Hepatotoxins

There has been a recent rash of liver related problems and deaths in Yunnan province this past year, more so than usual. There have been a lot of theories as to why Chinese citizens are being diagnosed with Acute Liver Failure (ALF), but one potential cause seems to be the most prevalent.

Bad mushrooms.

The Chinese in Yunnan province, and in the western part of China, tend to not farm mushrooms, but go out into the wild and pick them. The consequences of these actions can be fatal.

Keep in mind, that about fifteen years ago, a group of well accomplished mushroom aficionados and specialists, some of them university professors, went scavenging for wild mushrooms in the Pacific Northwest of the US. As I remember, seven of them got very ill (ALF), one or two died, a few required liver transplantation. The moral of the story is, even the best minds make mistakes with these things. The wrong mushroom can be deadly.

A discussion about hepatotoxins and acute liver failure is in order.

Acute Liver Failure

ALF is defined as the onset of coagulopathy and any degree of hepatic encephalopathy within 26 weeks of the appearance of symptoms in the absence of underlying liver disease. It can be stratified into an acute (<4 weeks) or subacute (4 weeks to 6 months) presentation. Exceptions include Wilson's disease, chronic hepatitis B virus (HBV) infection, or autoimmune hepatitis (AIH), which may present with ALF despite the presence of chronic liver disease or cirrhosis.

Acute liver failure (ALF) is an uncommon condition in which the rapid deterioration of liver function results in coagulopathy and alteration in the mental status of a previously healthy individual. Acute liver failure often affects young people and carries a very high mortality. The term acute liver failure is used to describe the development of coagulopathy, usually an international normalized ratio (INR) of greater than 1.5, and any degree of mental alteration (encephalopathy) in a patient without preexisting cirrhosis  and with an illness of less than 26 weeks' duration.

Acute liver failure is a broad term and encompasses both fulminant hepatic failure (FHF) and subfulminant hepatic failure (or late-onset hepatic failure). Fulminant hepatic failure is generally used to describe the development of encephalopathy within 8 weeks of the onset of symptoms in a patient with a previously healthy liver. Subfulminant hepatic failure is reserved for patients with liver disease for up to 26 weeks before the development of hepatic encephalopathy.

When damage to the hepatic parenchyma is so severe that the liver is no longer able to meet the metabolic requirements of the body, the syndrome of ALF develops. The outcome is characterized by coagulopathy, hepatic encephalopathy, often associated with cerebral edema, hemodynamic changes, electrolyte disturbance, and renal failure.

Hepatotoxins

Hepatotoxicity is the most common reason that medications and herbal products are removed from the market place (e.g., bromfenac, troglitazone, and kava kava), and numerous products have been associated with ALF. Acetaminophen (N-acetyl-p-aminophenol or APAP) is the most common offender (affecting 45–50% of ALF patients) followed by liver injury from other drugs (11–15%).  These products are divided into intrinsic, or direct, hepatotoxins and idiosyncratic hepatotoxins. Direct hepatotoxins cause predictable dose-dependent hepatocellular necrosis. Idiosyncratic hepatotoxins are unpredictable, unrelated to dose, and present as either immune-mediated hypersensitivity or metabolic injury.

Acetaminophen (also known as paracetamol and APAP) is a direct hepatotoxin that at supratherapeutic doses (generally greater than 7–10 grams per day) may result in both nonfatal and fatal hepatic necrosis. The toxicity is dose related, the higher the dose consumed, the more likely the possibility of liver damage. There are also reports of transient asymptomatic aminotransferase elevations in normal individuals taking therapeutic doses and hepatotoxicity at therapeutic doses under certain conditions (i.e., alcohol consumption and malnutrition). There may be a greatly increased susceptibility to hepatotoxicity because of depleted glutathione stores in the setting of chronic alcohol use and malnourishment syndromes. APAP overdose overwhelms the hepatic detoxification process. It remains controversial to what degree excessive cytochrome activation, such as that induced by other medications, or depletion of glutathione stores (i.e., from malnutrition or alcohol) contributes to APAP toxicity. Intentional (suicidal) APAP overdose is the leading cause of ALF in the UK and it is a major cause in other Western nations. Unintentional (accidental) overdose makes up over 50% of cases of APAP overdose in the USA.

