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Year : 2006  |  Volume : 38  |  Issue : 4  |  Page : 238-242

Drugs and non-alcoholic steatohepatitis

Department of Biochemistry, Amrita Institute of Medical Sciences, Elamakkara P.O., Cochin-682 026, Kerala, India

Correspondence Address:
S K Das
Department of Biochemistry, Amrita Institute of Medical Sciences, Elamakkara P.O., Cochin-682 026, Kerala
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0253-7613.27019

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 ╗ Abstract 

Health complications associated with obesity include diabetes, hypertension, hyperlipidemia, cardiovascular disease, and associated co-morbidities including non-alcoholic steatohepatitis (NASH). Additionally, NASH has been associated with several drugs. Though steatohepatitis is a rare form of drug induced liver disease, it has generated great interest in the recent past. Oral hypoglycemic agents, lipid lowering agents, antihypertensives, and antiobesity medication underlie a significant proportion of well-recognized hepatotoxicity. While some medications have predictable toxicity, many more are associated with idiosyncratic reactions. The toxic mechanism appears to involve mitochondrial injury, impaired β -oxidation, generation of reactive oxygen species and ATP depletion. If a drug is suspected, it is probably prudent to stop this medication.

Keywords: Antihypertensive drugs, antiobesity drugs, liver disease.

How to cite this article:
Das S K, Vasudevan D M. Drugs and non-alcoholic steatohepatitis. Indian J Pharmacol 2006;38:238-42

How to cite this URL:
Das S K, Vasudevan D M. Drugs and non-alcoholic steatohepatitis. Indian J Pharmacol [serial online] 2006 [cited 2023 Mar 29];38:238-42. Available from: https://www.ijp-online.com/text.asp?2006/38/4/238/27019

 ╗ Introduction Top

Ludwig introduced the term nonalcoholic steatohepatitis (NASH) to describe a form of liver disease that is histologically indistinguishable from alcoholic hepatitis but occurs in people who do not consume excess ethanol.[1] It is now clear that the spectrum of nonalcoholic fatty liver (NAFL) extends from non-progressive disease, through NASH and finally to "cryptogenic" cirrhosis in which steatosis may be inconspicuous.[2],[3] NASH is now conceptualized as encompassing at least three components among the tetrad of steatosis, hepatocellular injury, focal mixed cell-type inflammation and fibrosis.[4] However, there is not yet complete agreement on the semantics (NAFL versus NASH) or definition of what constitutes steatohepatitis. Pathological definition of NASH requires steatosis, significant hepatocellular injury (most often indicated by ballooning degeneration), diffuse mixed lobular inflammation, and perisinusoidal and perivenular fibrosis.[5]

 ╗ Drug induced steatohepatitis Top

Drug-induced liver diseases (DILDs) are clinicopathologic patterns of liver injury related to drugs.[6] Steatohepatitis is a rare form of DILD[5],[6] and drugs account for fewer than 2% cases of NASH. It is noteworthy that drugs that cause steatohepatitis are often associated with other types of liver injury, particularly acute hepatitis. Some agents implicated as causing cirrhosis or other forms of NAFL in obese middle-aged diabetic women (methyl dopa, calcium channel blockers, estrogens, methotrexate) may be fortuitous co-associations with "primary" NASH, which most often occurs among persons with the insulin resistance or metabolic syndrome.[3],[4],[7],[8],[9]

 ╗ Obesity and steatohepatitis Top

Obesity, an ever-expanding global health problem contributes significantly to individual poor health and societal burden of disease.[10] It leads to the development of more than 50 distinct medical disorders and alters the response to the treatment of many others. They include diabetes, hypertension, hyperlipidemia, and cardiovascular disease with all their associated co-morbidities. It is not surprising therefore that both the complications of obesity and, increasingly, obesity itself are aggressively targeted for pharmacotherapy. This has included oral hypoglycemic agents, lipid lowering agents, antihypertensives and antiobesity medications. These four categories of medication constitute a significant proportion of well-recognized hepatotoxic medications. In many instances, these medications have been withheld from patients because of liver abnormalities.[11] NASH is a liver disease in which obesity and insulin resistance are frequently implicated.[12]

