Tc-99m Sulfur Colloid Liver-Spleen Scintigraphy

Tc-99m sulfur colloid liver-spleen scintigraphy is a functional study, not an anatomic one. The tracer is a colloidal particle that the phagocytic cells of the reticuloendothelial system (RES) — the Kupffer cells of the liver, the macrophages of the spleen, and the bone marrow — actively engulf. The resulting image maps functioning phagocytic tissue, so a mass that lacks Kupffer cells appears as a cold defect regardless of what it looks like on CT or ultrasound. ^{1, 4}

This mechanism is what makes the study physically interesting and clinically distinct. Where cross-sectional imaging asks "what is the shape and density of this lesion?", colloid scintigraphy asks "does this tissue contain functioning phagocytic cells?" — a question that cleanly separates lesions such as focal nodular hyperplasia, which retains Kupffer cells, from adenoma and most malignancies, which do not. ^{5, 6, 7}

Introduction

Liver-spleen scintigraphy predates modern cross-sectional imaging and has been largely displaced by CT and MRI for anatomic lesion detection. But it retains a specific, physics-based niche that no anatomic modality can fill: it images reticuloendothelial function. The ACR-ACNM-SNMMI-SPR practice parameter for hepatic and splenic scintigraphy defines the study around exactly this — intravenous administration of a radiopharmaceutical that localizes in the RES of the liver and spleen. ¹

Understanding the study is fundamentally about understanding a colloid: how particle size determines where the particles go, how phagocytic clearance concentrates them, and how disease changes that distribution. Those principles also underlie several related agents and workflows — the same Kupffer-cell uptake is what Tc-99m sulfur colloid exploits in GI bleeding studies and, in filtered form, in sentinel-node lymphoscintigraphy. This guide walks through the colloid physics, the biodistribution it drives, the lesion uptake patterns that give the study its diagnostic value, the role of SPECT/CT, and the patient dosimetry. DRPS supports nuclear medicine programs that perform these studies through PET/CT and nuclear medicine physics and medical physics consulting across Florida, Maryland, Virginia, Washington DC, California, and Nevada.

Topic Explanation

The radiopharmaceutical

Tc-99m sulfur colloid is prepared by labeling a sulfur colloid suspension with technetium-99m, which emits a 140 keV gamma photon well matched to the gamma camera. Once injected intravenously, the colloidal particles behave as foreign particulates: the phagocytic cells of the RES recognize and engulf them, removing them from the blood within minutes. In a normal adult, the great majority of the activity is cleared by the liver's Kupffer cells, a smaller fraction by the spleen, and a small amount by bone marrow. ⁴

Because the clearance is rapid and the particles are effectively trapped where they are phagocytized, the image that forms is a snapshot of where functioning phagocytic cells are. A normal study shows a uniformly active liver, a less-active spleen, and little else. For the radiochemistry that governs tracer quality, see Radiochemical Purity and TLC Quality Control and Tc-99m Generator Quality Control.

Particle size governs biodistribution

The single most important physical property of the colloid is its particle-size distribution, because size determines which RES compartment the particles reach. Tc-99m sulfur colloid is commonly described as having particles in the range of roughly 0.1 to 1 micron, and the preparation method and any filtration step shift that distribution. ⁹ The classic teaching maps size to organ: mid-size particles are predominantly phagocytized by the Kupffer cells of the liver, larger particles favor the spleen, and very small particles distribute to the bone marrow and, when deliberately filtered to the sub-micron range, migrate through lymphatic channels. Phillips and colleagues demonstrated this directly, showing that 0.22-micron-filtered sulfur colloid migrated and was retained in lymph nodes far better than the unfiltered preparation — the basis for using filtered colloid in sentinel-node lymphoscintigraphy. ⁹

This size dependence is not merely academic. It means the same chemical agent, prepared or filtered differently, becomes a liver-spleen agent, a bone-marrow agent, or a lymphatic agent. It also means that preparation quality control matters: an aberrant particle-size distribution changes the biodistribution and can degrade the study.

Key Technical Principles

The reticuloendothelial uptake mechanism

The uptake mechanism is phagocytosis, an active biological process, which is why the study reports function. Al-Saeedi and Loutfi used Tc-99m sulfur colloid precisely as a probe of this function, showing that induced diabetes measurably reduced the liver-to-whole-body uptake ratio and raised the cardiac blood-pool activity — a direct readout of impaired hepatic phagocytic (Kupffer-cell) function. ⁴ Tong and colleagues similarly used the dynamic clearance of colloid from the blood into the liver as a measure of combined hepatic blood flow and Kupffer-cell activity. ⁸

The diagnostic consequence follows directly: a focal lesion is seen only through its effect on local phagocytic function.