Prescription Medications

Hepatotoxicity can occur with the use of prescription medications (idiosyncratic hypersensitivity reactions) from the following:
o Antibiotics (ampicillin-clavulanate, ciprofloxacin, doxycycline, erythromycin, isoniazid, nitrofurantoin, tetracycline)
o Antivirals (fialuridine)
o Antidepressants (amitriptyline, nortriptyline)
o Antidiabetics (troglitazone)
o Antiepileptics (phenytoin, valproate)
o Anesthetic agents (halothane)
o Lipid-lowering medications (atorvastatin, lovastatin, simvastatin)
o Immunosuppressive agents (cyclophosphamide, methotrexate)
o Nonsteroidal anti-inflammatory agents (NSAIDs)
o Salicylates (Reye syndrome)
o Oral hypoglycemic agents (troglitazone)
o Others (disulfiram, flutamide, gold, propylthiouracil)

Many products cause an immune-mediated type of liver injury (e.g., phenytoin, amoxicillin–clavulanate, erythromycin, sulfonamides, halothane, dapsone, diclofenac, carbamazepine, and sulindac). Metabolic idiosyncratic reactions show no hypersensitivity and can occur up to several weeks after drug discontinuation (e.g., isoniazid, ketoconazole, disulfiram, valproate, troglitazone, and amiodarone).

Food

Amanita phalloides, responsible for most mushroom poisoning deaths, is seen in areas where the mushroom is prevalent – the Pacific Northwest and Appalachian Mountain regions. The amantinin toxin is dose-dependent and disrupts hepatocyte mRNA synthesis. Mortality approaches 10–30%.  Other substances are associated with dose-related toxicity, including Amanita phalloides mushroom toxin, Bacillus cereus toxin, Cyanobacteria toxin, Organic solvents (eg, carbon tetrachloride), and yellow phosphorus.

Direct hepatotoxins usually are recognized quickly and removed from use (i.e., carbon tetrachloride, chloroform, and tannic acid). Certain direct hepatotoxins have been allowed to remain in clinical use because the toxicity is known and occurs only at high doses [i.e., APAP, iron sulfate, intravenous (i.v.) tetracycline, ethanol, and phosphorus]. Environmental toxins may also lead to ALF, including yellow phosphorus, used in rat poison and fireworks, Bacillus cereus toxin, and aflatoxin.  Aflatoxins can be commonly found in peanut butter, but usually in doses that are far too low to be of problem.

Illicit Drug Use

Two illicit drugs are commonly associated with hepatotoxicity. Ecstasy (3,4-methylenedioxymethamphetamine [MDMA] and Cocaine. The causation may be the result of hepatic ischemia.  Also, any illicit drug overdose that results in systemic hypoxia can cause liver failure.

Viral Hepatitis

ALF occurs in less than 5% of hepatitis viral infections, and HBV accounts for the majority of cases. Hepatitis E virus-induced ALF is uncommon in western countries, but accounts for sporadic and major epidemics of viral hepatitis in underdeveloped nations (India, Pakistan, Mexico, Central Asia, Southeast Asia, Russia, and North Africa) and in travelers returning from these areas. Other viruses causing ALF include herpes simplex virus (HSV), varicella zoster virus, cytomegalovirus, Epstein–Barr virus, parvovirus B19, and yellow-fever virus. These viruses generally lead to ALF in the setting of immune compromise or pregnancy, but cases in immunocompetent individuals have been reported.

