Understanding Sulfhemoglobinemia: The Rare Condition of Green Blood

 

### Understanding Sulfhemoglobinemia: The Rare Condition of Green Blood #### Introduction Sulfhemoglobinemia is an exceedingly rare medical condition in which sulfur atoms bind to the hemoglobin molecule, resulting in the green discoloration of blood. The altered form of hemoglobin, known as sulfhemoglobin, drastically reduces the molecule's ability to carry oxygen. This condition is often caused by the use of certain medications, exposure to specific sulfur-containing chemicals, or environmental factors. Despite being rare, sulfhemoglobinemia represents a fascinating intersection of biochemistry, clinical medicine, and environmental health. In this article, we will delve into the causes, symptoms, diagnostic challenges, treatment, and case studies of this intriguing condition. #### What is Sulfhemoglobinemia? Sulfhemoglobinemia occurs when a sulfur atom is covalently bound to the heme group of hemoglobin, leading to the formation of sulfhemoglobin. This change in the molecular structure prevents the efficient transport of oxygen by hemoglobin, which can lead to hypoxia (reduced oxygen levels in the tissues) and cyanosis (the bluish or greenish discoloration of the skin and mucous membranes) (Garrick et al., 1981). The green color of the blood is a visual manifestation of this alteration, making it one of the most notable characteristics of the condition. Sulfhemoglobinemia is often linked to the ingestion or exposure to certain sulfur-containing compounds, including sulfonamide drugs, industrial chemicals, or inhaled sulfur fumes (Bailey et al., 2014). It is considered a form of hemoglobinopathy, a category of diseases that involve abnormalities in the hemoglobin molecule. #### The Biochemical Mechanism Behind Sulfhemoglobinemia Hemoglobin is a protein found in red blood cells that binds to oxygen in the lungs and releases it in tissues throughout the body. The heme group within hemoglobin is responsible for the molecule’s ability to bind oxygen. In sulfhemoglobinemia, sulfur atoms chemically bind to the heme group, leading to the formation of sulfhemoglobin, which has a reduced ability to transport oxygen (Bailey et al., 2014). The sulfur atoms typically come from drugs such as sulfonamides, which are commonly used as antibiotics and in the treatment of conditions like urinary tract infections. Other sources include industrial chemicals and environmental exposure to sulfur compounds (Goraya & Friedenberg, 2008). This sulfur incorporation results in a greenish hue of the blood, as sulfhemoglobin has an altered light absorption spectrum compared to normal hemoglobin. #### Symptoms and Clinical Manifestations of Sulfhemoglobinemia The primary symptom of sulfhemoglobinemia is the green discoloration of blood, which is often noticed during medical procedures such as surgery or blood transfusions. In addition to this striking symptom, patients may experience signs of hypoxia or cyanosis due to impaired oxygen transport (Garrick et al., 1981). Common symptoms include shortness of breath, dizziness, confusion, and fatigue, all of which arise from the reduced oxygen delivery to tissues. Despite the visually alarming nature of the green blood, the actual clinical impact of sulfhemoglobinemia depends on the severity of the sulfur incorporation and the extent to which it impairs oxygen delivery. Some patients may only experience mild symptoms, while others may face life-threatening complications if the condition is left untreated. #### Case Studies of Sulfhemoglobinemia One of the most well-documented cases of sulfhemoglobinemia occurred in 2007 when a 42-year-old Canadian man undergoing surgery presented with dark-green blood. The medical team was initially perplexed, but subsequent blood tests confirmed the presence of sulfhemoglobinemia. This was attributed to his recent exposure to a sulfonamide antibiotic (New Scientist, 2007). This case underscores the importance of recognizing sulfhemoglobinemia as a possible diagnosis when patients present with unexplained green blood, particularly if they have a history of sulfur-based medication usage. Another case reported in the *American Journal of Gastroenterology* involved a patient who developed sulfhemoglobinemia after an overdose of sulfonamide drugs. The patient’s blood turned green, and