Focal nodular hyperplasia versus adenoma

The FNH-versus-adenoma distinction is the textbook application of the mechanism. FNH is a hyperplastic, non-neoplastic lesion that contains the normal cellular elements of the liver — including Kupffer cells — so it can take up colloid, often appearing isointense to the surrounding liver and sometimes as a focus of increased ("hot") uptake. Hepatic adenoma, by contrast, is typically devoid of functioning Kupffer cells and appears cold. ^{5, 6}

The important caveat, which the physics makes unavoidable, is variability. Hsu and colleagues, using the related RES colloid Tc-99m phytate with SPECT, found FNH uptake ranged across cold, isointense/warm, and hot patterns in a series of 15 lesions, with no statistically significant correlation to tumor size — though increased or equal uptake in small lesions still provided useful specificity. ⁵ Schmidt and colleagues made the same point from the other direction, showing that combining colloid, blood-pool, and hepatobiliary imaging with SPECT is often necessary because the appearance of FNH varies. ⁶ D'Souza and colleagues had already noted decades earlier that radiocolloid uptake by Kupffer cells, combined with the hypervascular pattern on radionuclide angiography, could establish the diagnosis of FNH in favorable cases. ⁷ The practical lesson: a "warm" or "hot" FNH on colloid scintigraphy is specific and useful, but a cold result does not exclude FNH, so the study is interpreted alongside other imaging.

The colloid shift

Diffuse hepatocellular disease changes the distribution globally rather than focally. As cirrhosis reduces hepatic RES function and alters portal hemodynamics, a larger fraction of the injected colloid is cleared by splenic and marrow macrophages instead of the liver. The scintigraphic result is the "colloid shift": a relatively faint liver with prominent spleen and visible bone marrow. ⁴ Because this is a functional readout of the whole RES, colloid scintigraphy historically served as a sensitive, if nonspecific, indicator of diffuse liver disease.

Worked dosimetry

The patient dose is modest and is calculated the same way as any radiopharmaceutical: the whole-body effective dose is the administered activity multiplied by the radionuclide- and agent-specific effective-dose coefficient. Using a representative adult coefficient from ICRP Publication 128 for Tc-99m colloid:

where $A$ is a typical administered activity (here 185 MBq, 5 mCi) and $e\approx 9.4\times 10^{-3}$ mSv/MBq is the effective-dose coefficient. ¹⁰ Administered activities for liver-spleen imaging are commonly on the order of a few millicuries (roughly 74 to 296 MBq), with the higher end used when SPECT is planned. ^{1, 10} The resulting effective dose, on the order of 1 to 2 mSv, is comparable to other routine Tc-99m studies — a point worth communicating when discussing the study with patients and referrers. For the general framework, see Radiopharmaceutical Dosimetry and ICRP 128.

Clinical Impact

In contemporary practice, liver-spleen scintigraphy is a problem-solving tool rather than a front-line test, and its value is tied directly to the function it uniquely images.

The clearest use is lesion characterization when a functional answer is decisive. When cross-sectional imaging cannot confidently separate FNH from adenoma — a distinction with real management consequences, since adenomas carry hemorrhage and malignancy risk — demonstrating functioning Kupffer cells in the lesion supports FNH. ^{5, 6} A warm or hot lesion on colloid scintigraphy is a specific finding that can redirect management away from biopsy or resection.

Beyond lesion characterization, colloid liver imaging can also reveal secondary findings; Weisgrau and Guiberteau, for example, described a pericholecystic "rim sign" of increased hepatic activity adjacent to the gallbladder fossa in complicated acute cholecystitis on Tc-99m sulfur colloid imaging, mirroring the same sign on hepatobiliary studies. ²

A second use is assessing diffuse hepatocellular disease and splenic function. The colloid shift provides a functional gauge of hepatic RES capacity, and splenic imaging with colloid (or heat-damaged red cells for splenic tissue specifically) answers questions about accessory spleens, splenosis, and post-traumatic splenic tissue that anatomic imaging can leave ambiguous. ¹

The study's limitations are also physics-based and must be stated plainly. Spatial resolution is limited compared with CT and MRI, small or superficial lesions can be missed on planar imaging, and the variability of FNH uptake means a single cold result is not diagnostic. This is why SPECT and SPECT/CT are important: tomographic acquisition removes overlying activity and, with CT correlation, localizes defects anatomically, materially improving detection of small or deep lesions. ⁶ Attenuation correction and the general principles of hybrid imaging apply here as in any SPECT study — see SPECT/CT Attenuation Correction.

