International Scholarly Research Notices

International Scholarly Research Notices / 2013 / Article

Review Article | Open Access

Volume 2013 |Article ID 617943 |

Nasir Hussain, Anirban Bhattacharyya, Suartcha Prueksaritanond, "Amiodarone-Induced Cirrhosis of Liver: What Predicts Mortality?", International Scholarly Research Notices, vol. 2013, Article ID 617943, 14 pages, 2013.

Amiodarone-Induced Cirrhosis of Liver: What Predicts Mortality?

Academic Editor: B. Strasberg
Received18 Jan 2013
Accepted11 Feb 2013
Published14 Mar 2013


Introduction. Amiodarone has been used for more than 5 decades for the treatment of various tachyarrhythmias and previously for the treatment of refractory angina. There are multiple well-established side effects of amiodarone. However, amiodarone-induced cirrhosis (AIC) of liver is an underrecognized complication. Methods. A systematic search of Medline from January 1970 to November 2012 by using the following terms, amiodarone and cirrhosis, identified 37 reported cases of which 30 were used in this analysis. Patients were divided into 2 subsets, survivors versus nonsurvivors, at 5 months. Results. Aspartate aminotransferase was significantly lower ( ) in patients who survived at 5-months (mean 103.33 IU/L) compared to nonsurvivors (mean 216.88 IU/L). There was no statistical difference in the levels of prothrombin time, total bilirubin, alanine aminotransferase, alkaline phosphatase, gamma-glutamyl transpeptidase, cumulative dose, and latency period between the two groups. The prevalence of DM, HTN, HLD, CAD, and CHF was similar in the two groups. None of the above-mentioned variables could be identified as a predictor of survival at 5 months. Conclusion. AIC carries a mortality risk of 60% at 5 months once the diagnosis is established. Further prospective studies are needed to identify predictors of AIC and of mortality or survival in cases of AIC.

1. Introduction

Amiodarone has been used since the 1960s for the management of various tachyarrhythmias and in the past for refractory angina. There are multiple reported and well-established side effects of amiodarone therapy such as effects on the thyroid, skin, lungs, nerves, and cornea.

The effect of amiodarone on the liver resulting in hepatotoxicity is a recognized complication of amiodarone, but this hepatotoxicity leading to cirrhosis of the liver is unfortunately an underrecognized side effect. Little has been written on amiodarone-induced cirrhosis (AIC) of the liver due to its rarity [14]. The purpose of this paper is to review what we know so far about AIC of the liver.

2. Materials and Methods

2.1. Selection of Studies

A systematic search of Medline from January 1970 to November 2012 by using the following terms, amiodarone and cirrhosis, was performed; 37 reported cases were identified (Table 1) of which 30 were used in this analysis. We also searched the reference lists of all reported cases to identify citations that were not identified during the initial search. Data that were extracted for each patient included age, gender, latency period in years, whether ≥200 mg/day amiodarone dosage was used (it is thought that low-dose amiodarone has lesser side effects), cumulative dose, presence or absence of hypertension (HTN), diabetes (DM), hyperlipidemia (HLD), coronary artery disease (CAD), congestive heart failure (CHF), values of bilirubin, aspartate transaminase (AST), alkaline phosphatase (ALK P), albumin, alanine transaminase (ALT), and prothrombin time. The outcomes in terms of survival or mortality at 5 months were used. This specific timeline was selected because more than 50% of patients in these case reports died within 5 months after the diagnosis was established. Not all of the studies we found had all these data; however, they were included if the outcome was provided. In some cases, the outcome was not available, authors were contacted, and the outcome was determined. Those cases, for which outcome could not be determined, were excluded from the final analysis. Of seven cases that were excluded from the final analysis, one case had indeterminate cause of cirrhosis and for the rest of cases, outcome could not be established. Some authors provided cumulative doses for amiodarone. If total cumulative dose was not given, a formula (cumulative dose in grams = 365 * no. of years * total daily dose/1000) was used to estimate the final cumulative doses, with an assumption that the patient had been 100% compliant with the medicine.

PMH other than arrhythmias, drugsPresentation
Etoh use
AuthorsLabsPathology Duration and dosagesOutcome after diagnosis of AIC

CAD s/p CABG, DM, HLD, No etoh, (amiodarone, warfarin, aspirin, rosiglitazone, and lovastatin)
No other hepatotoxic drugs
Abdominal distensionPuli et al. [2]23.94
Micronodular cirrhosis, bridging fibrosis, lymphocytic infiltrate, macrophages, plasma cells, microvesicular steatosis, and lysosomal bodies on electron microscopy600 mg/day for 10 days, then 200 mg/day for 22.5 months cumulative dose of approx. 141 gSurvived

Digitoxin, alpha methyldopa
No DM, and no etoh
Cirrhosis diagnosed during studyGuigui et al. [3]15, 28
?, 53
GGT 151,
PT 76%
Portal fibrosis, steatosis, PMN, myelin figures, dense deposits, and cirrhosis120 months, cumulative dosage of 520 g Could not establish an outcome

