Amiodarone-Induced Cirrhosis of Liver: What Predicts Mortality?

Table 1

𝑁	Age; Sex; Race	PMH other than arrhythmias, drugs	Presentation; Etoh use	Authors	Labs	Pathology	Duration and dosages	Outcome after diagnosis of AIC
1	63; M; W	CAD s/p CABG, DM, HLD, No etoh, (amiodarone, warfarin, aspirin, rosiglitazone, and lovastatin); No other hepatotoxic drugs	Abdominal distension	Puli et al. [2]	23.94; 114; ?; 23; 82	Micronodular cirrhosis, bridging fibrosis, lymphocytic infiltrate, macrophages, plasma cells, microvesicular steatosis, and lysosomal bodies on electron microscopy	600 mg/day for 10 days, then 200 mg/day for 22.5 months cumulative dose of approx. 141 g	Survived
2	81; F; —	Digitoxin, alpha methyldopa; No DM, and no etoh	Cirrhosis diagnosed during study	Guigui et al. [3]	15, 28; 186,; ?, 53; GGT 151,; PT 76%	Portal fibrosis, steatosis, PMN, myelin figures, dense deposits, and cirrhosis	120 months, cumulative dosage of 520 g	Could not establish an outcome
3	72; M; W	DM, HTN, and CKD; No etoh, (amiodarone,; simvastatin, and glipizide)	Ascites and fatigue	Atiq et al. [5]	32.49, 106, 147, ?, 75,; PT 20	Steatohepatitis, Mallory hyaline, neutrophilic infiltrate, and cirrhosis	200 PO mg/day * 3 years; Cumulative dose of approx. 219 g	Died during the same admission due to complication of liver disease
4	67; F; AA	CAD, CHF, and s/p AICD; No etoh	Confusion	Atiq et al. [5]	?; 377; 551; ?; 277; PT 12.7	Mallory hyaline, neutrophil infiltrate, pericellular/bridging fibrosis, and degenerating hepatocytes; (cirrhosis found on autopsy)	Low dose * 2 years	Died 2 weeks after the workup due to cardiopulmonary failure
5	63; M; —	COPD, DM, and hypothyroidism; (digoxin, furosemide, and thyroxin)	Abnormal LFTs on screening	Rigas et al. [6]	?; 59; 207; ?; 28	Portal, central, and sinusoidal fibrosis and loss of lobular architecture and regenerative nodules, central vein sclerosis, Mallory bodies, lysosomal inclusion, and cirrhosis	400 mg/day Amiodarone * 18 months; Cumulative dose 216	No information about the outcome
6	73; M; —	Heart failure, no significant etoh, complete right and left anterior hemiblock; (translated through Google)	Jaundice, hepatomegaly	Capron-Chivrac et al. [7]	269; 55; 708; 68; ?; 224; 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
7	70; F; —	—	Weight loos and blurred vision	Chaabane et al. [8]	—	Micronodular cirrhosis, steatohepatitis	200 mg/day * 15 years; Cumulative dose of approx. 1095 g	Could not establish an outcome
8	62; M; —	CAD, HTN, CHF, emphysema, pulmonary HTN, HLD, renal insufficiency, migraine, ulcerative colitis, cholelithiasis, and no etoh	Progressive weakness, abdominal discomfort, and jaundice	Anonymous [9]	51.3; 734; 119; 29; 781; PT 12.4	Micronodular cirrhosis with ballooning degeneration of hepatocytes and Mallory bodies, some steatosis	150–1000 mg/day, averaging 400 mg/day * 8.5 years Cumulative dose of approx. 1241 g	Died 2 weeks after stopping medicine, probably hepatic encephalopathy
9	73; M; —	Obesity, moderate alcohol intake	Fatigue, weakness	Anonymous [9]	34.2; ?; 115; ?; 67	Mallory bodies, minimal fatty change, and cirrhosis	Amiodarone 300 mg/day * approx. 6 months; Cumulative dose of approx. 55 g	Survived for more than 3 years
10	64; M; —	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; 149; 176; ?; 112; INR 2.4; GGT 277	Ballooned hepatocytes, Mallory bodies, fibrosis, phospholipidosis, inflammatory infiltrate, and cirrhosis	2.8 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
11	74; M; —	Ischemic heart disease, CVA, poliomyelitis, carotid endarterectomy, and peripheral neuropathy; Etoh Consumption = negligible	Muscle weakness, hepatomegaly	Gilinsky et al. [11]	133.4; 110; 275; 16; 231; PT 17	Fibrosis, Mallory hyaline, lysosomal inclusions,; amiodarone, and desmethylamiodarone conc. 0.6, 0.5 mg/L, respectively	Amiodarone; 300–600 mg/day * 28 months; Cumulative dose of approx. 378 g	Died despite discontinuation of therapy, probably liver failure
