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LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases; 2012-.

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LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet].

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Arsenic

Last Update: July 25, 2017.

OVERVIEW

Introduction

Arsenic is a nonessential trace element that is widely distributed in nature. Arsenic was used in medicinal agents in the 19th and early 20th centuries, but has been replaced by safer and more effective agents and has not been in use for over 50 years. Nevertheless, arsenic is found widely in nature and accidental or intentional acute or chronic exposures to moderate or high levels of arsenic can cause liver injury, sometimes presenting long after the exposure.

Background

Arsenic is a nonessential trace element and well known poison that is found widely in low concentrations in the environment. Typical arsenic concentrations are 2 to 5 parts per billion in soil and sea water. In the United States, the maximal allowable concentration of arsenic in well and drinking water is 50 parts per billion. Arsenic is used in pesticides and herbicides and is a byproduct of the mining of other metals, such as copper and lead. Arsenic can also contaminate herbal preparations and dietary supplements. As a consequence, occupational or accidental exposure to moderate or high doses of arsenic can occur, but are fortunately rare, at least in the United States and most of the developed world. Arsenic was formerly used medically as Fowler's solution (1% arsenic trioxide) to treat inflammatory conditions such as asthma, psoriasis and leukemia, and as various organic arsenicals such as arsphenamine (Salvarsan), mapharsen and tryparsamide to treat syphilis and protozoal infections. These agents are no longer used and have been replaced by more effective and safer agents. Arsenic is still a component of some traditional and herbal preparations and is still used to treat acute promyelocytic leukemia under the brand name Trisenox (arsenic trioxide) in intravenous doses of 10 mg daily for up to 60 days, followed by different dosing in consolidation and maintenance regimens.

Hepatotoxicity

Acute poisoning with arsenic is marked by severe abdominal pain, nausea and vomiting, diarrhea, muscle cramps, metallic taste and extreme thirst, followed by stupor, coma, cardiovascular collapse and death. Death can occur within 24 hours of exposure, but with sublethal doses, survival is possible and liver injury may arise 24 to 48 hours after the acute ingestion. Other symptoms include conjunctival and respiratory tract inflammation, epistaxis, rash, renal insufficiency and painful neuropathy. The characteristics of the liver injury have not been well defined, but are likely similar to those with acute iron poisoning, with a clinical phenotype of acute hepatic necrosis, marked elevations in serum aminotransferase levels, early onset of hepatic failure and rapid recovery in cases without early fatality.

Chronic, lower dose exposure to arsenic can be toxic and result in arsenosis, a syndrome marked by fatigue, nausea and vomiting, abdominal crampy pain, weakness, stupor, seizures and neuropathy. Skin manifestations are frequent and characteristic with chronic excessive exposure marked by hyper- and hypo-pigmentation, a "rain-drop" pattern of skin discoloration, skin dryness and exfoliation, keratosis of the palms and soles, and skin cancers. Arsenic is also deposited in the hair and nails, where it can be detected even after it is no longer measureable in urine. Liver injury can also occur with chronic arsenic exposure, typically with appearance of signs and symptoms of portal hypertension, without obvious cirrhosis (idiopathic or noncirrhotic portal hypertension). The clinical onset of noncirrhotic portal hypertension is often insidious with weight loss, fatigue and abdominal swelling and minor, nonspecific elevations in serum enzymes, followed by appearance of variceal hemorrhage or ascites. Features of portal hypertension (ascites, variceal hemorrhage) rather than hepatic failure (jaundice, encephalopathy or coagulopathy) predominate. Symptoms generally improve slowly upon withdrawal of arsenic exposure and long term survival is not uncommon, although porto-caval shunting may be needed to manage portal hypertension and variceal hemorrhage. Serum enzyme elevations and jaundice are uncommon, but may occur. Chronic exposure is usually due to environmental contamination, from elevated arsenic levels in water due to run-offs from mining or storage of arsenic containing compounds such as herbicides and pesticides. When arsenic was still being used as a medicinal agent, cases of chronic poisoning were linked to use of Fowler's solution for psoriasis and asthma and arsphenamine for syphilis generally after 5 to 25 years of use. Furthermore, some cases became clinically apparent several years after the arsenical was stopped and at a time that arsenic could no longer be detected in urine, tissue or hair samples. Chronic arsenic exposure has also been linked to cirrhosis, although the contribution of alcohol and other chronic liver diseases in reported cases could not be excluded. Chronic exposure has also been linked to liver cancer, including hepatic angiosarcoma and hepatocellular carcinoma. Other long term complications of arsenic exposure include skin discoloration, palmar and plantar keratosis, peripheral neuropathy, and skin and lung cancer which can arise several decades after exposure. Patients presenting with noncirrhotic portal hypertension due to arsenic frequently have other manifestations of its chronic toxicity such as skin discoloration, palmar keratosis and skin cancers.