DM, HTN, and CKD
No etoh, (amiodarone,
simvastatin, and glipizide)
Ascites and fatigueAtiq et al. [5]32.49, 106, 147, ?, 75,
PT 20
Steatohepatitis, Mallory hyaline, neutrophilic infiltrate, and cirrhosis200 PO mg/day * 3 years
Cumulative dose of approx. 219 g
Died during the same admission due to complication of liver disease

CAD, CHF, and s/p AICD
No etoh
ConfusionAtiq et al. [5]?
PT 12.7
Mallory hyaline, neutrophil infiltrate, pericellular/bridging fibrosis, and degenerating hepatocytes
(cirrhosis found on autopsy)
Low dose * 2 yearsDied 2 weeks after the workup due to cardiopulmonary failure

COPD, DM, and hypothyroidism
(digoxin, furosemide, and thyroxin)
Abnormal LFTs on screening Rigas et al. [6]?
Portal, central, and sinusoidal fibrosis and loss of lobular architecture and regenerative nodules, central vein sclerosis, Mallory bodies, lysosomal inclusion, and cirrhosis400 mg/day Amiodarone * 18 months
Cumulative dose 216
No information about the outcome

Heart failure, no significant etoh, complete right and left anterior hemiblock
(translated through Google)
Jaundice, hepatomegaly Capron-Chivrac et al. [7]269
GGT 781
Portal, periportal fibrosis, mixed inflammatory infiltrate, ductal proliferation, lysosomal inclusions, no Mallory bodies, and cirrhosis Amiodarone 100 mg/day * 5 days/wk * 2 months
Cumulative dose of 4 g
“We strongly suspect in this case cirrhosis may have been due to some other cause”
Died 2 months after stopping amiodarone, died of pulmonary edema

Weight loos and blurred visionChaabane et al. [8]Micronodular cirrhosis, steatohepatitis 200 mg/day * 15 years
Cumulative dose of approx. 1095 g
Could not establish an outcome

CAD, HTN, CHF, emphysema, pulmonary HTN, HLD, renal insufficiency, migraine, ulcerative colitis, cholelithiasis, and no etohProgressive weakness, abdominal discomfort, and jaundiceAnonymous [9]51.3
PT 12.4
Micronodular cirrhosis with ballooning degeneration of hepatocytes and Mallory bodies, some steatosis150–1000 mg/day, averaging 400 mg/day * 8.5 years Cumulative dose of approx. 1241 gDied 2 weeks after stopping medicine, probably hepatic encephalopathy

Obesity, moderate alcohol intake Fatigue, weakness Anonymous [9]34.2
Mallory bodies, minimal fatty change, and cirrhosisAmiodarone 300 mg/day * approx. 6 months
Cumulative dose of approx. 55 g
Survived for more than 3 years

Gout, CAD, and renal failure secondary to lead intoxication, MI, pulmonary edema, and sylvian microembolism
(digoxin, warfarin, diclofenac, amiodarone, and allopurinol)
Fatigue, weight loss,
1-2 alcoholic beverages on social occasions
Richer and Robert [10]12
INR 2.4
GGT 277
Ballooned hepatocytes, Mallory bodies, fibrosis, phospholipidosis, inflammatory infiltrate, and cirrhosis2.8 g * 4 days, then amiodarone 400 mg–600/day * 13 months,
cumulative dose of approx. 206 g
Died 69 days after cessation of therapy, due to hepatorenal syndrome

Ischemic heart disease, CVA, poliomyelitis, carotid endarterectomy, and peripheral neuropathy
Etoh Consumption = negligible
Muscle weakness, hepatomegalyGilinsky et al. [11]133.4
PT 17
Fibrosis, Mallory hyaline, lysosomal inclusions,
amiodarone, and desmethylamiodarone conc. 0.6, 0.5 mg/L, respectively
300–600 mg/day * 28 months
Cumulative dose of approx. 378 g
Died despite discontinuation of therapy, probably liver failure

No significant past history other than recurrent SVTsAbdominal pain, anorexia, and wastingTordjman et al. [12]n
Mallory bodies, fibrosis, severely damaged hepatocytes, bile duct proliferation, and cirrhosis200 mg daily * 5 years
Cumulative dose od approx. 365 g
Died 2 weeks after evaluation due to hepatic encephalopathy

Anorexia, abdominal pain, and malaise Rene et al. [13]20.52, 16
324, 39
GGT 66
PT 70%
Micronodular cirrhosis, central and periportal fibrosis, and probable phospholipidosis
400 mg/day * 9 years
Cumulative dose of approx. 1314 g
Outcome could not be determined