12	76; F; —	No significant past history other than recurrent SVTs	Abdominal pain, anorexia, and wasting	Tordjman et al. [12]	n; 225; 317; 29; ?	Mallory bodies, fibrosis, severely damaged hepatocytes, bile duct proliferation, and cirrhosis	200 mg daily * 5 years; Cumulative dose od approx. 365 g	Died 2 weeks after evaluation due to hepatic encephalopathy
13	77; F; —	—	Anorexia, abdominal pain, and malaise	Rene et al. [13]	20.52, 16; 324, 39; 10,; 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
14	79; M; —	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; 67; 216; 27; GGT 443	PMN infiltrate, reduplicating bile ducts in hepatic nodules, degenerating hepatocytes, Mallory bodies, extensive fibrosis, and cirrhosis	200 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
15	75; F; —	s/p MI, left ventricular aneurysm, and normal coronaries	Abnormal LFTs; —	Bach et al. [15]	?; 140; 850; ?; ?	Micronodular cirrhosis, portal fibrosis, Mallory bodies, ballooning hepatocytes, phospholipidosis, inflammatory cells, and lysosomal inclusions	800 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
16	63; F; —	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; 198; 301; 35; 86,; GGT 475; PT 20%	Postmortem liver biopsy showed incipient cirrhosis, portal fibrosis, inflammatory ductal infiltration and mixed leukocytic infiltration, steatosis, Mallory bodies, and acidophilic change	400 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
17	58; M; —	CAD, MI; (amiodarone, aspirin, furosemide, diltiazem, isosorbide dinitrate, digoxin, famotidine); No etoh, no herbs used	Abdominal distension and fatigue	Çoban et al.; [17]	?; 64; ?; 11; ?; PT 16.9; GGT 133	Polymorph nuclear infiltrate, ductal proliferation, fibrosis, bridging necrosis, vacuolar degeneration, lysosomal inclusions (73+), and cirrhosis	200 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
18	85; M; —	Ischemic heart disease; No obesity, no etoh, and no DM	Cardiac congestion	Oikawa; et al. [18]	20.52; 81; 452; ?; 35; 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
19	49; M; —	Rheumatic heart disease, endocarditis, HTN, and DM; (amiodarone, acebutolol, and glibenclamide)	Pain in RUQ and fever	Lamproye et al. [19]	n; n; n; 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
20	56; F; —	s/p pacemaker, goiter; No DM, no obesity, and no etoh abuse; (digoxin, acenocoumarin, and amiodarone )	—	Babany; et al. [20]	15; 38; 73; ?; 63; 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
21	83; F; —	Angina pectoris; No DM, no obesity, and no etoh abuse; (amiodarone )	Hepatomegaly	Babany; et al. [20]	15; 63; 139; ?; 139; 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
22	68; F; —	Commissurotomy for mitral stenosis; No DM, No obesity, No etoh abuse; (hydroxyzine, amiodarone, tiodomarol, and clonazepam)	Abnormal LFTs	Babany; et al. [20]	11; 43; 88; ?; 60; 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
23	68; M; —	No sig. PMH; (isosorbide, warfarin); No etoh	No significant history besides arrhythmia	Rinder; et al. [21]	?; 180; 422; ?; ?	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 g	Died one month after discontinuation of drug due to hepatic encephalopathy and hepatorenal syndrome
24	64; F; —	WPW syndrome, no significant PMH; (amiodarone, diuretic, and beta blocker); No etoh used	Weakness, bedridden, and ascites	Shepherd et al. [22]	44; 172; 150; ?; ?	Micronodular cirrhosis with extensive necrosis of regenerating nodules, fibrosis, and swollen hepatocytes	600 mg/day * 4 years; Cumulative dose of approx. 876 g	Died due to bronchopneumonia, diagnosis of cirrhosis made at postmortem
