Lesão hepática induzida por ervas e suplementos alimentares: uma análise agrupada de estudos de caso

ASSIS, Michelle Hoff de; ALVES, Bruna Cherubini; LUFT, Vivian Cristine; DALL’ALBA, Valesca

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Sumário

REVIEW • Arq. Gastroenterol. 59 (04) • Oct-Dec 2022 • https://doi.org/10.1590/S0004-2803.202204000-84 copiar

Lesão hepática induzida por ervas e suplementos alimentares: uma análise agrupada de estudos de caso

Autoria SCIMAGO INSTITUTIONS RANKINGS

RESUMO

Contexto:

O consumo de ervas medicinais e suplementos alimentares é muito popular no mundo. Contudo, esses produtos não são inócuos e sua ingestão pode causar danos à saúde, especialmente dano hepático.

Objetivo:

Descrever os casos clínicos de lesão hepática induzida por ervas e suplementos alimentares, identificando os principais produtos envolvidos e as manifestações relacionadas a eles.

Métodos:

A busca na literatura foi realizada na base de dados PubMed, EMBASE, Google Escolar e LILACS usando as seguintes palavras-chaves: “Chemical and Drug-Induced Liver Injury”, “Dietary Supplements”, e “Herbal”, incluindo seus sinônimos.

Resultados:

Foram incluídos 189 artigos no estudo, totalizando 428 casos clínicos de lesão hepática induzida por drogas. Os agentes de lesão hepática mais frequentes foram produtos Herbalife, associados a 50 casos, Polygonum Multiflorum, a 25 casos, produtos Hydroxycut e chá verde, ambos associados a 19 casos, e produtos Hydroxycut e chá verde, associados a 16 casos. A maioria dos indivíduos necessitou de hospitalização (82,6%) e um número importante de casos evoluiu para óbito (3,6%), transplante hepático (8,9%) ou doença hepática crônica (1,9%).

Conclusão:

O uso indiscriminado de suplementos alimentares e ervas foi associado com um número alarmante de casos de lesão hepática. Os mecanismos pelos quais cada um dos produtos causa danos ao fígado ainda precisam ser melhor compreendidos, mas esta revisão é um alerta sobre o risco associado ao uso de produtos considerados inofensivos por grande parte da população.

Palavras-chave:
Lesão hepática induzida por drogas; hepatotoxicidade; suplementos dietéticos; interações erva-droga