CAD s/p CABG, HLD hypothyroidism, and s/p pacemaker
(amiodarone, ASA, furosemide, atorvastatin, and ranitidine)
<2 units etoh/month
No herbal medicines
Upper GI bleed, lethargy * 2 months Singhal et al. [14]14
GGT 443
PMN infiltrate, reduplicating bile ducts in hepatic nodules, degenerating hepatocytes, Mallory bodies, extensive fibrosis, and cirrhosis200 PO mg/ day * 33 months
Cumulative dose of approx. 198 g
Died 3 months after diagnosis
despite of stopping amiodarone due to heart and renal failure and hepatic encephalopathy

s/p MI, left ventricular aneurysm, and normal coronariesAbnormal LFTs
Bach et al. [15]?
Micronodular cirrhosis, portal fibrosis, Mallory bodies, ballooning hepatocytes, phospholipidosis, inflammatory cells, and lysosomal inclusions800 mg/day * 7 months, then 600 mg/day * 24 months, then 200 mg/day for 3 months
Cumulative dose of approx. 624 g
Survived for more than 3 years

Mitral valve stenosis s/p replacement 5 years ago, moderate TR, no obesity, and no diabetes
(amiodarone, coumadin derivative)
Asthenia, anorexia, and weight loss of 8 kg for 5 months Martinez et al. [16]18.8
GGT 475
PT 20%
Postmortem liver biopsy showed incipient cirrhosis, portal fibrosis, inflammatory ductal infiltration and mixed leukocytic infiltration, steatosis, Mallory bodies, and acidophilic change400 mg daily * 5 days/week, duration not specified, may be >12 years
Cumulative dose of approx. >1152 g
Died due to massive upper GI bleed during same admission

(amiodarone, aspirin, furosemide, diltiazem, isosorbide dinitrate, digoxin, famotidine)
No etoh, no herbs used
Abdominal distension and fatigueÇoban et al.
PT 16.9
GGT 133
Polymorph nuclear infiltrate, ductal proliferation, fibrosis, bridging necrosis, vacuolar degeneration, lysosomal inclusions (73+), and cirrhosis200 mg daily * 1 year, stopped due to side effects, restarted 200 mg daily * 6 years
Cumulative dose of approx. 511 g
Died 3 months after diagnosis due to hepatorenal syndrome and hepatic encephalopathy

Ischemic heart disease
No obesity, no etoh, and no DM
Cardiac congestionOikawa
et al. [18]
GGT 210
PT 59%
Polymorph nuclear infiltrate, ductal proliferation, fibrosis, micro/macrovesicular steatosis, lysosomal inclusions, and cirrhosis
(cumulative dose given by author = 528)
400 mg daily * 17 days, then 200 mg daily for 84 months
Cumulative dose of approx. 518 g
Died 5 months after diagnosis due to renal failure and pneumonia

Rheumatic heart disease, endocarditis, HTN, and DM
(amiodarone, acebutolol, and glibenclamide)
Pain in RUQ and feverLamproye et al. [19]n
*5ULN PT n
Micronodular cirrhosis, portal fibrosis, leukocytic infiltrates, Mallory bodies, micro and macrovesicular steatosis 400 mg/day * 5 days a week * 12 years
Cumulative dose of approx. 1152
No outcome given

s/p pacemaker, goiter
No DM, no obesity, and no etoh abuse
(digoxin, acenocoumarin, and amiodarone )
et al. [20]
PT 100%
Micronodular cirrhosis, marked steatosis, inflammatory infiltrate, Mallory bodies, lysosomal inclusions (268 g cumulative dose given by author)
Amiodarone and N-desmethylamiodarone plasma conc. 0.42, 0.70 g/L
400 mg/day * 5 days per week 2 years, then 200 mg * 5 days per week * 11 months.
Cumulative dose of approx. 236 g
Survived for more than 10 months

Angina pectoris
No DM, no obesity, and no etoh abuse
(amiodarone )
Hepatomegaly Babany
et al. [20]
PT 100%, GGT 460
Fibrosis, steatosis, Mallory bodies, inflammatory infiltrate, cirrhosis, and lysosomal inclusions on electron microscopy
(220 g cumulative dose given by author)
Amiodarone 200 mg/day * 3.5 years
Cumulative dose of approx. 256 g
Survived for more than 1.5 years

Commissurotomy for mitral stenosis
No DM, No obesity, No etoh abuse
(hydroxyzine, amiodarone, tiodomarol, and clonazepam)
Abnormal LFTsBabany
et al. [20]
PT 100%
Moderate fibrosis, steatosis, polymorph nuclear infiltrate, Mallory bodies, cirrhosis, and lysosomal inclusions
(211 g cumulative dose given by author)
Amiodarone 200 mg daily * 5 days/week for 3 years, then 100 mg/day for 2 years, and then 200 mg/day * 6 months
Cumulative dose  approx. = 254 g
Survived at least more than 9 months

No sig. PMH
(isosorbide, warfarin)
No etoh
No significant history besides arrhythmiaRinder
et al. [21]
Active cirrhosis, ongoing hepatocytes destruction, and Mallory bodies
(165 g given by author)
Loading dose for 1 month, then 400 mg/day * 13.5 months. Cumulative dose of approx. 162 gDied one month after discontinuation of drug due to hepatic encephalopathy and hepatorenal syndrome