Herbal Products

Herbal or alternative medicines, have been implicated, after the use of high dosages, in liver damage. Some of these include Ginseng, Pennyroyal oil, Teucrium polium, Chaparral or germander tea, and Kawakawa. Perceptions of safety and/or cultural mores prompt individuals to seek herbal slimming aids in preference to conventional dietary, physical activity and medication-based protocols. In recent years, terpenoid-containing dietary supplements have been implicated in causing severe and sometimes fatal hepatotoxicity. Teucrium polium (germander) was the first of these herbal products to be clearly linked to cases of acute liver failure. Subsequently, similar hepatotoxicity has been observed with other members of the Teucrium genus. While diterpenoid-derived reactive metabolites are central to germander hepatotoxicity, it may also be that the hepatic effects of compounds such as Sho-saiko-to, Centella asiatica and Black cohosh are linked to their triterpenoid content. Other non-terpenoid-containing herbal remedies marketed for weight reduction have been causally associated with significant liver injury. Important among these are preparations containing N-nitrosofenfluramine, usnic acid and ephedra alkaloids. Finally, we review recent data on known and emerging hepatotoxins such as Boh-Gol-Zhee, Kava, pyrrolizidine alkaloids and Shou-Wu-Pian. Better public and physician awareness through health education, early recognition and management of herbal toxicity and tighter regulation of complementary/alternative medicine systems are required to minimize the dangers of herbal product use.

Chemical Agents

The following are a known list of hepatotoxic chemical agents. These agents can be inhaled to cause liver damage.

• Aliphatic Nitros: 2-Nitropropane, such as Dimethylnitromethane, iso-Nitropropane, 2-NP
• Aromatic Amines:   4,4'-Methylenedianiline, such as  MDA; 4,4'-Diaminodiphenylmethane; para, para'-Diaminodiphenyl-methane; Dianilinomethane; 4,4'-Diphenylmethanediamine; 4,4' Methylene bis (2-chloraniline); diaminodiphenylmethane; DDM;
• Aromatic Nitros: 2,4,6-Trinitrotoluene, such as 1-Methyl-2,4,6-trinitrobenzene; TNT; Trinitrotoluene; sym-Trinitrotoluene; Trinitrotoluol
• Chlorinated Solvents: Ethylene dichloride, such as 1,2-Dichloroethane; Ethylene chloride; Glycol dichloride
• Chlorinated Solvents: 1,1,2,2-Tetrachloroethane, such as Acetylene tetrachloride
• Chlorinated Solvents: Carbon tetrachloride, such as Tetrachloromethane
• Chlorinated Solvents: Propylene dichloride, such as 1-2-Dichloropropane
• Halogenated Solvents: Carbon tetrabromide, such as Carbon bromide, Methane tetrabromide, Tetrabromomethane;
• Halogenated Solvents: Acetylene tetrabromide, such as Symmetrical tetrabromoethane; TBE; Tetrabromoacetylene; Tetrabromoethane; 1,1,2,2-Tetrabromoethane;
• Halogenated Solvents: Ethylene dibromide, such as 1,2-Dibromoethane; Ethylene bromide; Glycol dibromide;
• Halowaxes: Hexachloronaphthalene, such as  Halowax 1014
• Halowaxes: Octachloronaphthalene, such as Halowax 1051
• Halowaxes: Pentachloronaphthalene, such as Halowax 1013; 1,2,3,4,5-Pentachloronaphthalene;
• Halowaxes: Tetrachloronaphthalene, such as Halowax, Nibren wax, Seekay wax;
• Halowaxes: Trichloronaphthalene, such as Halowax, Nibren wax, Seekay wax;
• Nitrosamines: N-Nitrosodimethylamine, such as Dimethylnitrosamine; DMNA; NDMA; N,N-Dimethylnitrosamine;
• Other Solvents: Dimethylformamide, such as Dimethyl formamide; N,N-Dimethylformamide; DMF;
• Other Solvents: Tetrahydrofuran, such as Diethylene oxide; 1,4-Epoxybutane; Tetramethylene oxide; THF;
• Other Solvents: Dimethyl acetamide, such as DMAC; Acetic acid, dimethylamide; Dimethyl Acetamide; acetdimethylamide; dimethylacetone amide; dimethylamide acetate;
• Other Organics: Diphenyl, such as Biphenyl, Phenyl benzene