Author/Year	Sex/ age	Product (s)	Daily dose	Latency (weeks)	Clinical presentations	Elevated liver markers	Type of liver injury	Outcome
Sheikh, 1997¹⁹19. Sheikh NM, Philen RM, Love LA. Chaparral-associated hepatotoxicity. Arch Intern Med. 1997;157:913-9.	F/59	Chaparral capsules	1800 mg	52	Abdominal pain, nausea/vomiting, jaundice, dark urine, light stools	ALT, AST, ALP, TB	Cholestatic	Transplant
Chow, 2008²⁰20. Chow EC, Teo M, Ring JA, Chen JW. Liver failure associated with the use of black cohosh for menopausal symptoms. Med J Aust. 2008;188:420-2. http://doi.org/10.5694/j.1326-5377.2008.tb01691.x. https://doi.org/10.5694/j.1326-5377.2008...	F/51	Preparation of black cohosh	40 mg	8	Weakness, nausea/vomiting, jaundice, ascites	ALT, AST, ALP, GGT, TB	Hepatocellular	Transplant
Lynch, 2006²¹21. Lynch CR, Folkers ME, Hutson WR. Fulminant hepatic failure associated with the use of black cohosh: a case report. Liver Transpl. 2006;12:989-92. http://doi.org/10.1002/lt.20778. https://doi.org/10.1002/lt.20778...	F/54	Black Cohosh	1000 mg	34	Weakness, encephalopathy	ALT, AST, ALP, GGT, TB	Mixed	Death
Jung, 2011²²22. Jung KA, Min HJ, Yoo SS, Kim HJ, Choi SN, Ha CY, et al. Drug-Induced Liver Injury: Twenty Five Cases of Acute Hepatitis Following Ingestion of Polygonum multiflorum Thunb. Gut Liver. 2011;5:493-9. http://doi.org/10.5009/gnl.2011.5.4.493. https://doi.org/10.5009/gnl.2011.5.4.493...	M/57	Polygonum multiflorum	UN	4	Fever, jaundice, encephalopathy	ALT, ALP, TB	Mixed	Death
Jung, 2011²²22. Jung KA, Min HJ, Yoo SS, Kim HJ, Choi SN, Ha CY, et al. Drug-Induced Liver Injury: Twenty Five Cases of Acute Hepatitis Following Ingestion of Polygonum multiflorum Thunb. Gut Liver. 2011;5:493-9. http://doi.org/10.5009/gnl.2011.5.4.493. https://doi.org/10.5009/gnl.2011.5.4.493...	M/24	Polygonum multiflorum	UN	2	Jaundice	ALT, ALP, TB	Hepatocellular	Transplant
Becker, 2019²³23. Becker MW, Lourencone EMS, De Mello AF, Branco A, Rodrigues Filho EM, Blatt CR, et al. Liver transplantation and the use of KAVA: Case report. Phytomedicine. 2019;56:21-6. http://doi.org/10.1016/j.phymed.2018.08.011. https://doi.org/10.1016/j.phymed.2018.08...	F/45	Kava herb	100 mg	7	Nausea/vomiting, Jaundice, encephalopathy	ALT, AST, TB	Hepatocellular	Transplant
Campo, 2002²⁴24. Campo JV, McNabb J, Perel JM, Mazariegos GV, Hasegawa SL, Reyes J. Kava-induced fulminant hepatic failure. J Am Acad Child Adolesc Psychiatry. 2002;41:631-2. http://doi.org/ 10.1097/00004583-200206000-00001. https://doi.org/10.1097/00004583-2002060...	F/14	Preparation of Kava	NI	13	Nausea/vomiting, weakness	ALT, AST, GGT, TB	Hepatocellular	Transplant
MMWR, 2002²⁵25. Centers for Disease Control (CDC). Chaparral-induced toxic hepatitis-California and Texas, 1992. MMWR Morb Mortal Wkly Rep. 1992;41:812-4. http://doi.org/10.1097/00004583-200206000-00001. https://doi.org/10.1097/00004583-2002060...	F/14	Kava Products	4 caps	17	Nausea/vomiting, jaundice, weakness	ALT, AST, GGT, TB	Hepatocellular	Transplant
Escher, 2001²⁶26. Escher M, Desmeules J, Giostra E, Mentha G. Hepatitis associated with Kava, a herbal remedy for anxiety. BMJ. 2001;322:139. http://doi.org/10.1136/bmj.322.7279.139. https://doi.org/10.1136/bmj.322.7279.139...	M/50	Capsules of kava extracts	4 caps	8	Jaundice, weakness, dark urine, encephalopathy	ALT, AST, ALP, GGT, TB	Hepatocellular	Transplant
Teschke, 2008²⁷27. Teschke R, Schwarzenboeck A, Hennermann KH. Kava hepatotoxicity: a clinical survey and critical analysis of 26 suspected cases. Eur J Gastroenterol Hepatol. 2008;20:1182-93. http://doi.org/10.1097/MEG.0b013e3283036768.	F/60	Kava extract	UN	52	Abdominal pain, jaundice, weakness	UN	Mixed	Transplant
Teschke, 2008²⁷27. Teschke R, Schwarzenboeck A, Hennermann KH. Kava hepatotoxicity: a clinical survey and critical analysis of 26 suspected cases. Eur J Gastroenterol Hepatol. 2008;20:1182-93. http://doi.org/10.1097/MEG.0b013e3283036768.	M/50	Kava extract	UN	8	Abdominal pain, jaundice, weakness	UN	Hepatocellular	Transplant
Fong, 2010²⁸28. Fong TL, Klontz KC, Canas-Coto A, Casper SJ, Durazo FA, Davern TJ, et al. Hepatotoxicity due to hydroxycut: a case series. Am J Gastroenterol . 2010;105:1561-6. http://doi.org/10.1038/ajg.2010.5. https://doi.org/10.1038/ajg.2010.5...	M/20	Hydroxycut	UN	13	Nausea/vomiting, jaundice, weakness, encephalopathy	ALT, AST, TB	UN	Death
Fong, 2010²⁸28. Fong TL, Klontz KC, Canas-Coto A, Casper SJ, Durazo FA, Davern TJ, et al. Hepatotoxicity due to hydroxycut: a case series. Am J Gastroenterol . 2010;105:1561-6. http://doi.org/10.1038/ajg.2010.5. https://doi.org/10.1038/ajg.2010.5...	NI/NI	Hydroxycut	UN	52	Nausea/vomiting	ALT, AST, ALP, TB	Hepatocellular	Transplant
Fong, 2010²⁸28. Fong TL, Klontz KC, Canas-Coto A, Casper SJ, Durazo FA, Davern TJ, et al. Hepatotoxicity due to hydroxycut: a case series. Am J Gastroenterol . 2010;105:1561-6. http://doi.org/10.1038/ajg.2010.5. https://doi.org/10.1038/ajg.2010.5...	NI/NI	Hydroxycut	UN	8	Abdominal pain, nausea/vomiting, weakness	ALT, AST, ALP, TB	Hepatocellular	Transplant