WPW syndrome, no significant PMH
(amiodarone, diuretic, and beta blocker)
No etoh used
Weakness, bedridden, and ascites Shepherd et al. [22]44
Micronodular cirrhosis with extensive necrosis of regenerating nodules, fibrosis, and swollen hepatocytes600 mg/day * 4 years
Cumulative dose of approx. 876 g
Died due to bronchopneumonia, diagnosis of cirrhosis made at postmortem

Ischemic heart disease, pulmonary edema
(amiodarone, isosorbide dinitrate, furosemide, and potassium)
No etoh
Jeyamalar et al. [23]?
PT normal
Moderate inflammatory cells, nodules enclosed in fibrous bands, fatty, bile ductules proliferation change, and early cirrhosis
Total cumulative dose 215 g
600 mg/day * 1 week, 400 mg/day * 1 month, and 200 mg * 5 days/week * 4 years
Estimated dose = 208.2 g
Survived for more than 4 years

Hypertrophic obstructive cardiomyopathy, s/p ICD, no obesity, no etoh, and no DMB/L hand tremor Ishida et al. [24]32.49
PT 17.4
Micronodular cirrhosis, swollen hepatocytes, proliferating bile ductules, inflammatory infiltrate, micro/macrovesicular steatosis, Mallory bodies, and lysosomal inclusion bodies
Calculated dose comes out to 158
200 mg/day * 26 months
Cumulative dose of 206 g
Died 8 days after admission due to prerenal failure


MILethargy, abdominal distensionHarrison and Elias [25]Micronodular cirrhosis, proliferating bile ducts, neutrophil infiltrate, Ballooning degeneration of hepatocytes, Mallory hyaline, lysosomal inclusion bodies, and epithelioid granulomas200 mg twice/day * 4 years 6 months
Cumulative dose of approx. 657 g
Needed liver transplant

HTN, DM, hypothyroidism, and GERD (Lisinopril, glimepiride, esomeprazole, levothyroxine, amiodarone, furosemide, spironolactone, propranolol, and isosorbide dinitrate)
No obesity, no alcohol
New onset ascites and variceal hemorrhage
Abdominal distension, lower extremity swelling, and SOB
Raja et al. [26]10.26
INR 1.2
GGT 230
Lymphocytic infiltration, macro/microvesicular steatosis, Mallory hyaline, ballooning degeneration, pericellular fibrosis, cirrhosis, and bridging fibrous septaAmiodarone 200 mg/day * 3 years
Cumulative dose of approx. 219 g
(No herbal medicines)
Survived more than 6 months confirmed with author

CAD, s/p MI, s/p CABG, hep. B infection, and CHF
No etoh for last 14 years
(serum amiodarone and N-desmethylamiodarone levels = 3 & 2.6 mg/L)
Fatigue, weight loss, and abdominal swelling Flaharty et al. [27]46.17
PT 39
GGT 738
Marked fibrosis, inflammatory infiltrate Mallory bodies, cirrhosis, proliferating ductules, and lysosomal inclusions
Cumulative dose of 202 g (given by author)
1200 mg * 13 days, 400–600 mg/day * 12 months
Cumulative dose of approx. 200 g
Died on day 21 of hospitalization due to bradycardia episode

No etohWeakness and jaundice Snir et al. [28]92.3, 520
329, 22
GGT 1493
Micronodular cirrhosis, moderate to severe fibrosis of portal tract, pericellular fibrosis, Mallory bodies, and cirrhosis on postmortem
Amiodarone 800 mg/day dose * 1 year
Estimated cumulative dose = 292 g
Died due to liver failure 3 weeks after stopping drug

HTN, CHF, obesity
(amiodarone, felodipine, furosemide, potassium supplement, aspirin, and cisapride)
No other drugs
No etoh
Dark brown urine for 7 daysChang et al. [29]142
Portal fibrosis, pericellular sinusoidal fibrosis, lysosomal inclusions, Mallory bodies, and cirrhosis
1.3/1.3 amiodarone/
desmethylamiodarone serum levels
400 mg/day * 5 years
Cumulative dose = 730 g
Died 4 months after diagnosis despite of stopping drug, no cause of death established

(amiodarone, felodipine, HCTZ, and aspirin)
No etoh
EF 70%
Sudden onset abdominal distensionSung and Yoon [30]46.1
GGT 385
INR 1.32
Cirrhosis, polymorphnuclear infiltrate, Mallory bodies, ballooning degeneration, and lysosomal inclusionsAmiodarone 200 mg/day * 5 years
Estimated cumulativ dose = 365 g
Survived, amiodarone discontinued, and other antiarrhythmic started

Unstable recurrent angina, ventricular aneurysm, and MI
No etoh, no DM
For surgical resection of ventricular aneurysm Poucell et al. [31]12
PT 11
Micronodular cirrhosis, Mallory bodies, ballooning, macrovesicular steatosis, fibrosis, inflammation, pleomorphic mitochondria, and lysosomal inclusion600 mg * 5 days/wk * 2 years
Cumulative dose of 288
Died shortly after liver biopsy, cause unknown may be MI, and no postmortem

