Title 6. DRUG INDUCED LIVER DISORDERS.pdf ✅

PHARMD GURU Page 1 DEFINITION: The liver disease/disorder resulting from the inhalation, ingestion or parenteral administration of any pharmacological or chemical agent is called as drug induced liver disease or drug induced liver disorder (DILD). PATTERNS/TYPES OF DILD: The most common and serious drug induced liver disorders are as follows: 1. Idiosyncratic reactions 2. Allergic hepatitis 3. Toxic hepatitis 4. Chronic active hepatitis 5. Toxic cirrhosis 6. Liver vascular disorders 1. IDIOSYNCRATIC REACTIONS:  For some drugs, a genetic or acquired abnormality must exist in a particular metabolic pathway for a toxic reaction to take place. In other cases, the reactions are typically associated with a drug concentration and often respond to simply lowering the dose of the drug.  Idiosyncratic reactions tend to occur without association to particular blood concentrations or specifically identified metabolic abnormalities.  Ex: sulfonylureas like glipizide and antibiotics like ciprofloxacin. Idiosyncratic reactions are rare and are sometimes described as liver hypersensitivity to a drug. 2. ALLERGIC HEPATITIS:  Allergic reactions in the liver can be caused by many drugs and result in many different kinds of hepatic damage. DRUG INDUCED LIVER DISORDERS
PHARMD GURU Page 2  It is marked by fever, pruritus, rash, eosinophilia, arthritis, and haemolytic anaemia. The formation of granulomas within the liver is often seen on biopsy. The reaction reverses with discontinued therapy and reappears upon rechallenge.  Ex: Most antibiotics have been associated with this type of reaction, including the fluoroquinolones, macrolides, fl-lactams, trimethoprim-sulfamethoxazole, penicillinase-resistant Penicillins such as dicloxacillin and allopurinol. SIGNS & SYMPTOMS: i) The onset of symptoms is 1 to 6 weeks after initiation of therapy. ii) The incidence, like all the allergic liver reactions, is low, estimated at less than 1%. iii) The clinical presentation includes eosinophilia, fever, rash, and arthritis. The biopsy may show a pattern of fibrin-ring granulomas similar to those seen in Q fever. 3. TOXIC HEPATITIS: Toxic reactions are predictable, often dose-related effects in the liver due to specific agents. Ex: Paracetamol (acetaminophen). When taken in overdose, acetaminophen becomes bioactivated to a toxic intermediate known as N-acetyl-p-benzoquinone imine (NAPQI). NAPQI is very reactive, with a high affinity for sulfhydryl groups and requires glutathione for further metabolism to non-toxic metabolites. After glutathione supplies are exhausted, the toxic metabolite binds to sulfhydryl-containing proteins in the liver cell and causes lipid peroxidation disrupting the cell membrane. These events eventually lead to cell death.
PHARMD GURU Page 3 Ex: Reye's syndrome is an aggressive form of toxic hepatitis often associated with aspirin use in children. Valproate toxicity can also present in this pattern. SIGNS & SYMPTOMS: i) Early in the process of Reye's syndrome, mitochondrial dysfunction leads to the depletion of acyl coenzyme A and carnitine. ii) Fatty acids accumulate and gluconeogenesis is impaired, resulting in hypoglycaemia. iii) A concurrent disruption of the urea cycle occurs, leading to a decrease in the removal of ammonia and a slowing of protein use. iv) A threefold rise in the blood ammonia level and an increase in the prothrombin time are common findings. v) In advanced stages of Reye's syndrome, many patients develop intracranial hypertension that can be life threatening and refractory to therapy. 4. CHRONIC ACTIVE TOXIC HEPATITIS: Patients experience periods of symptomatic hepatitis followed by periods of convalescence, only to repeat the experience months later. It is a progressive disease with a high mortality rate and is more common in females than males. Antinuclear antibodies appear in most patients. These drugs appear to form anti-organelle antibodies. The exact identification of a causative agent is sometimes difficult since diagnosis requires multiple episodes occurring long after exposure to the offending drug. Ex: Dantrolene, isoniazid, phenytoin, nitrofurantoin, and trazodone have been reported in association with a type of autoimmune mediated disease in the liver. 5. TOXIC CIRRHOSIS: The scarring effect of hepatitis in the liver leads to the development of cirrhosis. Some drugs tend to cause such a mild case of hepatitis that it may not be detected. Mild hepatitis can be easily mistaken for a more routine generalized viral infection. If the offending drug or agent is not discontinued, this damage will continue to progress. The patient eventually presents not with hepatitis, but with cirrhosis.
PHARMD GURU Page 4 Ex: Methotrexate and vitamin A toxicity. i) Methotrexate causes periportal fibrosis in most patients who experience hepatotoxicity. The lesion results from the action of a bioactivated metabolite produced by cytochrome P450. This process has most commonly been noted in patients treated for psoriasis and arthritis. The extent of damage can be reduced or controlled by increasing the dosage interval to once weekly or by routine use of folic acid supplements. ii) Vitamin A is normally stored in liver cells, and causes significant hypertrophy and fibrosis when taken for long periods in high doses. Hepatomegaly is a common finding, along with ascites and portal hypertension. In patients with vitamin A toxicity, gingivitis and dry skin are also very common. This is accelerated by ethanol, which competes with retinol for aldehyde dehydrogenase. 6. LIVER VASCULAR DISORDERS:  Focal lesions in hepatic venules, sinusoids, and portal veins occur with various drugs.  Ex: Cytotoxic agents used to treat cancer, the pyrrolizidine alkaloids, and the sex hormones.  A centralized necrosis often follows and can result in cirrhosis. Azathioprine and herbal teas that contain comfrey (a source of pyrrolizidine alkaloids) are associated with the development of veno-occlusive disease. The exact incidence is rare and may be dose related.  "Peliosis hepatitis" is a rare type of hepatic vascular lesion that can be seen as both an acute and a chronic disease. The liver develops large, blood-filled lacunae within the parenchyma. Rupture of the lacunae can lead to severe peritoneal haemorrhage. Ex: Peliosis hepatitis has been associated with exposure of the liver to androgens, oestrogens, tamoxifen, azathioprine, and danazol.