Hepatotoxicity (from hepatic toxicity) implies chemical-driven liver The liver is a vital organ present in vertebrates and some other animals. It has a wide range of functions, including detoxification, protein synthesis, and production of biochemicals necessary for digestion. The liver is necessary for survival; there is currently no way to compensate for the absence of liver function damage.

The liver plays a central role in transforming and clearing chemicals and is susceptible to the toxicity from these agents. Certain medicinal agents, when taken in overdoses and sometimes even when introduced within therapeutic ranges The therapeutic index , is a comparison of the amount of a therapeutic agent that causes the therapeutic effect to the amount that causes death. Quantitatively, it is the ratio given by the lethal dose divided by the therapeutic dose. A therapeutic index is the lethal dose of a drug for 50% of the population (LD50) divided by the minimum effective, may injure the organ. Other chemical agents, such as those used in laboratories and industries, natural chemicals (e.g. microcystins) and herbal remedies Herbalism is a traditional medicinal or folk medicine practice based on the use of plants and plant extracts. Herbalism is also known as botanical medicine, medical herbalism, herbal medicine, herbology, and phytotherapy. The scope of herbal medicine is sometimes extended to include fungal and bee products, as well as minerals, shells and certain can also induce hepatotoxicity. Chemicals that cause liver injury are called hepatotoxins A hepatotoxin is a toxic chemical substance which damages the liver. It can be a side-effect of medication, or found naturally, as microcystins, or in laboratory environments. The effects of hepatotoxins depend on the amount, point of entry and distribution speed of the toxin, and on the health of the person.

More than 900 drugs have been implicated in causing liver injury^[1] and it is the most common reason for a drug to be withdrawn from the market. Chemicals often cause subclinical In medicine, a disease is asymptomatic if a patient carries a disease or infection but experiences no symptoms. A condition might be asymptomatic if it fails to show the noticeable symptoms with which it is usually associated. Asymptomatic infections are also called subclinical infections. The term clinically silent is also used injury to liver which manifests only as abnormal liver enzyme tests Liver function tests , which include liver enzymes, are groups of clinical biochemistry laboratory blood assays designed to give information about the state of a patient's liver. Most liver diseases cause only mild symptoms initially, but it is vital that these diseases be detected early. Hepatic (liver) involvement in some diseases can be of. Drug induced liver injury is responsible for 5% of all hospital admissions and 50% of all acute liver failures Acute liver failure is the appearance of severe complications rapidly after the first signs of liver disease , and indicates that the liver has sustained severe damage (loss of function of 80-90% of liver cells). The complications are hepatic encephalopathy and impaired protein synthesis (as measured by the levels of serum albumin and the.^[2][3]

Drug metabolism in liver

The human body identifies almost all drugs as foreign substances (i.e. xenobiotics A xenobiotic is a chemical which is found in an organism but which is not normally produced or expected to be present in it. It can also cover substances which are present in much higher concentrations than are usual. Specifically, drugs such as antibiotics are xenobiotics in humans because the human body does not produce them itself, nor are they) and subjects them to various chemical processes (i.e. metabolism Metabolism is the set of chemical reactions that happen in living organisms to maintain life. These processes allow organisms to grow and reproduce, maintain their structures, and respond to their environments. Metabolism is usually divided into two categories. Catabolism breaks down organic matter, for example to harvest energy in cellular) to make them suitable for elimination. This involves chemical transformations to (a) reduce fat solubility and (b) to change biological activity. Although almost all tissue in the body have some ability to metabolize chemicals, smooth endoplasmic reticulum in liver is the principal "metabolic clearing house" for both endogenous Endogenous substances are those that originate from within an organism, tissue, or cell . Endogenous retroviruses are caused by ancient infections of germ cells in humans, mammals and other vertebrates. Their proviruses remain in the genome and are passed on to the next generation chemicals (e.g., cholesterol Cholesterol is a waxy steroid metabolite found in the cell membranes and transported in the blood plasma of all animals. It is an essential structural component of mammalian cell membranes, where it is required to establish proper membrane permeability and fluidity. In addition, cholesterol is an important component for the manufacture of bile, steroid hormones, fatty acids In chemistry, especially biochemistry, a fatty acid is a carboxylic acid with a long unbranched aliphatic tail , which is either saturated or unsaturated. Carboxylic acids as short as butyric acid (4 carbon atoms) are considered to be fatty acids, whereas fatty acids derived from natural fats and oils may be assumed to have at least eight carbon, and proteins Proteins are organic compounds made of amino acids arranged in a linear chain and folded into a globular form. The amino acids in a polymer are joined together by the peptide bonds between the carboxyl and amino groups of adjacent amino acid residues. The sequence of amino acids in a protein is defined by the sequence of a gene, which is encoded), and exogenous Exogenous (from the Greek words "exo" and "gen", meaning "outside" and "production") refers to an action or object coming from outside a system. It is the opposite of endogenous, something generated from within the system substances (e.g. drugs).^[4] The central role played by liver in the clearance and transformation of chemicals also makes it susceptible to drug induced injury.