Etoh 85 g/day, s/p MI, CAD Hepatomegaly despite normal LFTs * 1 year, presented for liver biopsyPoucell et al. [31]8.5
PT 11
Micro nodular cirrhosis, Mallory bodies, ballooning, macro vesicular steatosis, fibrosis, inflammation, pleomorphic mitochondria, lysosomal inclusion600 mg * 5 days/wk * 2 years
Cumulative dose 288 g
Continued on amiodarone and survived

Alcoholic cardiomyopathy, adrenal insufficiency
(amiodarone, hydrocortisone)
Etoh was DC when heart problem diagnosed
Jaundice, pruritus, and deterioration of conditionSalti et al. [32]481
GGT 1231
Portal and septal fibrosis, polymorph infiltrate, Mallory bodies, lysosomal inclusions, macrovesicular steatosis, and cirrhosis Amiodarone 200 mg * 5 days/wk * 2 years
Estimated cumulative
dose of 96
Survived for more than 5 months at least

A fibWeakness, nausea, vomiting, abdominal distension, lethargy, and confusionChandraprakasam and Whitcraft [33]?
Neutrophilic satellitosis, Mallory hyaline, foam cells representing phospholipidosis, macrovesicular steatosis, and cirrhosisAmiodarone 200 mg/day * 4 years
Cumulative dose = 292
No information about outcome

Depression, heart failure
(digoxin, doxepin, and bumetanide)
Vomiting and muscle weakness of one month durationLim et al. [34]28
400 mg/day * 5 months, then 600 mg/day for 16 months
Cumulative dose of approx. 348 g
Died due to liver failure 5 months after diagnosis despite of stopping amiodarone

: number, DM: diabetes mellitus, HTN: hypertension, HLD: hyperlipidemia, CAD: coronary artery disease, CABG: coronary artery bypass grafting, SVT: supra ventricular tachycardia, CHF: congestive heart failure, etoh: alcohol, HCTZ: hydrochlorothiazide, ASA: aspirin, SOB: shortness of breath, n: normal, TR: tricuspid regurgitation, ULN: upper limit of normal, and W: white.
Labs are written in the following sequence, Bili, AST, ALK P, Albumin, and ALT in all tables. AST, ALT, ALK P, and GGT values are given in IU/L, bilirubin is given as Mmol: micromole/L (2–17) normal range, albumin is given as g/L.
*ULN stands for upper limits of the normal and the written lab is for ALT being 5 times the ULN.

Prothrombin time for some cases was given as percentage activity rather than in seconds. We could not find any convertor for percentage activity to seconds (which is a normally reported unit). For cases in which prothrombin time was reported as a percentage prothrombin activity, values were not used in this analysis.

2.2. Statistical Analysis

Of 37 cases analyzed, outcome was available only for 31 cases. One case had indeterminate cause of cirrhosis and was excluded, and 30 cases were used for our analysis.

Survival at 5 months determined the patient subset and common pathophysiologic factors like DM, HTN, HLD, CAD, and CHF; lab values comprising of prothrombin time, total bilirubin, AST, ALT, ALK P, and GGT were compared between these two subsets. Logistic regression was used for comparing continuous independent variables, and chi-square test was used for comparing categorical variables. When the expected frequency was less than five, Fisher’s exact test was used for categorical variables. Cox proportional hazards ratios were employed in determining prognosis. All statistical tests were two tailed with significance set at 95% level ( ). STATA 11 IC software was used for statistical analysis.

3. Results

AST was significantly lower ( ) in patients who survived at 5 months (mean 103.33 IU/L) compared to nonsurvivors (mean 216.88 IU/L). AST levels overall were raised in both groups and ranged between 64 IU/L and 734 IU/L (Tables 2 and 3). There was no significant difference in the levels of prothrombin time, total bilirubin, ALT, ALK P, and GGT between the two groups. The prevalence of DM, HTN, HLD, CAD, and CHF was similar in these two groups. Mean cumulative dose in cases of AIC was 280 g with a median latency period of 2.92 years and was statistically nonsignificant.

All cases, Survivors
Nonsurvivors at 5 months

Median age (years) 68 (56–85)69.5 (56–83) 67.5 (58–85) 0.84
Male/female 18/127/511/71.00
Diabetes 210.23
HTN 251.00
Hyperlipidemia 231.00
CAD 5110.26
CHF 380.39
>200 mg/<200 mg Amiodarone dose given18/125/713/50.33
Latency period 2.92 (0.5–12) 3.06 (0.5–5.5) 2.54 (1–12)0.45
Cumulative dose279.92 (55–1241)279.92 (55–657)465 (165–1241)0.07
Prothrombin time 16.76 (11–39) 13.68 (11–17) 18.92 (11–39) 0.08
Bilirubin (micromole/liter)55.73 (9–481)71.67 (9–481)46.16 (12–142)0.53
AST177.58 (64–734) 103.33 (38–317)216.88 (64–734)0.03
ALK P352.96 (73–1451)331.5 (73–1451)365.59 (119–854) 0.78
Albumin28 (11–39)31 (23–39)26.91 (11–38) 0.32
ALT134.59 (32–781)92.1 (32–237) 170 (35–781) 0.16
GGT 569 (133–1493)640.33 (230–1231)538.43 (133–1493)0.74

refers to the number of patients in each group. Not all studies had data on all variables.
Median values given for latency period, and for all other variables, mean values are given.