Fong, 2010 (28)	NI/NI	Hydroxycut	UN	4	Nausea/vomiting, weakness	ALT, AST, ALP, TB	Hepatocellular	Transplant
Elinav, 2007²⁹29. Elinav E, Pinsker G, Safadi R, Pappo O, Bromberg M, Anis E, et al. Association between consumption of Herbalife nutritional supplements and acute hepatotoxicity. J Hepatol. 2007;47:514-20. http://doi.org/10.1016/j.jhep.2007.06.016. https://doi.org/10.1016/j.jhep.2007.06.0...	F/33	Protein mix drink, Herbalifeline (fish oil concentrate), Thermojetics herbal mix (tea), Thermojetics Green and beige capsules (herbal extract), Tang Kuei Plus, Instant drink with plant extracts, Sesame and Herbs tablets, Safflower oil capsules	UN	13	Jaundice, weakness	UN	Hepatocellular	Transplant
Favreau, 2002³⁰30. Favreau JT, Ryu ML, Braunstein G, Orshansky G, Park SS, Coody GL, et al. Severe hepatotoxicity associated with the dietary supplement LipoKinetix. Ann Intern Med. 2002;136:590-5. http://doi.org/10.7326/0003-4819-136-8-200204160-00008. https://doi.org/10.7326/0003-4819-136-8-... ,³¹31. Scott BA, Troppmann C, Rossaro L. Hepatotoxicity associated with a dietary supplement. Ann Intern Med . 2003;138:49. http://doi.org/10.7326/0003-4819-138-8-200304150-00035-w1. https://doi.org/10.7326/0003-4819-138-8-...	F/20	Lipokinetix	UN	2	Abdominal pain, fever, jaundice, encephalopathy	ALT, AST, TB	Hepatocellular	Transplant
Scott, 2003³²32. Neff GW, Reddy KR, Durazo FA, Meyer D, Marrero R, Kaplowitz N. Severe hepatotoxicity associated with the use of weight loss diet supplements containing ma huang or usnic acid. J Hepatol. 2004;41:1062-4. http://doi.org/10.1016/j.jhep.2004.06.028. https://doi.org/10.1016/j.jhep.2004.06.0...	F/24	Lipokinetix	UN	13	Nausea/vomiting, jaundice, encephalopathy	ALT, AST, TB	Hepatocellular	Transplant
Neff, 2004³³33. Foley S, Butlin E, Shields W, Lacey B. Experience with OxyELITE pro and acute liver injury in active duty service members. Dig Dis Sci. 2014;59:3117-21. http://doi.org/10.1007/s10620-014-3221-4. https://doi.org/10.1007/s10620-014-3221-...	F/32	Lipokinetix	UN	2	UN	ALT, AST, TB	Hepatocellular	Transplant
Foley, 2014 (34)	F/45	OxyELITE Pro	UN	104	Jaundice, weakness, encephalopathy	ALT, AST, ALP, TB	UN	Transplant
Foley, 2014³⁴34. Roytman MM, Porzgen P, Lee CL, Huddleston L, Kuo TT, Bryant-Greenwood P, et al. Outbreak of severe hepatitis linked to weight-loss supplement OxyELITE Pro. Am J Gastroenterol . 2014;109:1296-8. http://doi.org/10.1038/ajg.2014.159. https://doi.org/10.1038/ajg.2014.159...	M/28	OxyELITE Pro	UN	8	Jaundice, weakness encephalopathy	ALT, AST, TB	UN	Transplant
Roytman, 2014 (35)	M/22	New OxyElite Pro	UN	2	Abdominal pain, nausea/vomiting, jaundice, weakness, encephalopathy	ALT, ALP, TB	UN	Transplant
Roytman, 2014³⁵35. Johnston DI, Chang A, Viray M, Chatham-Stephens K, He H, Taylor E, et al. Hepatotoxicity associated with the dietary supplement OxyELITE Pro - Hawaii, 2013. Drug Test Anal. 2016;8:319-27. http://doi.org/10.1002/dta.1894. https://doi.org/10.1002/dta.1894...	F/48	New OxyElite Pro	UN	4	Abdominal pain, nausea/vomiting encephalopathy	ALT, ALP, TB	UN	Death
Johnston, 2016³⁶36. Heidemann LA, Navarro VJ, Ahmad J, Hayashi PH, Stolz A, Kleiner DE, Fontana RJ. Severe Acute Hepatocellular Injury Attributed to OxyELITE Pro: A Case Series. Dig Dis Sci . 2016;61:2741-8. http://doi.org/10.1007/s10620-016-4181-7. https://doi.org/10.1007/s10620-016-4181-...	F/42	New OxyELITE Pro	UN	UN	Nausea/vomiting, encephalopathy	ALT, AST, ALP, TB	UN	Death
Roytman, 2014³⁵35. Johnston DI, Chang A, Viray M, Chatham-Stephens K, He H, Taylor E, et al. Hepatotoxicity associated with the dietary supplement OxyELITE Pro - Hawaii, 2013. Drug Test Anal. 2016;8:319-27. http://doi.org/10.1002/dta.1894. https://doi.org/10.1002/dta.1894...	F/31	New OxyElite Pro; Garcinia Cambogia; Cellucor Super HD; HCA Supreme	UN	4	Nausea/vomiting weakness, jaundice, encephalopathy	ALT, ALP, TB	UN	Transplant
Heidemann, 2016³⁶36. Heidemann LA, Navarro VJ, Ahmad J, Hayashi PH, Stolz A, Kleiner DE, Fontana RJ. Severe Acute Hepatocellular Injury Attributed to OxyELITE Pro: A Case Series. Dig Dis Sci . 2016;61:2741-8. http://doi.org/10.1007/s10620-016-4181-7. https://doi.org/10.1007/s10620-016-4181-...	F/46	OxyELITE Pro; Stacker	1 cap	17	Jaundice	ALT, ALP, TB	Hepatocellular	Transplant
Heidemann, 2016 (36)	M/36	OxyELITE Pro; Ravage; Hydroxycut	3 cap	31	Jaundice	ALT, ALP, TB	Hepatocellular	Transplant
Sheikh, 1997¹⁹19. Sheikh NM, Philen RM, Love LA. Chaparral-associated hepatotoxicity. Arch Intern Med. 1997;157:913-9.	F/38	Chaparral capsules; multivitamins; folic acid; calcium	UN	UN	UN	TB	UN	Transplant
Perera, 2013³⁷37. Perera NJ, Steinbeck KS, Shackel N. The adverse health consequences of the use of multiple performance-enhancing substances--a deadly cocktail. J Clin Endocrinol Metab. 2013;98:4613-8. http://doi.org/10.1210/jc.2013-2310. https://doi.org/10.1210/jc.2013-2310...	M/35	anabolic steroid; T propionate; nandrolone decanoate, L-glutamine; leucine, protein powder; vitamin C; zinc	UN	UN	Abdominal pain, Nausea/vomiting, jaundice, pruritus	AST, ALT, ALP, GGT, TB	Mixed	Death