Drug metabolism Drug metabolism is the biochemical modification of pharmaceutical substances by living organisms, usually through specialized enzymatic systems. This is a form of xenobiotic metabolism. Drug metabolism often converts lipophilic chemical compounds into more readily excreted polar products. Its rate is an important determinant of the duration and is usually divided into two phases: phase 1 and phase 2. Phase 1 reaction is thought to prepare a drug for phase 2. However many compounds can be metabolised by phase 2 directly. Phase 1 reaction involves oxidation Redox describes all chemical reactions in which atoms have their oxidation number (oxidation state) changed. This can be either a simple redox process, such as the oxidation of carbon to yield carbon dioxide (CO2) or the reduction of carbon by hydrogen to yield methane (CH4), or a complex process such as the oxidation of sugar(C6H12O6) in the, reduction Redox describes all chemical reactions in which atoms have their oxidation number (oxidation state) changed. This can be either a simple redox process such as the oxidation of carbon to yield carbon dioxide or the reduction of carbon by hydrogen to yield methane (CH4), or it can be a complex process such as the oxidation of sugar in the human body, hydrolysis Hydrolysis is a chemical reaction during which molecules of water are split into hydrogen cations (H+) (conventionally referred to as protons) and hydroxide anions (OH−) in the process of a chemical mechanism. It is the type of reaction that is used to break down certain polymers, especially those made by step-growth polymerization. Such polymer, hydration In organic chemistry, a hydration reaction is a chemical reaction in which a hydroxyl group and a hydrogen cation (an acidic proton) are added to the two carbon atoms bonded together in the carbon-carbon double bond which makes up an alkene functional group. The reaction usually runs in a strong acidic, aqueous solution. Hydration differs from and many other rare chemical reactions. These processes tend to increase water solubility of the drug and can generate metabolites which are more chemically active and potentially toxic. Most of phase 2 reactions take place in cytosol The cytosol or intracellular fluid is the liquid found inside cells. In eukaryotes this liquid is separated by cell membranes from the contents of the organelles suspended in the cytosol, such as the mitochondrial matrix inside the mitochondrion. The entire contents of a eukaryotic cell within cell membrane, minus the contents of the cell nucleus, and involve conjugation with endogenous compounds via transferase In biochemistry, a transferase is an enzyme that catalyzes the transfer of a functional group from one molecule (called the donor) to another (called the acceptor). For example, an enzyme that catalyzed this reaction would be a transferase: enzymes. Chemically active phase 1 products are rendered relatively inert and suitable for elimination by this step.

A group of enzymes Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process are called substrates, and the enzyme converts them into different molecules, called the products. Almost all processes in a biological cell need enzymes to occur at significant rates. Since enzymes are selective for their located in the endoplasmic reticulum, known as cytochrome P-450, is the most important family of metabolizing enzymes in the liver. Cytochrome P-450 is the terminal oxidase An oxidase is any enzyme that catalyzes an oxidation/reduction reaction involving molecular oxygen as the electron acceptor. In these reactions, oxygen is reduced to water (H2O) or hydrogen peroxide (H2O2) component of an electron transport chain An electron transport chain couples a chemical reaction between an electron donor (such as NADH) and an electron acceptor (such as O2) to the transfer of H+ ions across a membrane, through a set of mediating biochemical reactions. These H+ ions are used to produce adenosine triphosphate (ATP), the main energy intermediate in living organisms, as. It is not a single enzyme, but rather consists of a family of closely related 50 isoforms A protein isoform is any of several different forms of the same protein. Different forms of a protein may be produced from related genes, or may arise from the same gene by alternative splicing. A large number of isoforms are caused by single-nucleotide polymorphisms or SNPs, small genetic differences between alleles of the same gene. These occur; six of them metabolize 90% of drugs.^[5][6] There is a tremendous diversity of individual P-450 gene products and this heterogeneity allows the liver to perform oxidation on a vast array of chemicals (including almost all drugs) in phase 1. Three important characteristics of the P450 system have roles in drug induced toxicity:

1. Genetic diversity:

Each of the P-450 proteins is unique and accounts to some extent for the variation in drug metabolism between individuals. Genetic variations (polymorphism Polymorphism in biology occurs when two or more clearly different phenotypes exist in the same population of a species — in other words, the occurrence of more than one form or morph. In order to be classified as such, morphs must occupy the same habitat at the same time and belong to a panmictic population) in CYP450 metabolism should be considered when patients exhibit unusual sensitivity or resistance to drug effects at normal doses. Such polymorphism is also responsible for variable drug response among patients of differing ethnic backgrounds.

2. Change in enzyme activity:

Many substances can influence P-450 enzyme mechanism. Drugs interact with the enzyme family in several ways.^[9] Drugs that modify Cytochrome P-450 enzyme are referred to as either inhibitors or inducers. Enzyme inhibitors block the metabolic activity of one or several P-450 enzymes. This effect usually occurs immediately. On the other hand inducers increase P-450 activity by increasing its synthesis. Depending on inducing drug's half life, there is usually a delay before enzyme activity increases.^[6]

3. Competitive inhibition:

Some drugs may share the same P-450 specificity and thus competitively block their bio transformation. This may lead to accumulation of drugs metabolised by the enzyme. This type of drug interaction may also reduce the rate of generation of toxic substrate.

Mechanism of liver damage

Drugs continue to be taken off the market due to late discovery of hepatotoxicity. Due to its unique metabolism and close relationship with the gastrointestinal tract The Human gastrointestinal tract or digestive system is the system by which ingested food is acted upon by physical and chemical means to provide the body with nutrients it can absorb and to excrete waste products; in mammals the system includes the alimentary canal extending from the mouth to the anus, and the hormones and enzymes assisting in, the liver is susceptible to injury from drugs and other substances. 75% of blood coming to the liver arrives directly from gastrointestinal organs and then spleen via portal veins The hepatic portal vein is a vein in the abdominal cavity that drains blood from the gastrointestinal tract and spleen to the liver. It is usually formed by the confluence of the superior mesenteric and splenic veins, and also receives blood from the inferior mesenteric, gastric, and cystic veins. The hepatic portal vein is a major component of which bring drugs and xenobiotics in concentrated form. Several mechanisms are responsible for either inducing hepatic injury or worsening the damage process. Many chemicals damage mitochondria In cell biology, a mitochondrion is a membrane-enclosed organelle found in most eukaryotic cells. These organelles range from 0.5 to 10 micrometers (μm) in diameter. Mitochondria are sometimes described as "cellular power plants" because they generate most of the cell's supply of adenosine triphosphate (ATP), used as a source of, an intracellular organelle that produce energy. Its dysfunction releases excessive amount of oxidants which in turn injures hepatic cells. Activation of some enzymes in the cytochrome P-450 system such as CYP2E1 also lead to oxidative stress.^[11] Injury to hepatocyte A hepatocyte is a cell of the main tissue of the liver. Hepatocytes make up 70-80% of the liver's cytoplasmic mass. These cells are involved in: and bile duct Bile, required for the digestion of food, is excreted by the liver into passages that carry bile toward the hepatic duct, which joins with the cystic duct to form the common bile duct, which opens into the intestine cells lead to accumulation of bile acid Bile acids are steroid acids found predominantly in the bile of mammals. Bile salts are bile acids conjugated to glycine or taurine. In humans, taurocholic acid and glycocholic acid represent approximately eighty percent of all bile salts. The two major bile acids are cholic acid, and chenodeoxycholic acid. Bile acids, glycine and taurine inside liver In medicine, cholestasis is a condition where bile cannot flow from the liver to the duodenum. The two basic distinctions are an obstructive type of cholestasis where there is a mechanical blockage in the duct system such as can occur from a gallstone or malignancy and (2) metabolic types of cholestasis which are disturbances in bile formation. This promotes further liver damage.^[12] Non-parenchymal cells such as Kupffer cells, fat storing stellate cells and leukocytes (i.e. neutrophil and monocyte) also have role in the mechanism.