 ╗ Pathology of drug induced steatohepatitis Top

Approximately 900 medications have been identified as potentially hepatotoxic, many of them have interactions and cross-reactivity, and the severity of injury can range from asymptomatic or mild to fatal. Medication induced hepatotoxicity can be divided into the unexpected, idiosyncratic reaction, and the predictable, intrinsically toxic one.[13] Generally, intrinsically toxic medications are not used clinically if liver function is known to be compromised. This type of liver injury is usually avoidable. However, idiosyncratic drug reactions are often not identified. The cause of these reactions is unclear and is postulated to be due to hypersensitivity, toxic metabolite production, or deficiencies of detoxification. Hypersensitivity reactions are characterized clinically by fever, rash, eosinophilia, eosinophilic infiltrates, and/ or granulomata, and tend to occur in close temporal relation to the administration of the drug. [13] Liver injury may be primarily hepatocellular, cholestatic, or mixed.

In general, drug-induced steatohepatitis resembles alcoholic liver disease more closely than NASH associated with diabetes and insulin resistance syndrome. Thus, cirrhosis and hepatic failure are common, and the liver pathology shows impressive polymorphonuclear leukocyte (polymorph) inflammation, ballooning degeneration of hepatocytes, and Mallory bodies. Progression of fibrosis to cirrhosis can occur over weeks or months in drug induced steatohepatitis, whereas it may take decades and often never occurs in patients with NASH.[5]

Myeloid bodies are a characteristic ultrastructure feature of drug-induced steatohepatitis. They are ascribed to phospholipidosis, which is a dose dependent phenomenon attributable to the physicochemical properties of cationic amphiphilic drugs.[14] These properties favor accumulation of the drug in the lipid membranes and proton-rich organelles, including lysosomes and mitochondria. Drugs associated with phospholipidosis may inhibit lysosomal phospholipases directly or by binding to phospholipids, thereby inhibiting the turnover of lipid bilayers.[15] While liver enzymes (transaminases and alkaline phosphatase) usually normalize after withdrawal of the drug, there has been some concerns sparked by persistent liver injury and cirrhosis following discontinuation of drug.[16],[17],[18]

 ╗ Hepatotxicity of drugs Top

Currently available medications in the treatment of obesity can be divided into those that decrease appetite or increase satiety. [Table - 1]

Type 2 diabetes is a well-recognized complication of obesity. It is associated with liver disease in and of itself, with the predominant etiology being NASH. Conversely, liver disease has not been associated with type 1 diabetes mellitus, which reflects the current understanding that insulin resistance, not insufficiency, is associated with this type of liver disease.[8],[26] However, it may be difficult to differentiate hepatic injury related to diabetic medications from that related to diabetes itself.

Other than insulin, the incidence of reported toxicity for sulfonylurea is ~1%, and is felt to be caused by hypersensitivity to the sulfur moiety.[27] Metformin, the only biguanide currently used in the treatment of type 2 diabetes, is generally considered to be safe, but has also shown cholestatic hepatitis.[35] The glucosidase inhibitors are useful adjunctive therapies for Type 2 diabetes. The prototype of this class is acarbose for which there is also a report of hepatotoxicity.[43] The thiazolidinediones (troglitazone, pioglitazone, and rosiglitazone) are peroxisome proliferator-activated receptor gamma (PPARg) ligands. They are used in the treatment of type 2 diabetes as insulin sensitizing medications, but their interest extends to the treat-ment of primary liver diseases, such as steatohepatitis.[38],[44] They have been shown to inhibit collagen deposition in animal models of fibrosis.[45]

Among the lipid lowering agents in use today, the HMGCoA reductase inhibitors (statins) have gained notoriety for their propensity to cause transaminase elevations. Hepatotoxicity appears to be a risk of all lipid lowering-agents. However, the overall incidence of significant hepatotoxicity with lipid-lowering agents is low, and concern over liver enzyme abnormalities may lead to inappropriate withdrawal in many individuals who need therapy.[11]