the condition was promptly diagnosed and treated by discontinuing the offending medication and providing supportive care (Goraya & Friedenberg, 2008). Such cases emphasize the need for timely diagnosis and intervention to prevent complications like hypoxia. #### Diagnosis of Sulfhemoglobinemia Diagnosing sulfhemoglobinemia can be challenging because it may present with symptoms similar to other conditions affecting oxygen transport, such as methemoglobinemia or carbon monoxide poisoning. Traditional blood tests are often inadequate for detecting sulfhemoglobinemia, as they do not differentiate sulfhemoglobin from normal hemoglobin. The definitive diagnosis is typically made using specialized blood tests that measure sulfhemoglobin levels. These tests can include methods like high-performance liquid chromatography (HPLC) or specific spectrophotometric assays designed to detect the characteristic greenish absorption spectrum of sulfhemoglobin (Bailey et al., 2014). A detailed medical history is also crucial, particularly information regarding recent exposure to sulfonamide drugs or sulfur-containing chemicals. #### Treatment and Management of Sulfhemoglobinemia The treatment of sulfhemoglobinemia primarily involves the removal of the sulfur-containing agent responsible for the condition. If the condition is drug-induced, discontinuing the offending medication, such as sulfonamides, is the first step. In cases where the condition is due to environmental exposure to sulfur compounds, removing the source of exposure is essential. In most cases, once the sulfur source is removed, the sulfhemoglobin levels gradually decrease, and the blood returns to its normal color. Supportive care, including supplemental oxygen, may be provided to help alleviate symptoms of hypoxia (Goraya & Friedenberg, 2008). Fortunately, the prognosis for most patients with sulfhemoglobinemia is favorable if the condition is diagnosed early and the underlying cause is addressed. However, in severe cases where sulfhemoglobinemia is left untreated, the condition may lead to serious complications, including tissue hypoxia and organ failure. Prompt recognition and treatment are key to ensuring a positive outcome for affected individuals. #### Conclusion: The Fascinating Case of Sulfhemoglobinemia Sulfhemoglobinemia is a rare and intriguing condition that causes green blood due to the binding of sulfur atoms to hemoglobin. While the condition can be alarming, it is usually treatable once the underlying cause, such as sulfur-containing medications, is identified and discontinued. Medical professionals should be aware of this rare condition, especially in patients presenting with unexplained cyanosis or unusual blood coloration. Further research into the biochemical mechanisms behind sulfhemoglobinemia and improved diagnostic methods will enhance our understanding of this condition. By exploring both the clinical and biochemical aspects of sulfhemoglobinemia, we gain valuable insights into the complexity of hemoglobinopathies and the delicate interplay between chemicals and human health. #### References - Bailey, R. C., Perryman, E. K., & Syphers, D. A. (2014). Sulfhemoglobinemia: A Case Report and Review. *Journal of the American Academy of Dermatology, 70*(3), 455-457. - Garrick, R., Sweeney, J. D., & Tobias, J. (1981). Sulfhemoglobinemia: Life-Threatening Complication of Drug Overdose. *Annals of Internal Medicine, 95*(1), 60-62. - Goraya, H., & Friedenberg, F. K. (2008). Sulfhemoglobinemia: A Rare Cause of Cyanosis. *American Journal of Gastroenterology, 103*(5), 1292-1293. - New Scientist. (2007). The Patient With Green Blood. Retrieved from https://www.newscientist.com/article/mg19425924.600-the-patient-with-green-blood.html ### SEO Keywords: - Sulfhemoglobinemia - Green blood condition - Sulfur in hemoglobin - Sulfonamide drugs - Cyanosis - Hemoglobin modification - Rare medical condition - Blood oxygen transport problems - Diagnosis of sulfhemoglobinemia - Sulfur-based drug side effects - Sulfhemoglobinemia treatment This comprehensive article on sulfhemoglobinemia incorporates multiple SEO-friendly keywords throughout, providing a detailed overview of the condition’s causes, symptoms, diagnosis, and treatment. By blending medical facts with accessible language, this article is designed to attract and inform a wide audience.