	Herbal products (n=209)	Dietary supplements (n=202)	Steroids (n=17)	Total (N=428)	P-value
Age (Years)	49 (39-60)	42 (31-53)	31 (26-37.5)	45 (33-56)	<0.001²
Sex (male), n (%)	67 (32.4)	62 (32.3)	17 (100)	146 (35.1)	<0.001¹
Hospitalization, n (%)	137 (84.6)	110 (78.6)	14 (100)	261 (82.6)	0.079¹
Latency (weeks)	6 (3-13)	8 (4-18.5)	7 (4-12)	7 (4-16)	0.016²
Clinical Presentations
Nausea/vomiting, n (%)	44 (21.9%)	56 (41.8%)	2 (11.8%)	102 (29%)	<0.001¹
Pruritus, n (%)	18 (9%)	24 (17.9%)	12 (70.6%)	54 (15.6%)	<0.001¹
Abdominal pain, n (%)	57 (28.4)	50 (37.3)	2 (18.8)	109 (31)	0.047¹
Dark urine, n (%)	38 (18.9)	21 (15.7)	4 (25.3)	63 (19.7)	0.619¹
Light Stools, n (%)	20 (10)	10 (7.5)	4 (23.5)	34 (9.7)	0.105¹
Fever, n (%)	20 (10)	15 (11.2)	1 (5.9)	36 (10.2)	0.778¹
Jaundice, n (%)	126 (62.7)	92 (68.7)	13 (76.5)	231 (65.6)	0.333¹
Encephalopathy, n (%)	8 (4)	16 (11.9)	2 (11.9)	26 (7.4)	0.019¹
Ascites, n (%)	7 (3.5)	3 (2.2)	0 (0)	10 (2.8)	0.615¹
Liver parameters
ALT (U/L)	1123 (520-1752)	1320 (370-2343)	236 (116-575)	1146 (370-2036.2)	<0.001²
AST (U/L)	926 (293.5-1557)	1062 (233.5-1861)	139 (80-332)	932.5 (226-1653.2)	0.006²
ALP (U/L)	197.5 (151.5-308.5)	200(144-302)	155.5 (116.2-336.2)	198 (145.5-304.5)	0.560²
GGT (U/L)	196 (121-365)	252 (109-370)	142 (72-382)	196 (110-368)	0.593²
TB (mg/dL)	9.25 (2.9-17.6)	11.5 (3.75-22.2)	10.82 (5.53-20.65)	10.4 (3.5-19.4)	0.274²
Type of liver injury					<0.001¹
Hepatocellular, n (%)	87 (59.2)	94 (71.2)	1 (7.1)	182 (62.1)
Cholestatic, n (%)	27 (18.4)	20 (15.2)	12 (85.7)	59 (20.1)
Mixed, n (%)	33 (22.4)	14 (10.6)	1 (7.1)	48 (16.4)
Veno occlusive, n (%)	0 (0)	2 (1.5)	0 (0)	2 (0.7)
Hepatoportal sclerosis, n (%)	0 (0)	2 (1.5)	0 (0)	2 (0.7)
Time to Outcome (weeks)
Recovered	8 (4-12)	8 (4-12)	13 (4-15)	8 (4-13)	0.293²
Transplant	4 (1-7)	2.5 (1.25-5)	-	3 (1-5.5)	0.702³

