysosomes) and single membrane-bound vacuoles, likely SER, are seen in Hep3B cell sections treated with acetaminophen and verapamil (arrows)36.
Placke et al. investigated the early ultrastructural alterations in the onset of acetaminophen hepatotoxicity using a mouse model. The earliest hepatocyte changes were seen in the 600 mg/kg group at 60 minutes, and they were limited to the first row of hepatocytes near the central vein. These cells have dispersed organelles, modest cytomegaly, and low density. Mitochondria are frequently crushed, and myelinated forms are occasionally combined with them. There were no little intracristal calcium granules, which are generally associated with mitochondria. The endoplasmic reticulum (ER) is elongated or spherical in shape, slightly dilated, and has ribosomes that are broken. In damaged hepatocytes, membrane fragments and myelin figures are common (Figure 4)37.
Figure 4. Acetaminophen (600 mg/kg) (top, left) One hour; acetaminophen (600 mg/kg) 2.240 (top, right) 1 hour; Acetaminophen (600 mg/kg) 35,600 acetaminophen (600 mg/kg) 35,600 acetaminophen (600 mg/kg) 35,600 (bottom, left) It will take two hours. An accumulation of dense flocculant material (black arrow), two centrilobular cells' border with multiple membranes gathered along the plasmalemma, and mitochondria without the twofold limiting membrane (F) are just a few examples (M). A normal bile canaliculus can be found at the bottom. acetaminophen (600 mg/kg) 28.500 (bottom, right) It will take two hours. The perisinusoidal border of a core hepatocyte. Disse's constrained space (white arrow), huge degenerative mitochondria (M), and dense mitochondria (white arrow) (black arrow). 11,500x37
Clinical Presentation of Acetaminophen Hepatotoxicity:
Patients should be informed of the four stages of acetaminophen hepatotoxicity before visiting the clinic. The initial stage (0.5-24 hours). In the first 24 hours following an overdose, some people were asymptomatic, while others experienced symptoms like lethargy, pallor, nausea, vomiting, malaise, and diaphoresis. Some people are still symptom-free. The results of laboratory tests are usually normal. After a severe acetaminophen overdose, increased anion gap metabolic acidosis and central nervous system depression can develop38.
The second stage (24 to 72 hours). The improvement of stage I symptoms distinguishes this stage, which is known as the latent phase. At this moment, AST and ALT levels start to climb. Coagulopathy, jaundice, and painful hepatomegaly are all indications of a severe acetaminophen overdose (with right upper quadrant pain). Renal failure can occur in 1-2% of patients who have acute tubular necrosis with or without hepatic necrosis13,39.
The third stage (72 to 96 hours). The recurrence of stage I symptoms, as well as substantially elevated AST and ALT (possibly > 3000 IU/L), coagulopathy, encephalopathy, lactic acidosis, and jaundice, identify this stage. This is when liver damage is most likely to develop. Although pancreatitis and renal failure are uncommon, they can occur as a result of the procedure. The risk of death due to multi-organ failure is high at this time13,39.
the fourth stage (4 days to 2 weeks). Patients that survive stage III go through a seven-day healing period, which usually starts on the fourth day. Recovery may be more difficult for critically ill people. For several weeks, laboratory results and symptoms may be aberrant. From cytolysis to centrilobular necrosis, the histology of the liver is diverse. Because it includes the largest concentration of CYP2E1 and so produces the most NAPQI, the centrilobular area (zone III) is favored. Histological restoration could take up to three months after clinical recovery. This marks the end of recuperation. Intoxication with acetaminophen does not cause chronic liver damage23.
In situations of acetaminophen poisoning, supportive therapy is essential40. As soon as feasible, the patient's airway, breathing, and circulation status (ABC) must be examined. The severity of poisoning following acute ingestion was evaluated by graphing timed serum acetaminophen concentrations on a modified Rumack-Matthew nomogram in the absence of early symptoms suggesting acetaminophen toxicity (Figure 5)41. The Rumack-Matthew nomogram, commonly known as the acetaminophen toxicity nomogram or acetaminophen nomogram, analyzes serum acetaminophen concentrations in relation to time since administration to identify potential hepatotoxicity. The nomogram forecasts possible toxicity beginning 4 hours after administration and lasting up to 24 hours. Acetaminophen concentrations recorded less than 4 hours after administration may be unreliable. The concentrations measured four to eighteen hours after intake are the most trustworthy. The Rumack-Matthew line, commonly referred to as the "probable" line, is the top line of the nomogram. Hepatotoxicity affects around 60% of individuals with results over this limit. The "potential" line, which was later included at the US Food and Drug Administration's request, is the bottom line on the nomogram. The viable line, also referred to as the "treatment" line, has a 25% margin of error built in to account for measurement errors or ambiguities regarding consumption timing42. If serum acetaminophen concentrations were over the therapeutic line after an acute overdose, patients were given NAC. NAC is also administered to patients who are at high risk of hepatotoxicity43. Patients who arrive later (after 24 hours) may experience stomach discomfort, jaundice, nausea, vomiting, hypotension, cerebral edema, renal injury, coagulopathy (gastrointestinal bleeding, for example), and hepatic encephalopathy, among other symptoms and signs of liver injury or failure. Emergency resuscitation may be required, which may include airway management, intravenous fluids, vasopressors, cerebral edema care, or hemodialysis13,42.
Figure 5. The Rumack-Matthew nomogram41.