Adverse drug reactions

Adverse drug reactions are classified as type A (intrinsic or pharmacological) or type B (idiosyncratic).^[13] Type A drug reaction accounts for 80% of all toxicities.^[14]

Drugs or toxins that have a pharmacological (type A) hepatotoxicity are those that have predictable dose-response curves (higher concentrations cause more liver damage) and well characterized mechanisms of toxicity such as directly damaging liver tissue or blocking a metabolic process. As in the case of acetaminophen overdose, this type of injury occurs shortly after some threshold for toxicity is reached.

Idiosyncratic (type B) injury occurs without warning; when agents cause non-predictable hepatotoxicity in susceptible individuals which is not related to dose and has variable latency period.^[15] This type of injury does not have a clear dose-response or temporal relationship, and most often do not have predictive models. Idiosyncratic hepatotoxicity has led to the withdrawal of several drugs from market even after rigorous clinical testing as part of the FDA approval process; Troglitazone (Rezulin) and trovafloxacin (Trovan) are two prime examples of idiosyncratic hepatotoxins.

Patterns of injury

Chemicals produce a wide variety of clinical and pathological hepatic injury. Biochemical markers (e.g. alanine transferase, alkaline phosphatase and bilirubin) are often used to indicate liver damage. Liver injury is defined as rise in either (a) ALT level more than three times of upper limit of normal (ULN), (b) ALP level more than twice ULN, or (c) total bilirubin level more than twice ULN when associated with increased ALT or ALP.^[16][17] Liver damage is further characterized into hepatocellular (predominantly initial Alanine transferase elevation) and cholestatic (initial alkaline phosphatase rise) types. However they are not mutually exclusive and mixed type of injuries are often encountered.

Specific histo-pathological patterns of liver injury from drug induced damage are discussed below.

Zonal Necrosis

This is the most common type of drug induced liver cell necrosis where the injury is largely confined to a particular zone of the liver lobule. It may manifest as very high level of ALT and severe disturbance of liver function leading to acute liver failure.

Causes include:

Paracetamol, carbon tetrachloride

Hepatitis

In this pattern hepatocellular necrosis is associated with infiltration of inflammatory cells. There can be three types of drug induced hepatitis. (A) viral hepatitis type picture is the commonest, where histological features are similar to acute viral hepatitis. (B) in the focal or non specific hepatitis scattered foci of cell necrosis may accompany lymphocytic infiltrate. (C) chronic hepatitis type is very similar to autoimmune hepatitis clinically, serologically as well as histologically.

Causes:

(a) Viral hepatitis like: Halothane, isoniazid, phenytoin

(b) Focal hepatitis: Aspirin

(c) Chronic hepatitis: Methyldopa, diclofenac

Cholestasis

Liver injury leads to impairment of bile flow and clinical picture is predominated by itching and jaundice. Histology may show inflammation (cholestatic hepatitis) or it can be bland without any parenchymal inflammation. In rare occasions it can produce features similar to primary biliary cirrhosis due to progressive destruction of small bile ducts (Vanishing duct syndrome).

Causes:

(a) Bland: Oral contraceptive pills, anabolic steroid, androgens

(b) Inflammatory: Allopurinol, co-amoxiclav, carbamazepine

(c) Ductal: Chlorpromazine, flucloxacillin

Steatosis

Hepatotoxicity may manifest as triglyceride accumulation which leads to either small droplet (microvesicular) or large droplet (macrovesicular) fatty liver. There is a separate type of steatosis where phospholipid accumulation leads to a pattern similar to the diseases with inherited phospholipid metabolism defects (e.g. Tay-Sachs disease)

Causes:

(a) Microvesicular: Aspirin (Reye's syndrome), ketoprofen, tetracycline

(b) Macrovesicular: Acetamenophen, methotrexate

(c) Phospholipidosis: Amiodarone, total parenteral nutrition

Granuloma

Drug induced hepatic granulomas are usually associated with granulomas in other tissues and patients typically have features of systemic vasculitis and hypersensitivity. More than 50 drugs have been implicated.