Practical Tips

• Match the particle preparation to the task. Standard (unfiltered) Tc-99m sulfur colloid is the liver-spleen agent; reserve filtered colloid for lymphoscintigraphy. Confirm the preparation and its quality control before injection. ⁹
• Image in multiple planar projections, then add SPECT. Anterior, posterior, and lateral or oblique planar views establish the overall distribution; SPECT or SPECT/CT resolves equivocal or small defects and localizes them. ⁶
• Recognize the colloid shift as a finding, not an artifact. Prominent spleen and marrow with a faint liver reflect diffuse hepatocellular disease, not a technical error. ⁴
• Interpret FNH uptake with its variability in mind. A warm or hot lesion supports FNH, but a cold lesion does not exclude it; correlate with other imaging rather than over-reading a single pattern. ^{5, 6}
• Keep administered activity ALARA. Use the lowest activity consistent with adequate counts for the planned planar-plus-SPECT protocol, following the practice parameter and ICRP dosimetry. ^{1, 10}
• Verify radiochemical purity and particle integrity. An off-spec particle-size distribution or poor labeling changes biodistribution and can mimic or mask disease.

DRPS helps nuclear medicine departments optimize these protocols and document the supporting physics through PET/CT and nuclear medicine physics services.

Regulatory Considerations

Tc-99m is byproduct material, so liver-spleen scintigraphy is performed under a radioactive material license governed by 10 CFR Part 20 and 10 CFR Part 35 (or the equivalent Agreement State rules), and the clinical conduct of the study follows the ACR-ACNM-SNMMI-SPR practice parameter. ^{1, 3} The practice parameter defines the indications, radiopharmaceutical, administered-activity ranges, acquisition protocol, and interpretation framework for adult and pediatric hepatic and splenic scintigraphy, and it is the document a reviewer expects a program to follow. ¹

Dosimetry and justification draw on ICRP Publication 128, which tabulates the effective-dose coefficients for Tc-99m colloids used in the worked example above. ¹⁰ The administering facility must also satisfy the general radiation-safety framework: dose calibration of the administered activity, an authorized user, appropriate patient and caregiver instructions, and documentation consistent with the medical-use rules. Because Tc-99m is byproduct material rather than an x-ray source, these obligations run to the NRC or the Agreement State, not to the state x-ray program.

Frequently Asked Questions (FAQs)

What does Tc-99m sulfur colloid liver-spleen scintigraphy show?

It shows the function of the reticuloendothelial system. Tc-99m sulfur colloid is a colloidal particle that the Kupffer cells of the liver, the macrophages of the spleen, and the bone marrow phagocytize, so areas with functioning phagocytic cells take up the tracer and areas without them (most tumors, cysts, and abscesses) appear as photopenic defects.

Why does particle size matter for sulfur colloid?

Particle size governs biodistribution. Tc-99m sulfur colloid particles are commonly described in the roughly 0.1 to 1 micron range; mid-size particles localize predominantly in the liver Kupffer cells, larger particles favor the spleen, and very small particles (such as filtered colloid) distribute to bone marrow and lymphatics, which is why filtered colloid is used for lymphoscintigraphy.

How does liver-spleen scintigraphy distinguish focal nodular hyperplasia from hepatic adenoma?

Focal nodular hyperplasia contains functioning Kupffer cells, so it typically shows isointense to increased colloid uptake, whereas hepatic adenoma usually lacks functioning Kupffer cells and appears cold. This functional difference is the classic value of colloid scintigraphy, although FNH uptake is variable and imaging is usually combined with other modalities.

What is a colloid shift?

A colloid shift is the redistribution of tracer away from the liver toward the spleen and bone marrow seen in diffuse hepatocellular disease such as cirrhosis. As hepatic reticuloendothelial function declines and portal hemodynamics change, a greater fraction of the colloid is cleared by splenic and marrow macrophages, producing prominent spleen and marrow visualization.