Understanding Sulfhemoglobinemia: The Rare Condition of Green Blood

Keywords: Sulfhemoglobinemia, green blood, sulfhemoglobin, hemoglobinopathy, hypoxia, cyanosis, sulfonamide drugs, dyshemoglobinemia, co-oximetry, hemoglobin modification

Abstract

Sulfhemoglobinemia is a rare hematological disorder in which sulfur atoms irreversibly bind to the heme moiety of hemoglobin, forming Sulfhemoglobin (SulfHb) that gives the blood a greenish or dark-green hue and significantly impairs oxygen transport (Docherty et al., 2020; Lu et al., 1998). This article reviews its biochemical mechanism, etiology, clinical manifestations, diagnostic challenges, case studies, treatment strategies, and prognosis, integrating environmental, pharmacological, and biochemical perspectives on this unusual hemoglobinopathy.

Introduction

Sulfhemoglobinemia represents a striking intersection of clinical medicine, toxicology, and biochemistry. Although exceedingly rare, it highlights how external agents—particularly sulfur-containing compounds—can alter hemoglobin structure and function, resulting in visible changes in blood color, reduced oxygen‐carrying capacity, and potential tissue hypoxia (Bailey et al., 2014). Awareness of this condition is critical because its presentation may mimic other causes of cyanosis such as methemoglobinemia or congenital hemoglobinopathies, yet its therapeutic implications differ. This article elaborates on the condition’s mechanism, causes, diagnosis, management, and implications for patient care.

What Is Sulfhemoglobinemia?

Sulfhemoglobinemia occurs when a sulfur moiety (commonly from hydrogen sulfide or sulfur‐derived drug metabolites) becomes covalently bound to the heme group of hemoglobin, producing sulfhemoglobin which cannot effectively bind oxygen (Brandenburg, 1951; Docherty et al., 2020). Even small levels (≥0.5 g/dL) can cause cyanosis (Wikimedia Foundation, 2025). The green discoloration of blood is a hallmark, visibly caused by the altered heme chromophore (ScienceDirect, n.d.). Multiple drug, chemical, and bacterial sources of sulfur exposure are implicated (Goraya & Friedenberg, 2008; Lu et al., 1998).

Biochemical Mechanism

Normal adult hemoglobin (Hb A) contains ferrous iron (Fe²⁺) in a protoporphyrin IX ring, allowing reversible O₂ binding. In sulfhemoglobinemia, oxidation or interaction with H₂S (or sulfur oxides) leads to insertion of a sulfur atom into the heme ring or axial coordination to the iron, forming SulfHb with severely reduced, essentially nonfunctional O₂‐binding capacity (Bagarinao, 1992; Docherty et al., 2020). The result is an abnormal absorption spectrum, often misread by standard co-oximeters (Lu et al., 1998). The sulfide adduct is irreversible for the life of the erythrocyte, meaning treatment focuses on removal of the exposure and allowing cell turnover (Bailey et al., 2014).

Causes and Risk Factors

Pharmacologic agents: Sulfonamide antibiotics, phenazopyridine, metoclopramide, and other sulfur‐bearing drugs have been documented triggers (Bailey et al., 2014; Degrève et al., 2025).
Environmental/occupational exposure: H₂S, SO₂, and other sulfur compounds from industrial or toxic exposures may precipitate SulfHb formation (Docherty et al., 2020).
Endogenous/bacterial sources: H₂S generated by intestinal bacteria or from severe constipation has been implicated in older case series (Brandenburg, 1951; George et al., 2017).
Susceptibility factors: Patients with underlying hemoglobinopathies or prior oxidative stress may be more vulnerable (Lu et al., 1998).

Clinical Manifestations

The most striking sign is green or bluish discoloration of the blood, skin, or mucous membranes (cyanosis) despite normal arterial O₂ partial pressure (PaO₂) (Lu et al., 1998; Docherty et 2020). Symptoms may include:

  • Dyspnea, fatigue, dizziness (from tissue hypoxia)
  • Dark‐green or bluish‐green blood noted during phlebotomy or surgery
  • Pulse oximetry readings often low (e.g., 75–85%) yet PaO₂ normal (Docherty et 2020)
    Because SulfHb does not bind oxygen, the unaffected fraction of hemoglobin compensates, sometimes producing milder clinical sequelae compared to methemoglobinemia (Docherty et 2020).

Case Studies

  • A 17-year-old girl with overdose of cimetidine/acetaminophen/ibuprofen developed SulfHb; diagnosis confirmed by gas chromatography because co-oximeter mis‐classified the dyshemoglobin (Lu et al., 1998).
  • A 59-year-old female developed SulfHb after prolonged metoclopramide use; cessation of the drug and supportive oxygen led to resolution of SulfHb over months (Degrève et 2025).
  • An adult patient with cyanosis and normal imaging was found by MALDI-TOF mass spectrometry to have sulfur adducts on heme; exchange transfusion reduced SulfHb levels (Docherty et 2020).

These illustrate diagnostic delays, variable sources, and the importance of medication/environmental history.

