Bone marrow - nonneoplastic
Benign changes
Arsenic toxicity

Author: Xiangrong (Alex) Zhao, M.D., Ph.D. (see Authors page)

Revised: 10 July 2017, last major update July 2013

Copyright: (c) 2002-2017, PathologyOutlines.com, Inc.

PubMed Search: Bone marrow arsenic toxicity

Cite this page: Arsenic toxicity. PathologyOutlines.com website. http://pathologyoutlines.com/topic/bonemarrowarsenic.html. Accessed August 18th, 2017.
Definition / general
  • Arsenic intoxication is associated with acute and chronic adverse health effects
  • Arsenic is pervasive in water, soil, air; has natural and anthropogenic sources
  • Its metabolism involves reduction to a trivalent state and oxidative methylation to a pentavalent state; the trivalent arsenicals, including those methylated, have more potent toxic properties than the pentavalent arsenicals (Toxicol Lett 2002;133:1)
  • Arsenic (As) belongs to fifth group of Mendeleyev's periodic table
  • Free element of arsenic appears in two allotropic forms: grey and yellow (crystalline)
  • Can also exist in various oxidation states, inorganic and organic forms, exposure to inorganic arsenic is associated with most cases of arsenic induced toxicity
Epidemiology
  • Arsenic contamination in drinking water identified in Russia, New Zealand, Romania, USA
  • Inorganic arsenic (e.g. arsenic trioxide) is present in air, usually due to volcanic eruption and purposeful human activities
  • Arsenic also found as sulphuric compound in lead, copper, nickel and ferrous ores; also in soil in small quantities
  • Also a medicinal used by physicians for 2000 years
Sites
Pathophysiology
  • Intracellularly, arsenic accumulates in mitochondria, where it inhibits succinic dehydrogenase and uncouples oxidative phosphorylation, resulting in low ATP levels
  • May also down regulate certain cytochrome P450 enzymes and activate c-Jun / AP1 transcription complex
  • High doses of inorganic arsenicals induce release of TNF alpha
  • Arsenic can induce cross tolerance to cytotoxicity, genotoxicity and apoptosis induced by nickel and other metals (Toxicol Appl Pharmacol 2001;176:127)
Etiology
  • Relative toxicities of arsenicals: As (III) > Mas (III) > DMAs (III) > DMAs (V) > Mas (V) > As (V); trivalent arsenicals increase cell proliferation at low concentrations (0.001 - 0.01 μmol) (Toxicol Appl Pharmacol 2001;172:225)
Clinical features
  • Bone marrow depression: due to acute or more commonly chronic arsenic intoxication, may initially manifest as pancytopenia and be reversible; may have nonspecific clinical presentation of pancytopenia, fatigue / weakness (anemia), frequent infections (leukopenia) and easy bruising / petechia (thrombocytopenia)
  • Anemia and leukopenia are common in chronic arsenic toxicity, are often accompanied by thrombocytopenia and mild eosinophilia
  • Chronic arsenic exposure may be associated with immunosuppression (National Research Council: Arsenic in Drinking Water, 1999)
  • Acute intoxication with arsine gas can cause fulminant intravascular hemolysis
  • Most sensitive endpoint from arsenic exposure is dermal effects
Diagnosis
  • Can measure arsenic in blood, urine, hair, fingernails
  • Current biological exposure index for U.S. workers of 35 μg/L total urinary arsenic may easily be exceeded by a healthy person eating a seafood meal (The Agency for Toxic Substances and Disease Registry (ATSDR): Arsenic Toxicity)
  • Urine test is most reliable method for arsenic exposure within past few days; needs to be done within 24 - 48 hours for accurate analysis of acute exposure
  • Hair and fingernail tests measure exposure to high levels over past 6 - 12 months
  • Newer microanalytical techniques include synchroton radiation based X ray fluorescence (SXRF) spectroscopy, microparticle induced X ray emission (PIXE) (Biochimie 2009;91:1260)
Uses by pathologists
Case reports
Treatment
  • Acute arsenic poisoning: dimercaprol and dimercaptosuccinic acid (DMSA) are chelating agents that sequester arsenic from blood proteins (Biochimie 2009;91:1260)
  • Supplemental potassium decreases risk of life threatening arrhythmias from arsenic trioxide
  • Sulfur containing substances in garlic may scavenge arsenic from tissue and blood
Clinical images

Images hosted on other servers:

Pigment changes and
palmoplantar hyperkeratoses
are characteristic of
chronic arsenic exposure

Arsenic keratosis -
so called "raindrops
on a dusty road"

Skin cancer

Microscopic (histologic) description
  • Peripheral smear: leukopenia including granulocytopenia and absolute eosinophilia, and profound anemia (normocytic or macrocytic) with coarse basophilic stippling and karyorrhexis (N Engl J Med 1965;273:18, West J Med 1983;139:219, Am J Clin Pathol 1984;81:533, Blut 1985;50:51)
  • Dyserythropoiesis including megaloblastic features and typical karyorrhexis in erythropoietic cells, accompanied by basophilic stippling and impairment of mitoses in megakaryocytes and granulopoietic components
  • Bone marrow biopsy shows nonspecific changes
Microscopic (histologic) images

Images hosted on PathOut server:

Bone marrow:

Erythroid precursors have marked
dysplastic changes including
nuclear lobulation and karyorrhexis

Peripheral smear images

Images hosted on PathOut server:

Erythroid precursor with
slightly lobulated
megaloblastoid nucleus

Electron microscopy description
  • Arsenic intoxication induces megaloblastic erythropoiesis and other bone marrow changes similar to other dyserythropoietic states, including marked nuclear aberrations involving shape, chromatin distribution and nuclear envelope (Blood 1979;53:820)
Electron microscopy images

Images hosted on other servers:

Abnormal erythroblasts - see figure 2 (pdf)

Molecular / cytogenetics description
  • No specific cytogenetic abnormalities
Differential diagnosis
  • Other heavy metal intoxications, especially those associated with anemia / pancytopenia
  • Other conditions associated with megaloblastic changes in erythroid precursors