Medicines are boon to mankind as they save people from diseases. Sometimes these medicine can also be harmful and cause damage to our bodies. Liver damage is one of the very common problems caused by drugs. One must be aware of the impacts of the drugs on liver when using drugs for the long term and prevent drug induced liver problems.

The liver is the largest gland in our body. It is placed in the upper right-hand region surrounded by the stomach, diaphragm, right kidney, and intestines. It weighs about 6.6 kilograms. The liver is one organ that is rich in vascular supply. It supplied oxygenated blood through the hepatic artery and also the nutrient-rich blood supply from the hepatic portal vein. So at any point in time, the liver holds about 13 percent or a pint of our blood.

It also accounts for about 20 percent of the resting total oxygen consumption of the body. It is demarcated into 2 lobes, almost 1000 lobules, and 8 segments. All of these lobules connect to form tubes that eventually form a larger tube called the common hepatic duct. This common hepatic duct takes away and delivers the bile produced in the liver to the consecutive organs.

Functions of the liver

  • The liver is found to be responsible for more than 500 functions in the body. 
  • This super gland runs all of these functions in combination with other organs and organ systems in the body. No artificial or man-made organ can replace the liver.
  • All the blood that processes in the liver, breaks down, balances, and forms nutrients. 
  • It also metabolizes the drugs into easier absorbable forms for the body. 
  • Production of proteins for the plasma. 
  • Conversion of surplus glucose into glycogen.
  • Processing the hemoglobin to store the iron. 
  • Production of urea from the harmful ammonia 
  • Detoxifying the blood from drugs and toxins
  • Regulated the blood clotting.
  • Clearing out the bilirubin timely from blood
  • Regulating the number of amino acids present in the blood.
  • Production of fat proteins and cholesterol 
  • Sending out bile byproducts to the intestines to be excreted by the body.

Malfunctions and diseases of the liver:

The liver is the only organ that can regenerate. A healthy liver works very efficiently. But an organ as big as that can draw in a lot of problems. 

A few of the malfunctions and diseases of the liver are

  • Fascioliasis is a condition caused by a liver fluke.
  • Cirrhosis is when the liver cells get destroyed 
  • Hepatitis is an inflamed liver
  • Fatty liver disease occurs alongside obesity and alcohol 
  • Primary sclerosing cholangitis is when the bile ducts are destroyed due to autoimmune inflammatory disease
  • Liver damage can be generally caused by drugs, medications, herbal supplements, chemicals, solvents, and alcohol causing toxicity in the liver. This is termed hepatic toxicity. 
  • Toxic hepatitis is the most adverse effect caused by antituberculosis drugs. 
  • Drug hepatotoxicity is the leading cause of acute liver failure in the world as of now. One in 10000-100000 is exposed to drug-induced liver injury. 
  • From the physician’s perspective, one of their regulatory decisions includes drug withdrawal. 
  • They are responsible indeed to weigh out the potential risks vs benefits of prescribing a drug and be aware of appropriate monitoring approaches for hepatotoxicity. 
  • However, many other limiting factors can’t always be totaled. Like the rare toxicity in some drugs, unfinished or lack of animal trials and models, inadequate practical issues drug-to-drug interactions, etc. 

Factors causing the hepatotoxicity:

Classification of drug-related hepatotoxicity is done by scuttling a series of tests that show the liver chemistry and its elevations and by observing the mechanism of toxicity. A liver biopsy outcome also infers toxicity. 

1. Nonsteroidal anti-inflammatory drugs:

  • Nonsteroidal anti-inflammatory drugs are the most used drugs worldwide. They are used to relieve pain, inflammation, and body pains and to bring down a fever. They are also used to relieve symptoms of headaches, painful periods, sprains and strains in the body, colds, flu, arthritis, and long-term pains. These are tablets, capsules, injections, gels, creams, and suppositories. 
  • Like all medicines, there’s a risk of side effects. Over-the-counter non-steroidal anti-inflammatory drugs have lesser side effects than high-prescription drugs. 
  • The potency of side effects is higher in people with poor health, or on a chronic treatment for a longer time. 
  • Acetaminophen budgets for the majority of cases of hepatotoxicity by drugs. 
  • Nonsteroidal anti-inflammatory drug-induced hepatotoxicity. It is the most widely used medication worldwide. 6 percent of the adult population uses nonsteroidal anti-inflammatory drugs of which 24 percent of them used nonprescription ibuprofen. 
  • Despite considerable progress in pharmacological studies, the relationship between liver toxicity in animals and humans seems poor. Nimesulide, sulindac, and diclofenac seem to be linked with the highest risk. 
  • Nimesulide marketing has been suspended in a few countries in concerns regarding hepatotoxicity. Diclofenac-induced liver injury is a paradigm for drug-related hepatotoxicity. 
  • Even a rare occurrence of hepatotoxicity related to nonsteroidal anti-inflammatory drugs contributes significantly to the total burden of drug-induced liver disease because of the large number of people taking these drugs.  