Hazard ratio95% Confidence interval

Age0.99(0.94–1.05) 0.80
Sex 0.90(0.34–2.37)0.83
Diabetes 0.40(0.05–3.08)0.32
>200 mg/ <200 mg Amiodarone dose given1.35(0.48–3.84)0.56
Latency period 1.12 (0.90–1.38) 0.33
Cumulative dose1.001(0.999–1.003)0.09
Prothrombin time 1.04 (0.97–1.11)0.36
Bilirubin (micromole/liter)0.998(0.99–1.00)0.45
AST1.003 (1.001–1.006)0.03
ALK P1.000(0.999–1.001)0.98
ALT1.002(0.999–1.005) 0.21
GGT 1.000(0.998–1.002)0.87

Not all studies had data on all the variables.

The risk of dying at 5 months was marginally higher in patients with high aspartate aminotransferase. Hazard ratio for death is 1.003 (95% CI ranging between 1.001 and 1.006). This finding was statistically significant ( ) (Table 3). Prothrombin time, total bilirubin, ALT, ALK P, GGT, and coexistence of DM, HTN, HLD, CAD, and CHF did not predict survival. Results are summarized in Tables 2 and 3.

Median age at the time of diagnosis of AIC was 68 years for all cases, 69.5 among survivors, and 67.5 among nonsurvivors. Most cases of AIC were observed among females though most who died were males.

4. Discussion

4.1. Pathogenesis of AIC

Amiodarone is a lipophilic agent [5] and tends to accumulate in lipid-laden organelles such as the liver. Amiodarone causes liver damage by different pathogenic mechanisms, one of which may include phospholipidosis. There are two different mechanisms by which amiodarone causes phospholipidosis. (I) Amiodarone and its metabolites (N-desmethylamiodarone) accumulate in lysosomes of hepatocytes, bile duct epithelium, and kupffer cells and leads to inhibition of phospholipase A1 and A2 [35, 36], which thereby inhibits removal of lysosomal lipids and leads to phospholipidosis. (II) Amiodarone binds to phospholipids in lysosomes and forms a nondigestible complex [37, 38], which leads to phospholipidosis.

The exact mechanism of phospholipidosis-induced liver damage is unclear. Phospholipidosis has been reported to occur within two months of starting amiodarone therapy [6, 7]. Phospholipidosis occurs in a much larger percentage of patients receiving amiodarone [5] than actual hepatocellular damage (1% to 3%), which suggests that phospholipidosis may or may not have a role in the pathogenesis of AIC. In fact, development of phospholipidosis is considered a marker for accumulation of amiodarone [4] rather than a marker of hepatotoxicity.

Leakage [3, 4, 39, 40] of proteolytic enzymes from abnormal lysosomes represents another pathogenic mechanism of amiodarone-induced liver damage. Leakage of proteolytic enzymes may contribute to the elevation of aminotransferases and may over time lead to hepatic necrosis, fibrosis, and eventually cirrhosis.

Immunologic mechanisms may be involved in pathogenesis in instances of amiodarone-induced acute hepatitis in patients with positive Coombs’ test [41].

Amiodarone-induced inhibition of cellular respiration is another possible pathogenic mechanism for amiodarone-induced liver damage. Impairment of mitochondrial β-oxidation and uncoupling of oxidative phosphorylation leads to the formation of reactive oxygen species, which in turn has a role in the development of AIC [4244].

4.2. Pathology

On histologic examination of biopsy samples obtained from amiodarone-induced cirrhotic patients; leukocytic infiltrate and strikingly high Mallory’s hyaline along with other usual pathologic findings of cirrhosis are noted. High Mallory’s hyaline or Mallory’s bodies are suggestive of AIC.

Mallory’s hyaline is an eosinophilic inclusion made up of intermediate keratin filaments. Mallory’s hyaline is not specific for AIC and may be seen in primary biliary cirrhosis, alcoholic cirrhosis or hepatitis, nonalcoholic cirrhosis, hepatocellular cancer, morbid obesity, and some other conditions. Mallory hyaline in AIC is present in zone 1 of acinus, whereas in alcoholic liver disease they are located usually in zone 3 [4].

Histologic findings in patients with amiodarone-induced hepatic damage are similar to those caused by alcohol [4, 45]. The complete pathologic spectrum of alcoholic like liver injury due to amiodarone includes micro- and macrovesicular steatosis, steatonecrosis, mega mitochondria, portal inflammation, fibrosis, and cirrhosis. Amiodarone-associated epithelloid granulomas have also been reported [8].