Causes:

Allopurinol, phenytoin, isoniazid, quinine, penicillin, quinidine

Vascular lesions

They result from injury to the vascular endothelium.

Causes:

Venoocclusive disease: Chemotherapeutic agents, bush tea

Peliosis hepatis: anabolic steroid

Hepatic vein thrombosis: Oral contraceptives

Neoplasm

Neoplasms have been described with prolonged exposure to some medications or toxins. Hepatocellular carcinoma, angiosarcoma and liver adenomas are the ones usually reported.

Causes:

Vinyl chloride, combined oral contraceptive pill, anabolic steroid, arsenic, thorotrast

Clinical assessment

This remains a challenge in clinical practice due to lack of reliable markers.^[18] Many other conditions lead to similar clinical as well as pathological picture. To diagnose hepatotoxicity, a causal relationship between the use of the toxin or drug and subsequent liver damage has to be established, but might be difficult, especially when idiosyncratic reaction is suspected.^[19] Simultaneous use of multiple drugs may add to the complexity. As in acetaminophen toxicity, well established dose dependent pharmacological hepatotoxicity is easier to spot. Several clinical scales such as CIOMS/RUCAM scale and Maria and Victorino criteria have been proposed to establish causal relationship between offending drug and liver damage. CIOMS/RUCAM scale involves a scoring system which categorizes the suspicion into "definite or highly probable" (score > 8), “probable” (score 6-8), “possible” (score 3-5), “unlikely” (score 1-2) and “excluded” (score ≤ 0). In clinical practice physicians put more emphasis on the presence or absence of similarity between the biochemical profile of the patient and known biochemical profile of the suspected toxicity ( e.g. cholestatic damage in amoxycillin-clauvonic acid ).^[18]

Treatment and prognosis

In most cases, liver function will return to normal if the offending drug is stopped early. Additionally, the patient may require supportive treatment. In acetaminophen toxicity, however, the initial insult can be fatal. Fulminant hepatic failure from drug-induced hepatotoxicity may require liver transplantation. In the past, glucocorticoides in allergic features and ursodeoxycholic acid in cholestatic pictures had been used, but there is no good evidence to support their effectiveness.

An elevation in serum bilirubin level of more that 2 times ULN with associated transaminase rise is an ominous sign. This indicates severe hepatotoxicity and is likely to lead to mortality in 10% to 15% of patients, especially if the offending drug is not stopped (Hy's Law).^[20][21] This is because it requires significant damage to the liver to impair bilirubin excretion, hence minor impairment (in the absence of biliary obstruction or Gilbert syndrome) would not lead to jaundice. Other poor predictors of outcome are old age, female sex, high AST.^[22][23]

Drugs withdrawn for hepatotoxicity

Troglitazone, bromfenac, trovafloxacin, ebrotidine, nimesulide, nefazodone, ximelagatran and pemoline.^[18][24]

Specific drug or toxin

Acetaminophen

Acetaminophen (paracetamol, also known by the brand name Tylenol and Panadol) is usually well tolerated in prescribed dose but overdose is the most common cause of drug induced liver disease and acute liver failure worldwide^[10]. Reports of death from acute hepatotoxicity have been reported to be as low as 2.5 grams over a 24 hour period^{[citation needed]}. Damage to the liver is not due to the drug itself but to a toxic metabolite (N-acetyl-p-benzoquinone imine NAPQI, or NABQI) which is produced by cytochrome P450 enzymes in the liver.^[25] In normal circumstances this metabolite is detoxified by conjugating with glutathione in phase 2 reaction. In overdose large amount of NAPQI is generated which overwhelm the detoxification process and lead to damage to liver cells. Nitric oxide also plays role in inducing toxicity.^[26] The risk of liver injury is influenced by several factors including the dose ingested, concurrent alcohol or other drug intake, interval between ingestion and antidote etc. The dose toxic to liver is quite variable and is lower in chronic alcoholics.^{[citation needed]} Measurement of blood level is important in assessing prognosis, higher levels predicting worse prognosis. Administration of Acetylcysteine, a precursor of glutathione, can limit the severity of the liver damage by capturing the toxic NAPQI. Those who develop acute liver failure can still recover spontaneously, but may require transplantation if poor prognostic signs such as encephalopathy or coagulopathy is present (see King's College Criteria).

