Educational Forum

Drugs and non-alcoholic steatohepatitissteatohepatitis

S.K. Das, D.M. Vasudevan

ABSTRACT Department of Biochemistry, Amrita Institute of Medical Health complications associated with include , hypertension, hyperlipidemia, Sciences, cardiovascular disease, and associated co-morbidities including non-alcoholic steatohepatitis Elamakkara P.O., (NASH). Additionally, NASH has been associated with several drugs. Though steatohepatitis Cochin-682 026, Kerala. India is a rare form of drug induced disease, it has generated great interest in the recent past. Oral hypoglycemic agents, lipid lowering agents, antihypertensives, and antiobesity Received: 24.12.2005 Revised: 10.3.2006 medication underlie a significant proportion of well-recognized hepatotoxicity. While some Accepted: 11.4.2006 medications have predictable toxicity, many more are associated with idiosyncratic reactions. The toxic mechanism appears to involve mitochondrial injury, impaired β-oxidation, Correspondence to: generation of reactive oxygen species and ATP depletion. If a drug is suspected, it is probably Subir Kumar Das prudent to stop this medication. E-mail: [email protected] KEY WORDS: Antihypertensive drugs, antiobesity drugs, .

Introduction Obesity and steatohepatitis Ludwig introduced the term nonalcoholic steatohepatitis Obesity, an ever-expanding global health problem (NASH) to describe a form of liver disease that is histologically contributes significantly to individual poor health and societal indistinguishable from alcoholic but occurs in people burden of disease.[10] It leads to the development of more than who do not consume excess ethanol.[1] It is now clear that the 50 distinct medical disorders and alters the response to the spectrum of nonalcoholic fatty liver (NAFL) extends from non- treatment of many others. They include diabetes, hypertension, progressive disease, through NASH and finally to “cryptogenic” hyperlipidemia, and cardiovascular disease with all their in which may be inconspicuous.[2, 3] NASH associated co-morbidities. It is not surprising therefore that is now conceptualized as encompassing at least three both the complications of obesity and, increasingly, obesity components among the tetrad of steatosis, hepatocellular itself are aggressively targeted for pharmacotherapy. This has injury, focal mixed cell-type and fibrosis.[4] included oral hypoglycemic agents, lipid lowering agents, However, there is not yet complete agreement on the semantics antihypertensives and antiobesity medications. These four (NAFL versus NASH) or definition of what constitutes categories of medication constitute a significant proportion of steatohepatitis. Pathological definition of NASH requires well-recognized hepatotoxic medications. In many instances, steatosis, significant hepatocellular injury (most often indicated these medications have been withheld from patients because by ), diffuse mixed lobular of liver abnormalities.[11] NASH is a liver disease in which inflammation, and perisinusoidal and perivenular fibrosis.[5] obesity and insulin resistance are frequently implicated.[12] Drug induced steatohepatitis Pathology of drug induced steatohepatitis Drug-induced liver diseases (DILDs) are clinicopathologic Approximately 900 medications have been identified as patterns of liver injury related to drugs.[6] Steatohepatitis is a potentially hepatotoxic, many of them have interactions and rare form of DILD[5, 6] and drugs account for fewer than 2% cross-reactivity, and the severity of injury can range from cases of NASH. It is noteworthy that drugs that cause asymptomatic or mild to fatal. Medication induced steatohepatitis are often associated with other types of liver hepatotoxicity can be divided into the unexpected, idiosyncratic injury, particularly acute hepatitis. Some agents implicated as reaction, and the predictable, intrinsically toxic one.[13] causing cirrhosis or other forms of NAFL in obese middle- Generally, intrinsically toxic medications are not used clinically aged diabetic women (methyl dopa, calcium channel blockers, if liver function is known to be compromised. This type of liver estrogens, methotrexate) may be fortuitous co-associations injury is usually avoidable. However, idiosyncratic drug with “primary” NASH, which most often occurs among persons reactions are often not identified. The cause of these reactions with the insulin resistance or .[3, 4, 7- 9] is unclear and is postulated to be due to hypersensitivity, toxic