Presence of phospholipids laden lamellar lysosomal inclusion bodies on electron microscopy [1, 4, 37] is another characteristic pathologic finding of AIC of liver. Yap et al. observed that amiodarone-induced lysosomal inclusions developed in nearly 100% of patients at a period of 2 weeks [46].

4.3. Diagnostic Workup

AIC is a diagnosis of exclusion. Extensive workups are normally done to exclude other diagnoses including viral etiology, Wilson’s disease, hemochromatosis, alpha 1 antitrypsin deficiency, alcoholic hepatitis, congestive liver damage, autoimmune liver pathologies, and hepatitis due to other drugs and toxins. There is no specific diagnostic lab test for AIC of the liver.

Furthermore, there is no specific imaging characteristic for AIC of the liver although sometimes increased liver density may be noted on a noncontract CT scan of liver. Increased liver density is thought to be secondary to increased iodine content in the liver. Amiodarone has two atoms of iodine that constitute 37% of molecular weight of the drug. Enhanced density due to amiodarone is reversible upon discontinuation of amiodarone [47].

Diagnosis of AIC is usually based on liver biopsy. Mallory hyaline and lamellar lysosomal inclusions are typical of amiodarone-induced liver damage.

4.4. Presentation

Amiodarone-induced liver damage may present as Reye’s syndrome in kids [9] and may present as asymptomatic elevation of liver enzymes in adults. Asymptomatic liver enzyme elevation occurs in 25% of the population treated with amiodarone [1] and is usually reversible upon discontinuation of therapy [45]. Normalization of liver enzymes may take place anywhere from three weeks to nine months [48]. Symptomatic hepatic dysfunction occurs in less than 1% of the population treated with amiodarone and includes acute and chronic liver injuries. Acute liver injury includes acute hepatitis (idiosyncratic reaction may be involved in pathogenesis), whereas chronic liver injury includes steatosis (macro and microvesicular steatosis) and cirrhosis.

5. General Discussion

Amiodarone is an iodinated benzofuran derivative, lipophilic drug with a half-life of 35–110 days and a very large volume of distribution (VD). Amiodarone comes as number eight in drugs that cause drug-related hepatic fatalities [9]. Major metabolite of amiodarone, N-desmethylamiodarone, is not only pharmacologically active but has a longer elimination half-life and a larger VD than the parent drug [1, 10, 4951]. Amiodarone and N-desmethylamiodarone may be detected even months after stopping the drug [51] as amiodarone accumulates in lipid reservoirs and is released slowly from these reservoirs. Due to this storage mechanism, amiodarone concentration in liver may be as high as 500-fold of serum level [52]. Based on these facts, damaging effects of amiodarone may persist up to one year after complete discontinuation of therapy [1]. Since amiodarone is mainly metabolized in the liver, any damage to the liver from any cause would hamper amiodarone metabolism and lead to a vicious cycle of accumulation of amiodarone and further amiodarone-induced hepatic damage [53].

Why some patients develop cirrhosis or hepatic damage as a side effect of amiodarone is not entirely clear. It has been suggested that differing sensitivity to amiodarone toxicity in population may exist [54]. Most patients who developed AIC usually used amiodarone PO 200 mg or more per day for more than 1-2 years. In light of the above-mentioned fact, researchers propose that the total cumulative dose of amiodarone may be important in estimating the risk of irreversible liver injury [55]. A cumulative dose of 380 g is suggested to associate with hepatotoxicity leading to cirrhosis [50]. Other prospective studies showed that amiodarone hepatic toxicity correlates to steady state serum levels of amiodarone rather than daily or cumulative doses [54, 5658]. For example, if daily dosage of amiodarone during long-term therapy is reduced, despite increasing lifetime cumulative dose, the steady state serum concentration will still be reduced and thus decreasing risk of hepatotoxicity from amiodarone. Researchers have suggested that amiodarone level less than 1.5 mg/L has a minimal risk of hepatotoxicity, whereas a level above 2.5 mg/L may have a risk up to 6% for hepatotoxicity [5]. Patients with lower eject fraction may be more prone to hepatotoxic effects of amiodarone as suggested by Tisdale et al. [59]. Although it seems logical that patients with preexisting liver damage may be more prone to amiodarone-induced AIC of the liver, results by Kum et al. suggest otherwise [60].

Besides chronic liver injury due to prolonged amiodarone use, acute hepatic side effects from amiodarone intravenous loading dose have been reported and are thought to be caused by polysorbate 80; a solvent used in drug preparation. This form of acute hepatotoxicity usually improves with discontinuation of medication, although fatalities have been reported [61].