Nonsteroidal anti-inflammatory drugs

Although individual analgesics rarely induce liver damage due to their widespread use, NSAIDs have emerged as a major group of drugs exhibiting hepatotoxicity. Both dose dependent and idiosyncratic reactions have been documented.^[27] Aspirin and phenylbutazone are associated with intrinsic hepatotoxicity; idiosyncratic reaction has been associated with ibuprofen, sulindac, phenylbutazone, piroxicam, diclofenac and indomethacin.

Glucocorticoids

Glucocorticoids are so named due to their effect on carbohydrate mechanism. they promote glycogen storage in liver. Enlarged liver is a rare side effect of long term steroid use in children.^[28] The classical effect of prolonged use both in adult and paediatric population is steatosis.^[29]

Isoniazid

Isoniazide (INH) is one of the most commonly used drug for tuberculosis; it is associated with mild elevation of liver enzymes in up to 20% of patients and severe hepatotoxicity in 1-2% of patients.^[30]

Natural products

Examples include many amanita mushrooms (particularly the destroying angels), and aflatoxins.^{[citation needed]}

Industrial toxin

Examples include arsenic, carbon tetrachloride, and vinyl chloride.^{[citation needed]}

Herbal and alternative remedies

Examples include Ackee fruit, Bajiaolian, Camphor, Copaltra, Cycasin, Kava, pyrrolizidine alkaloids, Horse chestnut leaf, Valerian, Comfrey (often used in herbal tea)^[31]

• Chinese herbal remedies:

Jin Bu Huan, Ma-huang, Sho-wu-pian

See also

• Hepatoprotection
• Reye's syndrome

References

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17. ^ Bénichou C (1990). "Criteria of drug-induced liver disorders. Report of an international consensus meeting". J. Hepatol. 11 (2): 272–6. doi:10.1016/0168-8278(90)90124-A. PMID 2254635.
18. ^ ^{a b c} Andrade RJ, Robles M, Fernández-Castañer A, López-Ortega S, López-Vega MC, Lucena MI (2007). "Assessment of drug-induced hepatotoxicity in clinical practice: a challenge for gastroenterologists". World J. Gastroenterol. 13 (3): 329–40. PMID 17230599. http://www.wjgnet.com/1007-9327/13/329.asp.
19. ^ Arundel C, Lewis JH (2007). "Drug-induced liver disease in 2006". Curr. Opin. Gastroenterol. 23 (3): 244–54. doi:10.1097/MOG.0b013e3280b17dfb. PMID 17414839.
20. ^ Reuben A (2004). "Hy's law". Hepatology 39 (2): 574–8. doi:10.1002/hep.20081. PMID 14768020.
21. ^ Arora N, Goldhaber SZ (2006). "Anticoagulants and transaminase elevation". Circulation 113 (15): e698–702. doi:10.1161/CIRCULATIONAHA.105.603100. PMID 16618822.
22. ^ Andrade RJ, Lucena MI, Kaplowitz N, et al. (2006). "Outcome of acute idiosyncratic drug-induced liver injury: Long-term follow-up in a hepatotoxicity registry". Hepatology 44 (6): 1581–8. doi:10.1002/hep.21424. PMID 17133470.
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25. ^ Wallace JL (2004). "Acetaminophen hepatotoxicity: NO to the rescue". Br. J. Pharmacol. 143 (1): 1–2. doi:10.1038/sj.bjp.0705781. PMID 15345657.
26. ^ James LP, Mayeux PR, Hinson JA (2003). "Acetaminophen-induced hepatotoxicity". Drug Metab. Dispos. 31 (12): 1499–506. doi:10.1124/dmd.31.12.1499. PMID 14625346.
27. ^ Manov I, Motanis H, Frumin I, Iancu TC (2006). "Hepatotoxicity of anti-inflammatory and analgesic drugs: ultrastructural aspects". Acta Pharmacol. Sin. 27 (3): 259–72. doi:10.1111/j.1745-7254.2006.00278.x. PMID 16490160.
28. ^ Iancu TC, Shiloh H, Dembo L (1986). "Hepatomegaly following short-term high-dose steroid therapy". J. Pediatr. Gastroenterol. Nutr. 5 (1): 41–6. doi:10.1097/00005176-198601000-00008. PMID 3944744.
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