Arsenic trioxide (Trisenox) given intravenously as therapy of acute promyelocytic leukemia has had limited use, but hepatotoxicity has been reported in 8% to 47% of patients, generally in the form of mild and transient serum enzyme elevations that resolve even with continuation of treatment. Nevertheless, more severe hepatic injury has been reported including cases of acute liver failure, although the clinical features of the injury and relatedness to the therapy were not well defined.

Likelihood score: A[HD] (well known cause of chronic liver injury when given in high dosess).

Mechanism of Injury

Arsenic uncouples oxidative phosphorylation and is a general cytoplasmic toxin binding to and inhibiting sulfhydryl groups on essential enzymes. With acute exposures, the skin, cardiac and neurologic toxicities are most prominent. With chronic exposure, skin and hepatic manifestations may dominant the clinical picture.

Outcome and Management

Arsenic poisoning is often treated with chelation, with uncertain efficacy. Both dimercaprol and succimer have been used, but their efficacy in ameliorating symptoms and signs and speeding clinical recovery has not been documented. The major invention should be directed at detection and elimination of the source of arsenic contamination and identification of others who might be exposed in the same manner.

Drug Class: Trace Elements and Metals

CASE REPORT

Case 1. Noncirrhotic portal hypertension attributed to arsenic exposure.

[Modified from: Upshaw CB Jr, Bryant MF, Claiborne TS Jr. Noncirrhotic portal hypertension after arsenic ingestion. South Med J 1979; 72: 1332-4. PubMed Citation; Upshaw CB Jr, Claiborne TS Jr. Medicinal arsenic poisoning: 27-year follow-up. South Med J 1995; 88: 892-3. PubMed Citation]

A 45 year old man developed recurrent variceal hemorrhage having taken an arsenic containing preparation for 2 years, several years in the past. He denied a history of liver disease, jaundice, alcohol abuse or risk factors for viral hepatitis. Several years in the past he had developed asthma and was treated with Fowler's solution (1% arsenic trioxide) for two years, between the ages of 40 and 42. The estimated total dose of arsenic was 1.6 grams. Thereafter, he felt well until he began developing episodes of hematemesis and melena approximately 3 years later. On examination, he appeared healthy but pale. A spleen tip was felt in the left upper quadrant, but there was no hepatomegaly, jaundice, ascites, peripheral edema, wasting or spider angiomata. Laboratory testing showed a hematocrit of 34%, white blood count 2,700/µL and platelet count 70,000/µL, but routine liver tests were normal. Gastrointestinal radiology showed esophageal varices and splenomegaly. A splenoportogram showed an elevated splenic pulp pressure [29 mm Hg, normal 3-17], but no evidence of splenic or portal vein thrombosis. He underwent splenectomy and anastomosis of the splenic vein to the left renal vein, which normalized the elevated portal pressure. He recovered from surgery uneventfully and had no further gastrointestinal bleeding or symptoms of liver disease, but had mildly abnormal liver test results (AST and Alk P < twice ULN) and an abnormal liver-spleen scan. He also developed several skin carcinomas, but died as a result of a farm accident 27 years after initial presentation and surgery.

