Indian Journal of Pharmacology Medknow Publications on behalf of Indian Pharmacological Society ISSN: 0253-7613 EISSN: 1998-3751 Vol. 38, Num. 4, 2006, pp. 238-242

Indian Journal of Pharmacology, Vol. 38, No. 4, July-August, 2006, pp. 238-242

Educational Forum

Drugs and non-alcoholic steatohepatitis

Das SK, Vasudevan DM

Department of Biochemistry, Amrita Institute of Medical Sciences, Elamakkara P.O., Cochin-682 026, Kerala
Correspondence Address:Department of Biochemistry, Amrita Institute of Medical Sciences, Elamakkara P.O., Cochin-682 026, Kerala, subirkumardas@aims.amrita.edu

Code Number: ph06066

Abstract

Keywords: Antihypertensive drugs, antiobesity drugs, liver disease.

Introduction

Drug induced steatohepatitis

Obesity and steatohepatitis

Pathology of drug induced steatohepatitis

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

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 (PPARγ) 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

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 β-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] PPARα is a transcription factor that governs both microsomal ( via CYP4A) and peroxisomal (β-oxidation) pathways of lipid oxidation and ultimately production of ROS.[73] PPARγ 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 PPARγ-activating drugs.

Prevention

Conclusion

References

Copyright 2006 - Indian Journal of Pharmacology

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