2. Antibiotics

  • Antibiotics are commonly implicated in the cause of drug-induced liver disease. Amoxicillin- clavulanic acid, minocycline, nitrofurantoin, trimethoprim-sulfamethoxazole, and trovafloxacin. In order, all of these are responsible for different diseases of the liver. 
  • Cholestasis is induced by the toxicity of amoxicillin and clavulanic acid, and autoimmune hepatitis is caused by the drug toxicity of minocycline.  
  • Antimicrobial agents amoxicillin and clavulanic acid, also called augmentin, are the most often reported antibiotic that is associated with nonsteroidal anti-inflammatory drugs. 
  • A recent large prospective case series involving 69 patients with amoxicillin clavulanate hepatotoxicity inferred that the type of hepatic injury varies according to the time from onset of therapy, where hepatocellular injury predominates at the first week, cholestatic injury starts at 2-3weeks and mixed liver injury after 3weeks. 
  • In this very case, there was a 3 percent probability of death and liver transplantation and a 7 percent chance of negative outcomes like death, chronic liver failure, and the need for a liver transplant. 
  • Cefazolin has been found to lead to liver injury 1-3 weeks after exposure to a single infusion. 
  • The other extreme is the nature of the nitrofurantoin-induced liver injury which occurs years after the treatment steering to acute liver failure. 
  • Patients with liver injury have a favorable prognosis with the use of antibiotics. But in patients with jaundice that have undergone a new liver transplant approximately a 10 percent risk of death is observed. 
  • Hepatotoxicity by antibiotics can also lead to chronic injury and vanishing bile duct syndrome. 
  • Telithromycin is an antibiotic to treat respiratory tract infections, bronchitis, and sinusitis. There are three reported cases of jaundice and elevated liver chemistry tests within 8 weeks of stopping the erythromycin antibiotic therapy. 
  • After this case, the usage of telithromycin is confined to acquired pneumonia alone.     

3. Hypoglycemic drug

  • Metformin is an oral hypoglycemic drug. It is prescribed for patients living with non-insulin-dependent diabetes mellitus. There have been three reports depicting its peculiar mechanism. 
  • Both cholestatic issues mean the flow of bile from the liver is either slowed down or blocked. 
  • The hepatocellular toxicity that is as said the inflammation of liver cells is another complication found. Another rare complication found associated with metformin is lactic acidosis. 
  • It is a serious concern in patients already with preexisting cardiac disease and renal failure. 

However, given its potential in treating hepatic impairment, it is safe in mild cases even in children. But in patients with significant hepatic impairment, it is advised to be avoided due to the underlying risk of lactic acidosis. 

4. Antiretroviral therapy

  • Antiretroviral therapy incidence in causing hepatotoxicity ranges from as low as three percent to eighteen percent. 
  • Although its toxicity does not end up in death or transplantation of the liver it is still prevalent. It is as prevalent as 1.1 per 100 years. 
  • All three classes of drugs belonging to antiretroviral therapy are associated with hepatotoxicity. 
  • Examples of this therapy include 
  • 1. Protease inhibitors: protease inhibitors like ritonavir, indinavir, darunavir, etc. Among these, ritonavir has the highest incidence of hepatotoxicity. To relieve low doses of ritonavir have a toxicity effect rather than high doses. Ritonavir – amprenavir combination is associated with severe hepatotoxicity. 
  • In patients with HIV and HCV co-infection, it’s a black box warning to avoid protease inhibitors. 
  • Up to 500mg of tipranavir, 800mg of indinavir, 1400mg of fosamprenavir, and also the same dose of amprenavir are allowed to treat the hepatic impairment. 
  • More than this limit is considered toxic. 
  • 2. The transcriptase inhibitors belonging to antiretroviral therapy are associated with hepatic steatosis and lactic acidosis. When exceeded the toxicity limit, these drugs have the potential to cause fatal lactic acidosis syndrome. 
  • Symptoms also include metabolic acidosis and liver dysfunction which can end up in death or a need for liver transplantation. 
  • The mortality rate is so high. 
  • That is why once lactic acidosis syndrome is diagnosed prompt discontinuation of transcriptase inhibitors is warranted.
  • 3. Non-nucleoside inhibitors do not usually cause hypertoxicity of the liver but manifest as a rash-like hypersensitivity reaction. Hepatic failure leading to liver transplantation and death are all rare. 