25	76; M; —	Ischemic heart disease, pulmonary edema; (amiodarone, isosorbide dinitrate, furosemide, and potassium); No etoh	—	Jeyamalar et al. [23]	?; 66; 148; 35; 69; 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
26	67; M; —	Hypertrophic obstructive cardiomyopathy, s/p ICD, no obesity, no etoh, and no DM	B/L hand tremor	Ishida et al. [24]	32.49; 88; 463; ?; 167; 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
27	57; M; —	MI	Lethargy, abdominal distension	Harrison and Elias [25]	—	Micronodular cirrhosis, proliferating bile ducts, neutrophil infiltrate, Ballooning degeneration of hepatocytes, Mallory hyaline, lysosomal inclusion bodies, and epithelioid granulomas	200 mg twice/day * 4 years 6 months; Cumulative dose of approx. 657 g	Needed liver transplant
28	77; F; —	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; 54; 216; 39; 32; INR 1.2; GGT 230	Lymphocytic infiltration, macro/microvesicular steatosis, Mallory hyaline, ballooning degeneration, pericellular fibrosis, cirrhosis, and bridging fibrous septa	Amiodarone 200 mg/day * 3 years; Cumulative dose of approx. 219 g; (No herbal medicines)	Survived more than 6 months confirmed with author
29	77; M; —	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; 223; 459; 30; 124; 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
30	62; F; W	No etoh	Weakness and jaundice	Snir et al. [28]	92.3, 520; 329, 22; 131; 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
31	84; F; W	HTN, CHF, obesity; (amiodarone, felodipine, furosemide, potassium supplement, aspirin, and cisapride); No other drugs; No etoh	Dark brown urine for 7 days	Chang et al. [29]	142; 130; 610; 30; 50	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
32	72; M; Korean	HTN; (amiodarone, felodipine, HCTZ, and aspirin); No etoh; EF 70%	Sudden onset abdominal distension	Sung and Yoon [30]	46.1; 317; 137; 27; 237; GGT 385; INR 1.32	Cirrhosis, polymorphnuclear infiltrate, Mallory bodies, ballooning degeneration, and lysosomal inclusions	Amiodarone 200 mg/day * 5 years; Estimated cumulativ dose = 365 g	Survived, amiodarone discontinued, and other antiarrhythmic started
33	64; F; —	Unstable recurrent angina, ventricular aneurysm, and MI; No etoh, no DM	For surgical resection of ventricular aneurysm	Poucell et al. [31]	12; ?; 188; 38; 82; PT 11	Micronodular cirrhosis, Mallory bodies, ballooning, macrovesicular steatosis, fibrosis, inflammation, pleomorphic mitochondria, and lysosomal inclusion	600 mg * 5 days/wk * 2 years; Cumulative dose of 288	Died shortly after liver biopsy, cause unknown may be MI, and no postmortem
34	62; M; —	Etoh 85 g/day, s/p MI, CAD	Hepatomegaly despite normal LFTs * 1 year, presented for liver biopsy	Poucell et al. [31]	8.5; ?; 98; 37; 80; PT 11	Micro nodular cirrhosis, Mallory bodies, ballooning, macro vesicular steatosis, fibrosis, inflammation, pleomorphic mitochondria, lysosomal inclusion	600 mg * 5 days/wk * 2 years; Cumulative dose 288 g	Continued on amiodarone and survived
35	70; M; —	Alcoholic cardiomyopathy, adrenal insufficiency; (amiodarone, hydrocortisone); Etoh was DC when heart problem diagnosed	Jaundice, pruritus, and deterioration of condition	Salti et al. [32]	481; 95; 1451; ?; 92; 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
36	77; F; —	A fib	Weakness, nausea, vomiting, abdominal distension, lethargy, and confusion	Chandraprakasam and Whitcraft [33]	?; 192; 122; ?; 162	Neutrophilic satellitosis, Mallory hyaline, foam cells representing phospholipidosis, macrovesicular steatosis, and cirrhosis	Amiodarone 200 mg/day * 4 years; Cumulative dose = 292	No information about outcome
37	68; M; —	Depression, heart failure; (digoxin, doxepin, and bumetanide)	Vomiting and muscle weakness of one month duration	Lim et al. [34]	28; 142; 854; 29; ?	—	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

𝑁: 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.