Key Points

Medication:Arsenic trioxide (1% solution) for 2 years
Pattern:None: normal serum enzymes
Severity:4+, variceal hemorrhage
Latency:4 years after a 2 year course of treatment
Recovery:Symptomatically complete
Other medications:None mentioned

Comment

This case was distinctive in having excellent long term follow up summarized in a subsequent letter to the editor by the authors, 16 years after the first report. Noncirrhotic portal hypertension generally arises as a result of chronic injury, probably to portal venules and arterioles as a result of direct toxic endothelial cell injury caused by the high levels of orally absorbed arsenic in the portal system. The usual markers of liver injury are generally absent, serum enzymes being normal or near normal in the majority of patients before and at the time of initial presentation. In addition, the clinical presentation may be months or years after portal hypertension has developed. The most sensitive marker for the progressive increase in portal pressure is a decline in platelet count, even when in the normal range. Strikingly, arsenic may no longer be detectable in plasma, urine, tissue or hair when the liver injury finally becomes clinically manifest. In this case, as in most instances, withdrawal of the arsenic exposure, conservative management and portal decompression, if needed, is generally effective in resolving the clinical complications. The long term prognosis is often dependent upon the other long term complications of arsenic exposure, including skin, liver and lung carcinoma.

PRODUCT INFORMATION

REPRESENTATIVE TRADE NAMES

Arsenic – Trisenox®

DRUG CLASS

Trace Elements and Metals

COMPLETE LABELING

Product labeling at DailyMed, National Library of Medicine, NIH

CHEMICAL FORMULA AND STRUCTURE

DRUGCAS REGISTRY NUMBERMOLECULAR FORMULASTRUCTURE
Arsenic Trioxide 1327-53-3 As2-O3
Image of Arsenic Chemical Structure