5. Statins:

  • Statins rarely cause clinically significant liver injury, even in patients with underlying liver disease. These are prescribed for the treatment of hyperlipidemia and coronary heart disease including other atherosclerotic diseases. 
  • They have several proven benefits but are also potential for myopathy, hepatotoxicity, and myalgias. 
  • However, concern for hepatotoxicity should not be a reason to avoid the use of statins in patients with appropriate cardiovascular and cerebrovascular clinical indications. 
  • Routine monitoring of liver function all along the statin therapy is no longer needed. Indeed, a liver function test is done before the initiation of the statin therapy itself. 
  • Statins can be safely used in underlying liver disease but should be entirely avoided in patients with liver failure, acute liver injury, or cirrhosis. 

6. Hepatotoxicity of chemotherapy:

  • Enlarging the availability of antineoplastic agents has laid the clinician the pressure of recognizing the spectrum of possible toxicities resulting from the administration of various drugs. 
  • Common variables that affect hepatotoxicity are already prevailing liver disease, genetics, sepsis, metastases, immunosuppression, exposure to blood products, and administration of hepatically metabolized agents.
  • Hepatic mastectomy, stauffers syndrome, renal cell carcinoma, venous occlusive disease, etc have been seen to complicate the clinical picture also influencing the hepatotoxicity of chemotherapy.
  • The hepatotoxicity is manifested by hepatocellular necrosis, cholestasis, steatosis, ductal injury fibrosis, peliosis hepatis, and venous occlusion. 
  • The most common pattern of hepatotoxicity is hepatocellular injury. Chemotherapeutic hepatic injury occurs in an idiosyncratic manner. 
  • In hepatitis B and C patients, the reactivation may be as high as 47 percent in hepatitis B hepatitis. 

7. Hepatotoxicity by Herbal and dietary supplements:

  • Herbal supplements hepatotoxicity is on the rise. The true incidence of toxicity is not calculated properly as they are regarded as safe. 
  • Despite their unproven efficacy, herbal therapy has been increasingly used for various diseases. Most of the herbal and dietary supplements are taken unprescribed which is why half of the patients admit that they did not reveal the use to their doctors. 
  • In particular, their usage is common in individuals with chronic liver disease. 30 to 62 percent of this population are susceptible to hepatotoxicity because they ingest silymarin as a supplement.
  • Ayurvedic medicine is the science of plant-based systems of healing for a spectrum of disorders. Hepatotoxicity from ayurvedic medicine has rarely been reported. 
  • Centella Asiatica, an ayurvedic medicine used to treat leprosy, has been reported to be attributed to hepatotoxicity. Examples are cirrhosis and granulomatous hepatitis. 
  • Chaparral which is perceived to have antimicrobial and antioxidant activities has been accountable for the acute and subacute hepatocellular injury, and cholestatic hepatitis. 
  • Histological findings include biliary changes, cholestasis, and massive hepatic necrosis. 
  • Geniposide, lycopodium serratum, Paeonia, polygonum, germander, celandine, green tea, penny royal, alkaloids, Java, Herbalife products, etc are also proven and tested patterns of liver injury. 

Practical ways to avoid Drug-induced hepatotoxicity:

  •  Drug-induced hepatotoxicity will remain a problem as long as there’s a new drug introduced. 
  • The presence of different steps in the mechanisms of the drugs makes it difficult to identify the genetic mutations or pathways that are contributing to hepatotoxicity. 
  • In addition, toxicity which is well described in an organ system may not translate to the other system. 
  • Thiopurine deficiency has predicted the neurological toxicity caused by azathioprine but failed to predict the hepatotoxicity of the same. So there’s a need for tailored therapy for an individual that works best for him and also there’s a need for monitoring for toxicity. 
  • Models of toxicity and genomic predators hold potential promise in preventing toxicity before it occurs. 
  • Administration of drugs in patients with underlying liver disease needs a balanced assessment of the risk-benefit ratio. Careful monitoring of drug interactions is especially important in patients who have undergone a liver transplant. 

“This article does not provide medical advice. It is intended for informational purposes only. It is not a substitute for professional medical advice, diagnosis, or treatment. Never ignore professional medical advice in seeking treatment because of something you have read on this website. If you think you may have a medical emergency, immediately call or visit your doctor.”
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