238 Indian J Pharmacol | August 2006 | Vol 38 | Issue 4 | 238-242 Drugs and non-alcoholic steatohepatitis metabolite production, or deficiencies of detoxification. can be divided into those that decrease appetite or increase Hypersensitivity reactions are characterized clinically by fever, satiety. [Table 1] rash, eosinophilia, eosinophilic infiltrates, and/ or granulomata, Type 2 diabetes is a well-recognized complication of obesity. and tend to occur in close temporal relation to the It is associated with liver disease in and of itself, with the administration of the drug. [13] Liver injury may be primarily predominant etiology being NASH. Conversely, liver disease hepatocellular, cholestatic, or mixed. has not been associated with type 1 diabetes mellitus, which In general, drug-induced steatohepatitis resembles reflects the current understanding that insulin resistance, not more closely than NASH associated with insufficiency, is associated with this type of liver disease.[8, 26] diabetes and insulin resistance syndrome. Thus, cirrhosis and However, it may be difficult to differentiate hepatic injury hepatic failure are common, and the liver pathology shows related to diabetic medications from that related to impressive polymorphonuclear leukocyte (polymorph) diabetes itself. inflammation, ballooning degeneration of hepatocytes, and Other than insulin, the incidence of reported toxicity for Mallory bodies. Progression of fibrosis to cirrhosis can occur sulfonylurea is ~1%, and is felt to be caused by hypersensitivity over weeks or months in drug induced steatohepatitis, whereas to the sulfur moiety.[27] Metformin, the only biguanide currently it may take decades and often never occurs in patients with used in the treatment of type 2 diabetes, is generally considered NASH.[5] to be safe, but has also shown cholestatic hepatitis.[35] The Myeloid bodies are a characteristic ultrastructure feature glucosidase inhibitors are useful adjunctive therapies for Type of drug-induced steatohepatitis. They are ascribed to 2 diabetes. The prototype of this class is acarbose for which phospholipidosis, which is a dose dependent phenomenon there is also a report of hepatotoxicity.[43] The thiazolidinediones attributable to the physicochemical properties of cationic (troglitazone, pioglitazone, and rosiglitazone) are peroxisome amphiphilic drugs.[14] These properties favor accumulation of proliferator-activated receptor gamma (PPARγ) ligands. They the drug in the lipid membranes and proton-rich organelles, are used in the treatment of type 2 diabetes as insulin including lysosomes and mitochondria. Drugs associated with sensitizing medications, but their interest extends to the treat­ phospholipidosis may inhibit lysosomal phospholipases directly ment of primary liver diseases, such as steatohepatitis.[38, 44] or by binding to phospholipids, thereby inhibiting the turnover They have been shown to inhibit collagen deposition in animal of lipid bilayers.[15] While liver enzymes (transaminases and models of fibrosis.[45] alkaline phosphatase) usually normalize after withdrawal Among the lipid lowering agents in use today, the HMGCoA of the drug, there has been some concerns sparked reductase inhibitors (statins) have gained notoriety for their by persistent liver injury and cirrhosis following propensity to cause transaminase elevations. Hepatotoxicity discontinuation of drug.[16-18] appears to be a risk of all lipid lowering-agents. However, the Hepatotxicity of drugs overall incidence of significant hepatotoxicity with lipid- Currently available medications in the treatment of obesity lowering agents is low, and concern over liver enzyme

Table 1

Common medications for the treatment of obesity

Name Mechanism Main toxicity

Sibutramine* Serotonin/ norepinephrine reuptake Hepatotoxic,[19,20] cardiovascular[11] inhibitor- may increase satiety or decrease appetite

Orlistat* Lipase inhibitor Hepatotoxic,[21] [11]

Amphetamine/Dexamphetamine Decreased appetite/ increased satiety Hepatotoxic,[22] cardiovascular[11]

Benzphetamine hydrochloride* Decreased appetite/ increased satiety Pulmonary hypertension[11]

Diethylpropion*/Phendimetrazine tartrate* Appetite suppressant Pulmonary hypertension[11] /Phenteramine*

Dexfenfluramine/Fenfluramine Increased serotonin levels Valvular heart defects, pulmonary hypertension[11]

Fluoxetine Increased serotonin levels Hepatotoxic,[23- 25] insomnia, tremor and asthenia[11]

Mazindol* Anorectic Xerostomia[11]

Phenyl propanolamine Sympathomimetic Hepatotoxic, hemorrhagic stroke[11]