ANNOTATED BIBLIOGRAPHY

References updated: 25 July 2017

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    (Arsenic levels were elevated in livers from autopsies of patients with cirrhosis [81 µg], noncirrhotic portal hypertension [26 µg] and other liver diseases [56 µg] compared to controls [2 µg/100g], casting doubt on its role in non-cirrhotic portal hypertension).
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    (Review of the problem of arsenic in the environment, in opium samples and Ayurvedic medicines and the effects of arsenic on the liver, including portal hypertension and its possible role in causing Indian childhood cirrhosis).
  • Kasper ML, Schoenfield L, Strom RL, Theologides A. Hepatic angiosarcoma and bronchioloalveolar carcinoma induced by Fowler's solution. JAMA 1984; 252: 3407-8. [PubMed: 6094851]
    (67 year old man developed weakness, anorexia, ascites and jaundice [bilirubin 8.5 mg/dL, AST 34 U/L, Alk P 130 U/L] and gave a history of taking Fowler's solution for 8 years, 40 years earlier, autopsy showing hepatic angiosarcoma and bronchioalveolar carcinoma).
  • Okuda K, Kono K, Ohnishi K, Kimura K, Omata M, Koen H, Nakajima Y, et al. Clinical study of eighty-six cases of idiopathic portal hypertension and comparison with cirrhosis with splenomegaly. Gastroenterology 1984; 86: 600-10. [PubMed: 6698361]
    (Description of 86 cases of idiopathic portal hypertension seen between 1965 and 1982 at Chiba University Hospital, 16 men and 70 women, ages 7 to 74 years, often presenting with variceal hemorrhage, ascites and abdominal pain, with splenomegaly and thrombocytopenia, but normal or near normal liver tests [ALT normal in 72% and Alk P in 49%], histology showing portal fibrosis and survival being better than matched control group with cirrhosis and portal hypertension).
  • Armstrong CW, Stroube RB, Rubio T, Siudyla EA, Miller GB Jr. Outbreak of fatal arsenic poisoning caused by contaminated drinking water. Arch Environ Health 1984; 39: 276-9. [PubMed: 6497443]
    (Nine family members developed arsenic poisoning caused by contamination of well water [by pesticide], 5 developing renal injury and 4 hepatitis; the most common symptoms were vomiting and diarrhea, periorbital swelling, epistaxis and anemia followed by seizures, fever, rash and coma; 2 dying of heart and renal failure with sepsis).
  • Winship KA. Toxicity of inorganic arsenic salts. Adverse Drug React Acute Poisoning Rev 1984; 3: 129-60. [PubMed: 6397979]
    (Review of the acute and chronic effects of arsenic exposure, both environmental and medicinal).
  • el Zayadi A, Khalil A, el Samny N, Hamza MR, Selim O. Hepatic angiosarcoma among Egyptian farmers exposed to pesticides. Hepatogastroenterology 1986; 33: 148-50. [PubMed: 3758905]
    (14 Egyptian farmers were diagnosed with hepatic angiosarcoma at a single referral hospital between 1980 and 1984; 10 had a history of arsenic exposure).
  • Guha Mazumder DN, Chakraborty AK, Ghose A, Gupta JD, Chakraborty DP, Dey SB, Chattopadhyay N. Chronic arsenic toxicity from drinking tubewell water in rural West Bengal. Bull World Health Organ 1988; 66: 499-506. [PMC free article: PMC2491171] [PubMed: 3262450]
    (Among 13 Indian patients [ages 15-50 years] with chronic arsenic skin toxicity, all had liver and 5 spleen enlargement, but routine liver tests were normal, while liver biopsies showed mild inflammation and fibrosis without cirrhosis; an epidemiological study of the patients' villages showed high levels of arsenic in the well water [2 mg/L] and frequent skin discoloration and hepatomegaly [both 93%], which were not found in villages with low arsenic levels in drinking water).
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    (67 year old woman who was treated with Fowler's solution since childhood for psoriasis developed non-cirrhotic portal hypertension and recurrent variceal hemorrhage; bleeding episodes resolving after portal decompression surgery).
  • Poklis A, Saady JJ. Arsenic poisoning: acute or chronic? Suicide or murder? Am J Forensic Med Pathol 1990; 11: 226-32. [PubMed: 2220708]
    (62 year old man developed intermittent bouts of abdominal pain, vomiting, dehydration and diarrhea with skin pigmentation and keratosis, neutropenia and peripheral neuropathy and on autopsy had elevated arsenic concentrations in hair and tissue; he being the 5th husband of an often widowed wife).
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    (Among 47 patients [3 women, 4 men, ages 24-55 years] with non-cirrhotic portal hypertension seen over a 10 year period, 8 gave a history of taking Fowler's solution for psoriasis; all had esophageal varices and splenomegaly with normal liver tests and liver history showing portal fibrosis without cirrhosis; estimated intake was 3-27 grams, over 2 to 15 years, and clinical presentation 2 to 16 years later with massive variceal bleeding in 7 and ovarian cancer in 1).
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    (38 year old alcoholic man underwent 3 liver biopsies for unexplained liver test abnormalities and during an admission for suspected self-inflicted arsenic poisoning, biopsies showed perisinusoidal fibrosis and sinusoidal dilatation, which subsequently resolved).
  • Salgado M, Sans M, Forns X, Bruguera M, Castells A, Navasa M, RodéJ. [Hepatic angiosarcoma: a report of a case associated with treatment with arsenic salts and a review of the literature]. Gastroenterol Hepatol 1995; 18: 132-5. Spanish. [PubMed: 7621289]
    (63 year old man presented with hemoperitoneum, emergency laparotomy demonstrating a large hepatic angiosarcoma; the only known toxic exposure was a course of intravenous arsenic containing Neosalvarrsan at the age of 17, 45 years before presentation).
  • Upshaw CB Jr, Claiborne TS Jr. Medicinal arsenic poisoning: 27-year follow-up. South Med J 1995; 88: 892-3. [PubMed: 7631226]