Steroids

Body building substances have been linked to liver damage, including shrinkage of the testes and male infertility, masculinization of women, breast enlargement in males, short stature in children, cardiac valvular damage, a higher predilection to misuse other drugs and alcohol, adverse effects on blood lipid levels, and increased risk of heart attack, stroke, and death. These are some of the agents commonly used by body builders, which may cause hepatotoxicity:

• 4Ever Fit D-Drol
• Advanced Muscle Science Dienedrone
• Advanced Muscle Science Liquidrone UTT
• Anabolic Xtreme Hyperdrol X2
• APS (aka Advanced Muscle Science) Mastavol
• APS (aka Advanced Muscle Science) Revamp
• APS (aka Advanced Muscle Science) Ultra Mass Stack
• APS (aka Advanced Muscle Science) Ripped Stack
• Better Body Sports Finadex
• Black China Labs Straight Drol
• Black China Labs Straight Phlexed
• Body Conditioning Solutions TestraFLEX
• Bjorklund Methyldrostanolone
• BOSC Enterprises Epi-Tren
• BOSC Enterprises Magna Drol
• Chaparral Labs Epivol
• Chaparral Labs Pheravol-V
• Competitive Edge Labs M-Drol
• Competitive Edge Labs P-Plex
• Competitive Edge Labs X-tren
• Diabolic Labs Epio-Plex
• Diabolic Labs Finabolic 50
• Diabolic Labs Revenge
• Ergopharm 6-OXO
• Ergopharm 6-OXO Extreme
• EST (aka Engineered Sports Technology) MethAnstance
• Extreme Labs Susto-Test Depot
• Fizogen ON Cycle II Hardcore
• G.E.T/ (Genetic Edge Technologies) SUS-500
• G.E.T/ (Genetic Edge Technologies) Tren-250
• Hardcore Formulations T-Roid
• I Force Nutrition 1,4 AD Bold 200
• I Force Dymethazine/Reversitol Combo Pack
• I Force Reversitol
• I Force Nutrition 17a PheraFLEX
• I Force Nutrition Dymethazine
• I Force Nutrition Methadrol
• IDS (aka Innovative Delivery Systems) Bromodrol
• IDS (aka Innovative Delivery Systems) Grow Tabs TR
• IDS (aka Innovative Delivery Systems) Mass Tabs
• IDS (aka Innovative Delivery Systems) Oxodrol Pro
• IDS (aka Innovative Delivery Systems) Ripped Tabs TR
• IDS (aka Innovative Delivery Systems) Rapid Release
• Ripped Tabs
• Kilo Sports Massdrol
• Kilo Sports Phera-Mass
• Kilo Sports Trenadrol
• Monster Caps Monster Caps
• Myogenix Spawn
• Nutra Coastal D-Stianozol
• Nutra Coastal H-Drol
• Nutra Coastal MDIT
• Nutra Coastal S-Drol
• Nutra Coastal Trena
• Performance Anabolics Methastadrol
• Performance Anabolics Tri-Methyl X
• Purus Labs E-pol Inslinsified
• Purus Labs Nasty Mass
• Rage RV2
• Rage RV3
• Rage RV4
• Rage RV5
• Redefine Nutrition Finaflex 550-XD
• Redefine Nutrition Finaflex Ripped
• Transform Supplements Forged Extreme Mass
• Transform Supplements Forged Lean Mass

Indeterminate

Indeterminate cases make up from 5 to 19% of ALF cases depending upon the country. Despite significant advances in diagnostic techniques, a cause for the ALF cannot be found.

Credits: Various pharmacology and pathophysiology texts, Medscape, various university and chemical sites