* Food and Drug Administration (FDA), USA approved drugs

Indian J Pharmacol | August 2006 | Vol 38 | Issue 4 | 238-242 239 Das, et al. abnormalities may lead to inappropriate withdrawal in many other cardiovascular disorders. The second is that the drug individuals who need therapy.[11] may precipitate or accentuate risk factors for NASH, such as There are some well known hepatotoxicity patterns central obesity, diabetes, and hypertriglyceridemia. A third is associated with antihypertensive medications. Such an that occult alcoholism may be involved. This has been example is α-methyldopa associated .[46] suspected in some reported associations between industrial With the advent of newer classes of antihypertensives, α­ solvents and hepatotoxicity.[6] The final possibility is that some methyldopa use has decreased. However, considering that it drugs may actually cause steatohepatitis by a direct is one of the few antihypertensive safe to use in pregnancy, it hepatotoxic mechanism. [Table 3] Establishing the diagnosis is still commonly prescribed in such cases.[47] Beta-blockers of drug-induced liver disease may be difficult. It requires: are in common use, and generally have a low incidence of (a) absence of other causes of liver disease, and hepatotoxicity, with the possible exception of labetalol. Calcium (b) that the ingestion of drug precedes the onset of liver channel blockers have been implicated in drug-induced disease.[66] steatohepatitis.[48] This seems to be the case for perhexiline maleate, coralgil Table 2 summarizes the major classes of antidiabetics and (4, 4’-diethylaminoethoxyhexestrol), amiodarone, and possibly antihypertensives reported to be hepatotoxic. for tamoxifen.[67] Perhexiline, amiodarone, and tamoxifen can Mechanisms accumulate in the mitochondria and inhibit mitochondrial β­ There are several reasons for associations between drugs oxidation, thereby causing steatosis.[68, 69] They also inhibit and steatohepatitis. The first possibility is that a person with oxidative phosphorylation. [68, 69] In the longer-term, electron NASH happens to be taking the drug for conditions associated leakage with production of reactive oxygen species (ROS), with the insulin resistance syndrome, such as hypertension or increase in lipid peroxidation and decrease in cellular ATP levels

Table 2

Major classes of antidiabetics and antihypertensives showing hepatotoxicity

Class Group Example

Antidiabetic Sulfonylurea Chlorpropamide,[27, 28] glibenclamide/ glyburide,[29, 30, 31] tolbutamide[32] and tolazamide[33, 34] Biguanide Metformin[35, 36, 37] Thiazolidinediones Troglitazone,[38, 39] pioglitazone,[40] rosiglitazone[41, 42]

Antihypertensive Calcium channel blockers.[48, 49] Nifedipine, diltiazem, amlodipine Angiotensin II antagonists.[50,51,52] Losartan, candesartan, valsartan Angiotensin converting enzyme Enalapril, ramipril, captopril, fosinopril (ACE) inhibitors.[18, 53] Central sympatholytics α-methyldopa.[54] Vasodilators Hydralazine.[55] Beta-blockers.[56] Carvedilol, labetalol

Table 3

Clinicopathological features and courses with specific agents

Drugs Indication Toxicity

Perhexiline maleate Angina pectoris Phospholipidosis, hepatocellular hyperplasia, granulomatous hepatitis, steatohepatitis and micronodular cirrhosis.[6, 57]

Amiodarone (Iodinated Ventricular Pulmonary infiltrates, cardiac failure, hypothyroidism, peripheral neuropathy, benzofuran derivative) tachyarrhythmias nephrotoxicity, corneal deposits and most serious liver disease.[58, 59, 60] Acute due to severe hepatitis or a Reye’s syndrome like illness, cholestatic hepatitis and granulomas.[59, 60, 61]

Tamoxifen,toremifene Breast cancer , benign liver tumors, hepatocellular carcinoma,[62, 63] , acute (an analog of tamoxifen) hepatitis, submassive hepatic necrosis,[64] steatosis and steatohepatitis.[65]

Stilbestrol (Estrogen) Metastatic prostate Hypertriglyceridemia, central obesity and insulin resistance.[5] cancer

Highly active antiretroviral HIV/AIDS Mitochondrial injury.[5] therapy (HAART)

240 Indian J Pharmacol | August 2006 | Vol 38 | Issue 4 | 238-242 Drugs and non-alcoholic steatohepatitis could be of relevance to the pathogenesis of liver injury. Thus Am J Clin Nutr 1992;55:495-502. drug-induced steatohepatitis may be a paradigm for injurious 11. Ghali P, Lindor KD. Hepatotoxicity of drugs used for treatment of obesity and events in common metabolic forms of NASH.[8, 9, 70, 71] its comorbidities. Semin Liv Dis 2004;24:389-97. 12. James OF, Day CP. Non-alcoholic steatohepatitis (NASH): A disease of emerg­ Other studies implicate peroxisome proliferator-activated ing identity and importance. J Hepatol 1998;29:495-501. receptors (PPARs) leading to NASH.[72] PPARα is a transcription 13. Zimmerman HJ. Drug-induced liver disease. Clin Liver Dis 2000;4:73-96. factor that governs both microsomal (via CYP4A) and 14. Pirovino M, Muller O, Zysset T, Honegger U. 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Silvercon 2006 25th Annual Conference of IPS Gujarat Chapter

Date : 8th October, 2006 Venue : B. J. Medical College, Ahmedabad

Last Date For Registration : 15th August, 2006 Organizing Secretaries : Dr. Dhara Shah, Mr. M. P. Patel E-Mail : [email protected]

242 Indian J Pharmacol | August 2006 | Vol 38 | Issue 4 | 238-242