There are some well known hepatotoxicity patterns associated with antihypertensive medications. Such an example is a-methyldopa associated autoimmune hepatitis.[46] With the advent of newer classes of antihypertensives, a-methyldopa use has decreased. However, considering that it is one of the few antihypertensive safe to use in pregnancy, it is still commonly prescribed in such cases.[47] Beta-blockers are in common use, and generally have a low incidence of hepatotoxicity, with the possible exception of labetalol. Calcium channel blockers have been implicated in drug-induced steatohepatitis.[48]

[Table - 2] summarizes the major classes of antidiabetics and antihypertensives reported to be hepatotoxic.

 ╗ Mechanisms Top

There are several reasons for associations between drugs and steatohepatitis. The first possibility is that a person with NASH happens to be taking the drug for conditions associated with the insulin resistance syndrome, such as hypertension or other cardiovascular disorders. The second is that the drug may precipitate or accentuate risk factors for NASH, such as central obesity, diabetes, and hypertriglyceridemia. A third is that occult alcoholism may be involved. This has been suspected in some reported associations between industrial solvents and hepatotoxicity.[6] The final possibility is that some drugs may actually cause steatohepatitis by a direct hepatotoxic mechanism. [Table - 3] Establishing the diagnosis of drug-induced liver disease may be difficult. It requires:

(a) absence of other causes of liver disease, and

(b) that the ingestion of drug precedes the onset of liver disease.[66]

This seems to be the case for perhexiline maleate, coralgil (4, 4'-diethylaminoethoxyhexestrol), amiodarone, and possibly for tamoxifen.[67] Perhexiline, amiodarone, and tamoxifen can accumulate in the mitochondria and inhibit mitochondrial b-oxidation, thereby causing steatosis.[68],[69] They also inhibit oxidative phosphorylation. [68],[69] In the longer-term, electron leakage with production of reactive oxygen species (ROS), increase in lipid peroxidation and decrease in cellular ATP levels could be of relevance to the pathogenesis of liver injury. Thus drug-induced steatohepatitis may be a paradigm for injurious events in common metabolic forms of NASH.[8], [9], [70], [71]

Other studies implicate peroxisome proliferator-activated receptors (PPARs) leading to NASH.[72] PPARa is a transcription factor that governs both microsomal ( via CYP4A) and peroxisomal (b-oxidation) pathways of lipid oxidation and ultimately production of ROS.[73] PPARg also plays a regulatory role in lipid homeostasis and is up-regulated in livers of obese and diabetic mice.[73] Thiazolidinediones (troglitazone, rosiglitazone), which reverse insulin resistance and correct hyperglycemia and hyperlipemia in type 2 diabetes, also bind to and activate this receptor.[73] It is therefore possible that type 2 diabetes may sensitize the liver to PPARg-activating drugs.

 ╗ Prevention Top

Liver enzyme abnormalities and liver disease may be attributable to drugs. If a drug is suspected, it is important to determine the dose, route, and duration of therapy, as well as possible interactions.[74] The latency between drug ingestion and the appearance of disease is also important. Other causes of liver diseases must be excluded. Finally, if suspicion of drug-related injury still remains, the drug should be discontinued.

 ╗ Conclusion Top

In addition to the usual associations with insulin resistance, type 2 diabetes, central obesity, and hypertriglyceridemia, nonalcoholic steatohepatitis has been associated with several drugs. Though, drug induced liver disease is a relatively uncommon cause of steatohepatitis, it has become the single major cause for regulatory actions concerning drugs, specifically during drug development. In spite of the recent increased interest, very little progress has been made toward understanding mechanisms underlying hepatotoxicity. Early recognition of hepatotoxicity is crucial to prevent the development of severe form of liver disease and improve the clinical outcome.

 ╗ References Top

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[Table - 1], [Table - 2], [Table - 3]

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