    (Letter with follow-up on patient who had non-cirrhotic portal hypertension after a 5 year course of arsenic therapy [Upshaw 1979], who subsequently had no further bleeding, but developed mildly abnormal liver tests and died from a farm accident 15 years later).
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    (Blood levels of chromium, manganese, cooper and rubidium were similar in patients with hepatitis C related cirrhosis as controls, but selenium and zinc levels were lower).
  • Hernáez-Zavala A, Del Razo LM, Aguilar C, GarcíVargas GG, Borja VH, CebriáME. Alteration in bilirubin excretion in individuals chronically exposed to arsenic in Mexico. Toxicol Lett 1998; 99: 79-84. [PubMed: 9817078]
    (Among 51 persons chronically exposure to high arsenic levels in drinking water, serum direct bilirubin and alkaline phosphatase were mildly elevated with little or no change in ALT, AST or GGT).
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    (Review of arsenic trioxide as therapy of promyelocytic leukemia; despite a lack of controlled trials the authors conclude that it is useful as salvage therapy; liver dysfunction was reported in 8-46% of treated patients in 3 case series).
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    (Review of contamination of ground and well water with arsenic that was particularly common in the well drilling in the Ganges delta during the 1960s).
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    (Analysis of trace element concentrations in 50 patients with chronic liver disease [39 with cirrhosis] and 10 controls found slight decreases in iron, zinc and selenium in patients with cirrhosis).
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    (Clinical description of 248 Indian patients with chronic arsenic toxicity found hepatomegaly in 77%, splenomegaly 30%, ascites 2%; liver tests done in 93 found ALT elevations in 26% and Alk P 29%; liver biopsy done in 69 cases showed portal fibrosis in 91% and cirrhosis in 3%).
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    (Clinical description of 248 Indian patients with chronic arsenic toxicity found hepatomegaly in 77%, splenomegaly 30%, ascites 2%; liver tests done in 93 found ALT elevations in 26% and Alk P 29%; liver biopsy done in 69 cases showed portal fibrosis in 91% and cirrhosis in 3%; in epidemiological studies, rates of hepatomegaly correlated with higher arsenic levels in drinking water [105] compared to controls [3%]).
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    (Among 2719 calls to an Indian poisoning center over a 3 year period, 48 [2%] were for copper sulfate and 6 [<0.5%] for heavy metals including arsenic, lead, mercury and thallium).
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    (36 year old man took a suicidal overdose of the herbicide monosodium methanarsenate [MSMA] and rapidly developed nausea, vomiting and drowsiness, followed by deafness and abnormal liver tests [bilirubin 9.8 mg/dL, ALT 394 U/L, Alk P 327 U/L, creatinine 1.4 mg/dL] that mostly improved with dimercaprol chelation therapy [bilirubin 1.0 mg/dL, ALT 58 U/L, Alk P 377 U/L]).
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    (Overview of arsenic contamination in groundwater from published reports from 42 areas from 6 continents).
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    (Among 83 patients with newly diagnosed acute promyelocytic leukemia who were treated with arsenic trioxide, 96% achieved remission and hepatotoxicity occurred in 29 [39%], but resolved despite continuing therapy in 21 and, of 8 who were rechallenged, only 1 had recurrence; toxicity was grade 4 [severe] in 8 patients, but none died from liver injury).
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    (Thorough review of the complications of chronic arsenic in take).
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    (Analysis of well water arsenic found high levels in 3 districts in Uttar Padesh with arsenical skin lesions in 20% of adults and 6% of children; no mention of liver related complications).
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    (Assessment of well water arsenic exposure and possible complications in Bangladesh, does not discuss hepatic side effects).
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    (In a study of 200 Bangladesh residents, a positive association was found between higher drinking water arsenic levels [>50 vs 10-50 vs <10 µg/L] and higher serum enzyme levels [ALT 34 vs 27 vs 24 U/L and Alk P 108 vs 91 vs 83 U/L]).
  • Das N, Paul S, Chatterjee D, Banerjee N, Majumder NS, Sarma N, Sau TJ, Basu S, et al. Arsenic exposure through drinking water increases the risk of liver and cardiovascular diseases in the population of West Bengal, India. BMC Public Health 2012; 12: 639. [PMC free article: PMC3441389] [PubMed: 22883023]
    (Comparison of 103 Bengali villagers with high arsenic drinking water exposure to 107 with low exposure found higher mean levels of ALT [37 vs 32 U/L] and Alk P [274 vs 217 U/L] in the higher arsenic exposed group).
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    (Analysis of arsenic levels in drinking water and mortality rates for liver cancer between 1971 and 1990 in 1103 persons from 138 villages in Taiwan found a positive association with liver cancer rates and arsenic levels in water above 640 µg/L, but not at lower levels of exposure).
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    (Review of the complications of chronic arsenic exposure including skin, lung, bladder, liver and prostate cancer, leukemia, neurologic effects, diabetes, skin conditions, cardiovascular disease and reproduction, but not liver disease or cirrhosis).
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