To prevent amiodarone-induced cirrhosis, the amiodarone should be titrated to lowest effective dose. Patients should have baseline LFTs and then periodic monitoring of LFTs while on amiodarone (at 1, 3, and 6 months and then semiannually) [62]. Studies have suggested that baseline LFTs monitoring is performed only in 44% of patients, and a follow-up testing at 6 months and 1 year is done in only 41% and 35% of patients, respectively [63]. Patients found to have asymptomatic elevation of transaminases while on amiodarone should have a thorough investigation of the cause [56]; repeated testing may be necessary before labeling diagnosis of amiodarone-induced hepatotoxicity [45]. According to some authors, discontinuation of amiodarone for liver-related toxicity may not be necessary [57]. Kum et al. noted in their study that 50% of patients with increased transaminases while on amiodarone did not improve even after 1.5 years of drug withdrawal [60]. However, most authors suggest that if aminotransferases are two times above baseline value or above three times the upper normal limit, then amiodarone either should be reduced or discontinued [58, 61, 64, 65]. Withdrawal of drug, when irreversible liver damage has already occurred, has a very little effect on restoration of liver function. Despite what is said, discontinuation of amiodarone for liver-related hepatotoxicity may not be necessary except in cases to prevent irreversible loss of liver function [11]. After discontinuation of amiodarone, monitoring period should continue for at least one year as the damaging effect of amiodarone might persist. Patients on amiodarone should be advised to avoid any potentially hepatotoxic agent to prevent additive hepatic damage. Discontinuation of amiodarone is reported to occur in nearly 20–40% of patients if changes in aminotransferases are detected during amiodarone therapy [66].

To date, the role of routine monitoring of amiodarone or its metabolite’s serum levels for predicting hepatic damage is not well established. Nonetheless, there are numerous patients who may develop AIC without any abnormality in liver enzymes. Such patient population will not be detected until very late. Routine imaging may have a role in this subset of patients, but there is no study to support this.

Based on our review (Table 1), we noted that AIC is extremely rare. However, once the diagnosis is established, the mortality risk may be as high as 60% at 5 months. The most common cause of death among reported cases was due to liver- and GI-related complications. Ethnic predisposition to AIC could not be determined due to lack of the published literature. The most common symptoms reported were generalized weakness, abdominal pain, and abdominal distension.

A cumulative dose of 380 g has been suggested to associate with cirrhosis. By reviewing published cases, we realize that cirrhosis has been reported to occur with a cumulative dose as low as 55 g [9]. Why some patients with a cumulative dose of 200 g develop cirrhosis and others do not until cumulative dose crosses above 1000 g is unclear, but it does suggest that it may be a steady state concentration rather than cumulative dose that may be important in predicting risk of cirrhosis. The diagnosis in most patients was made by liver biopsy. Although Mallory hyaline and lysosomal inclusions are characteristic features of amiodarone-induced cirrhosis, the dilemma is that the above-mentioned pathologic characteristics may be identified in patients on amiodarone who do not have cirrhosis. Liver biopsy alone for diagnosis of AIC may not be enough. In fact, a thorough evaluation for all possible causes of cirrhosis should be done. Once all possible causes of cirrhosis have been ruled out, then only the presence of Mallory hyaline and lysosomal inclusions in cirrhotic liver may be suggestive of AIC of the liver. In all published cases, a thorough investigation for the cause of cirrhosis was carried out. In most published cases, obesity, DM, and ethanol consumption were given special attention to rule out the possibility of alcoholic and nonalcoholic steatohepatitis (NASH). Risk factors for development of amiodarone-induced hepatotoxicity and cirrhosis have not been clearly defined. Whether it is cumulative dose or steady state concentration of amiodarone that predicts risk of cirrhosis has not been determined. In most patients even after discontinuation of amiodarone, toxicity effects did not subside. Majority of patients have had amiodarone-related hepatotoxicity before onset of cirrhosis leading to a decrease in dose or discontinuation of the drug. However, the drug was restarted for various reasons, which unfortunately lead to cirrhosis. Although AST and ALTs are said to be mainly elevated in amiodarone-related hepatotoxicity and not the ALK P or GGT [56], our analysis suggests otherwise. According to our analysis, the only statistically significant variable different among survivors versus nonsurvivors at 5 months was the level of AST at time of diagnosis of AIC. We suggest that if patients on amiodarone have a persistent increase in aminotransferases, a liver imaging and a liver biopsy should be done.

There is no treatment available for amiodarone-induced hepatotoxicity or cirrhosis besides discontinuation of the offending agent and switching to some other antiarrhythmic agent. Previously, antioxidants vitamin E and selenium have been tried without any success. We recommend against using antioxidants for counteracting amiodarone hepatotoxicity, as there is no strong scientific evidence for such practices.

We are aware that there are limitations in our study because of the smaller sample size, which may have affected our analysis. Future prospective studies using larger patient population may be able to identify predictors of survival in case of AIC.

6. Conclusion

Although amiodarone does have very serious and fatal effects on the liver, such effects are rare. With a closer monitoring and taking appropriate actions when prompted, amiodarone can be safely used on long-term basis. Further prospective studies are needed to identify predictors of AIC and of mortality or survival in cases of AIC. Role of routine imaging and biopsy of the liver in patients taking amiodarone is unclear; future studies are needed to address this issue.


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