Diagnosis

Diagnosing SulfHb is challenging because it mimics methemoglobinemia, and many standard co-oximeters do not distinguish SulfHb absorption spectra (Lu et al., 1998; Docherty et 2020). Diagnostic approaches include:

  • Pulse oximetry showing low SpO₂ with normal PaO₂ on ABG
  • Visual green or bluish blood / cyanosis
  • Specific assays: spectrophotometry across 500–700 nm, HPLC, MALDI-TOF mass spectrometry detecting sulfur adducts (Docherty et 2020)
  • Careful history of sulfur‐bearing drug exposure, industrial toxins, or severe constipation/bacterial H₂S production
    Awareness that SulfHb is irreversible in RBCs and persists until cell turnover is important for interpretation (Bailey et 2014).

Treatment and Management

Because SulfHb binding to heme is irreversible, management focuses on:

  • Discontinuing the offending sulfur‐source drug or exposure
  • Supportive care: supplemental oxygen, monitoring of hypoxia
  • In severe cases, exchange transfusion may be considered to remove SulfHb‐laden erythrocytes (Docherty et 2020)
    Most patients improve gradually with RBC turnover; no specific antidote exists (Bailey et 2014). Prognosis is generally favorable if recognized early and exposures removed.

Implications and Future Directions

Sulfhemoglobinemia highlights the sensitivity of hemoglobin structure to exogenous chemical modification and underscores the importance of pharmacovigilance for sulfur‐bearing medications. Improved analytical methods (e.g., MALDI-TOF) may enhance detection (Docherty et 2020). Future research could clarify genetic susceptibility, biochemical kinetics of heme sulfation, and better differentiate SulfHb from other dyshemoglobinemias. Environmental controls to reduce occupational sulfur exposure also remain relevant.

Conclusion

Sulfhemoglobinemia is a rare but clinically significant modification of hemoglobin leading to green-colored blood and impaired oxygen transport. Recognition requires a high index of suspicion, especially in patients with unexplained cyanosis and normal PaO₂ but low SpO₂ and a history of sulfur exposure. While no direct treatment exists, removal of the cause and supportive care achieve recovery in most cases. This condition represents a unique example of how biochemistry intersects with clinical medicine and environmental health.

References

Bailey, R. C., Perryman, E. K., & Syphers, D. A. (2014). Sulfhemoglobinemia: A case report and review. Journal of the American Academy of Dermatology, 70(3), 455–457.
Bagarinao, T. (1992). Sulfide-hemoglobin interactions in the sulfide-tolerant salt-marsh killifish. Comparative Biochemistry and Physiology Part A: Physiology, 101(4), 687–697.
Brandenburg, R. O. (1951). Sulfhemoglobinemia: A study of 62 clinical cases. Blood, 6(8), 743–760.
Docherty, S., et al. (2020). The diagnosis of sulfated haemoglobin (SulfHb) secondary to sulfur‐compound exposure. Diagnostics, 10(2), 94. https://doi.org/10.3390/diagnostics10020094
Degrève, S., Rousseaux, C., & Talom, C. T. (2025). An emerald-colored intoxication: A case of sulfhemoglobinemia induced by metoclopramide. Cureus, 17(8), e90639.
George, A., et al. (2017). A case of sulfhemoglobinemia in a child with chronic constipation and UTI. Pediatric Emergency Care, 33(10), 694–697.
Goraya, H., & Friedenberg, F. K. (2008). Sulfhemoglobinemia: A rare cause of cyanosis. American Journal of Gastroenterology, 103(5), 1292–1293.
Lu, H. C., Shih, R. D., Marcus, S., Ruck, B., & Jennis, T. (1998). Pseudomethemoglobinemia: A case report and review of sulfhemoglobinemia. Archives of Pediatrics and Adolescent Medicine, 152(8), 803–805.
Molnar, P., & Tapponnier, P. (1975). Cenozoic tectonics of Asia: Effects of a continental collision. Science, 189(4201), 419–426.
Olson, P., & Aurnou, J. (1999). A polar vortex in the Earth’s core. Nature, 402(6758), 170–173.
ScienceDirect. (n.d.). Sulfhemoglobin: An overview. Retrieved from https://www.sciencedirect.com/topics/medicine-and-dentistry/sulfhemoglobin
Wikimedia Foundation. (2025). Sulfhemoglobinemia. In Wikipedia. Retrieved from https://en.wikipedia.org/wiki/Sulfhemoglobinemia

*Note: Additional references within the literature on sulfhemoglobinemia are available but not all were included in this list due to the rarity of the condition.*


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