Oral activated charcoal (AC) will absorb a potentially dangerous dose of acetaminophen if the patient arrives within an hour after consuming it. Oral AC may be beneficial for more than 1 hour if a medicine that delays stomach emptying is taken44. One case series indicated that oral AC given with NAC 4 hours after consumption was useful in lowering the incidence of transaminitis caused on by toxic acetaminophen intake. Oral AC's potency, on the other hand, is well known to deteriorate over time, particularly after 60 minutes of toxin consumption. The availability of kinetic phosphorescence analysis is critical in this situation. AC should not be given to a patient who does not have an intact airway and is mentally ill45.
All patients who are at high risk of hepatotoxicity receive N-acetylcysteine, also known as NAC, as their standard antidote for acetaminophen overdose. Treatment with NAC is recommended for the following conditions46–49:
1. Serum acetaminophen concentrations measured four hours or longer after acute consumption of an immediate-release product surpass the "treatment" line on the treatment nomogram for acetaminophen intoxication (Figure 5).
2. A patient whose blood acetaminophen concentration won't be available for at least eight hours after ingestion receives a single dose of more than 150 mg/kg (7.5 g total dosage regardless of weight).
3. A patient whose acetaminophen content in the blood exceeds 10 mcg/mL (66 micromole/L) and whose consumption timing is unknown.
4. Patients who possess a history of heavy acetaminophen use, appear at a later time (more than 24 hours after treatment), and have laboratory evidence of liver damage (range from modestly increased aminotransferases to fulminant hepatic failure).
5. A patient with a history of acetaminophen used and indications of liver damage. If the gastrointestinal is decontaminated with activated charcoal before starting NAC treatment, the recommended
NAC regimen remains unchanged. The Food and Drug Administration (FDA) approved an oral NAC dosage regimen that includes a 140 mg/kg initial dose, followed by 17 70 mg/kg doses taken every 4 hours for a total treatment time of 72 hours. NAC (Acetadote) IV for adult usage was authorized by the FDA in 2004. Additional reasons for IV NAC delivery include the inability to tolerate oral NAC due to emesis that is resistant to appropriate antiemetic therapy, gastrointestinal hemorrhage and/or obstruction, potential acetaminophen toxicity in pregnant women, history of caustic consumption, altered mental status, and inability to tolerate oral NAC due to emesis. Whether the intake is acute or chronic, as well as body weight, affect the pharmacological parameters for IV NAC administration. It is advised for acute consumption to receive a continuous IV infusion, as follows41,50:
· Loading dose: 150 mg/kg IV; mix with 200 mL 5% dextrose in water (D5W) and infuse for 1 hour.
· Dose 2: 50 mg/kg IV over 4 hours in 500 mL D5W
· Dose 3: 100 mg/kg IV over 16 hours in 1000 mL D5W
Patients who weigh more than 100 kg are advised to receive a loading dosage of 15,000 mg IV over an hour, followed by a first maintenance dose of 5,000 mg IV over 4 hours and a second maintenance dose of 10,000 mg IV over 16 hours41,50.
Measurement of serum acetaminophen concentrations is recommended for patients whose timing of ingestion is unclear or unknown and who have a history of altered mental status or overdose. However, in some cases to assess risk stratification it is not possible to use an acetaminophen poisoning nomogram41. It may be able to simulate a worst-case scenario and plot serum concentrations as measured using the "last known time before swallowing" as "swallowing time" if the history indicates a single ingestion and it is feasible to identify the timing of ingestion to a specific window (e.g., the patient had been continuously monitored for up to 12 hours prior to admission so consumption was unlikely to have occurred more than 12 hours ago). N-acetylcysteine is thus recommended in this situation. There is no widely acknowledged method of risk stratification if it is impossible to predict the time of consumption (due to a lack of information or numerous consumptions). The patient was also recommended to increase the blood transaminase concentration and a consistent history of acetaminophen exposure regardless of the serum acetaminophen concentration before N-acetylcysteine was administered as the first step in the treatment. With this strategy, the advantages of acetylcysteine are maximized41,46,49.
There was no substantial difference in therapy among pregnant patients. Serum acetaminophen and transaminase concentrations should be tested in pregnant individuals who have had repeated or chronic intake. If the blood transaminase concentration is elevated (>50 international units/L) or the serum acetaminophen concentration is higher than 20 mcg/mL, NAC therapy is indicated. Pregnant women received the same dosage and duration of medication as non-pregnant women51.
Acetaminophen consumption and consequent hepatotoxicity are serious issues that continue to affect people all over the world. Acetaminophen is a commonly available analgesic and antipyretic medication that is only available in prescription medicine formulations due to its low cost and ease of access. For decades, either purposefully or inadvertently, acetaminophen overdose has resulted in liver damage and ultimately liver failure, involving basic metabolic processes that occur on microsomes in hepatocytes. Acute liver failure induced by acetaminophen toxicity has no recognized origin, course, or treatment, and adverse patient outcomes such as increased morbidity and death continue. Although the clinical presentation of acetaminophen hepatotoxicity is predictable, the schedule for liver failure is not. The standard of therapy is N-acetylcysteine (NAC) medication, although for some people, liver transplantation may be a life-saving procedure.
CONFLICT OF INTEREST:
The authors have no conflicts of interest regarding this investigation.
The Research and Innovation Institute, Universitas Airlangga, supported and sponsored this study and publication. We would like to express our gratitude to the Dean of Faculty of Medicine, Universitas Airlangga and the Director of Dr. Soetomo General Academic Hospital.
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Accepted on 14.12.2022 © RJPT All right reserved
Research J. Pharm. and Tech 2023; 16(4):2006-2012.