Products	Latency (weeks)	Hospitalization (%)	Encephalopathy (%)	Ascites (%)	Recovered (%)	Transplant (%)	Chronic (%)	Death (%)
Camellia sinensis (n=16)	6 (4-16)	69.2	0	0	94.4	0	5.6	0
Aloe vera (n=9)	8 (4-23)	88.9	0	11.1	100	0	0	0
Chaparral (n=13)	8 (5-16)	66.7	0	7.7	85.7	14.3	0	0
Black Cohosh (n=8)	17 (2.5-34)	66.7	12.5	0	87.5	0	0	12.5
Polygonum multiflorum (n=25)	4 (1-8)	96	4	0	92	4	0	4
Kava (n=15)	10.5 (5.2-17)	83.3	12.5	0	62.5	37.5	0	0
Ashwagandha (n=5)	2 (1-14)	ND	0	0	100	0	0	0
Teucrium Polium (n=5)	8 (3-20)	100	0		80	20	0	0
Noni Juice (n=6)	2 (1.5-6)	60	0	0	100	0	0	0
Herbal Mix (n=44)	5 (3-8)	90.9	5.9	9.8	84.6	7.7	0	7.7
Armolipid Plus^® (n=6)	7.5 (3.5-19)				100	0	0	0
Herbalife^® (n=50)	17 (9.5-52)	67.9	4.3	0	91.7	4.2	4.2	0
Lipokinetix^® (n=6)	3.5 (2-7.5)	60	33.3	0	62.5	37.5	0	0
OxyElite Pro^® (n=16)	6 (3-52)	81.3	40	0	56.3	18.8	12.5	12.5
Hydroxycut^® (n=19)	8 (4-10)	88.2	5.9	0	78.9	15.8	0	5.3
Polyuse (n=34)	4 (4-16)	87	9.1	2	74.2	19.4	0	6.5
Move Free (n=63)	3 (2.7-9.7)	50	0	2.7	100	0	0	0
Steroids (n=15)	7 (4-12)	100	11.8	0	88.2	0	5.9	5.9
P-value	<0.001²	0.006¹	0.015¹	0.404¹	0.048¹

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[1] Corresponding author: Valesca Dall’Alba. E-mail: valba@hcpa.edu.br