Does liver-spleen scintigraphy use SPECT?

Yes. Planar imaging in multiple projections is often supplemented by SPECT or SPECT/CT, which improves lesion localization and detection of small defects by removing overlying activity and adding anatomic correlation. SPECT is particularly helpful for small or deep lesions where planar imaging is ambiguous.

What radiation dose does the patient receive?

The effective dose is modest. Using a representative adult effective-dose coefficient from ICRP Publication 128 for Tc-99m colloid of about 9.4 by 10 to the minus 3 millisievert per megabecquerel and a typical administered activity of a few millicuries, the whole-body effective dose is on the order of 1 to 2 millisievert, comparable to other routine Tc-99m studies.

Key Takeaways

• It images function, not anatomy. Tc-99m sulfur colloid maps functioning reticuloendothelial (phagocytic) tissue, so lesions without Kupffer cells appear cold regardless of their anatomic features.
• Particle size is the key physical variable. Roughly 0.1 to 1 micron particles favor the liver and spleen; filtered sub-micron colloid is used for lymphoscintigraphy. Preparation quality control matters.
• FNH versus adenoma is the signature use. FNH retains Kupffer cells and can appear warm or hot; adenoma is typically cold — but FNH uptake is variable, so a cold result does not exclude it.
• The colloid shift is a functional sign. A faint liver with prominent spleen and marrow reflects diffuse hepatocellular disease.
• SPECT/CT adds real value. Tomography and anatomic correlation improve detection and localization of small or deep lesions.
• The dose is modest. An effective dose on the order of 1 to 2 mSv, per ICRP 128 coefficients, is comparable to routine Tc-99m imaging.

Conclusion

Tc-99m sulfur colloid liver-spleen scintigraphy is a study whose entire behavior follows from one physical fact: a colloidal particle, sized in the sub-micron to micron range, is phagocytized by the reticuloendothelial system. That fact determines where the tracer goes, why the image reflects phagocytic function rather than anatomy, and how disease — focal or diffuse — changes the picture. In an era dominated by CT and MRI, the study survives precisely because no anatomic modality can answer the functional question it asks.

For the nuclear medicine physicist and technologist, the practical mastery is in the colloid itself: preparing and verifying the right particle-size distribution, acquiring planar and SPECT images that exploit the functional contrast, and keeping the administered activity and dose appropriate. Done well, it remains a precise, physics-grounded problem-solver.

How DRPS Can Help

Diagnostic Radiation Physics Services supports nuclear medicine departments that perform liver-spleen and other reticuloendothelial studies with protocol optimization, SPECT/CT quality control, dose-calibrator and camera performance testing, radiopharmaceutical dosimetry documentation, and radiation safety program support through PET/CT and nuclear medicine physics and medical physics consulting.

DRPS supports facilities across our service locations, including Florida, Maryland, Virginia, Washington DC, California, Nevada, New York, Pennsylvania, New Jersey, and Delaware.

Related Resources

• SPECT/CT Attenuation Correction
• Radiopharmaceutical Dosimetry and ICRP 128
• Radiochemical Purity and TLC Quality Control
• Tc-99m Generator Quality Control
• Hepatobiliary (HIDA) Scintigraphy and GBEF
• GI Bleeding Scintigraphy with Tc-99m RBCs
• PET/CT and Nuclear Medicine Physics
• Medical Physicist Consulting

References

1. American College of Radiology; American College of Nuclear Medicine; Society of Nuclear Medicine and Molecular Imaging; Society for Pediatric Radiology. ACR-ACNM-SNMMI-SPR Practice Parameter for the Performance of Gastrointestinal Tract, Hepatic, and Splenic Scintigraphy. Revised 2020 (Resolution 16). acr.org
2. Weisgrau RA, Guiberteau MJ. The diagnosis of acute complicated cholecystitis by Tc-99m sulfur colloid liver imaging. Clinical Nuclear Medicine. 1990;15(4):240-242. doi:10.1097/00003072-199004000-00006. PubMed
3. U.S. Nuclear Regulatory Commission. 10 CFR Part 35: Medical Use of Byproduct Material. ecfr.gov
4. Al-Saeedi F, Loutfi I. 99mTc sulfur colloid and 99mTc mebrofenin hepatobiliary functional liver imaging in normal and diabetic rats. Medical Principles and Practice. 2011;20(2):129-132. doi:10.1159/000321216. PubMed
5. Hsu YL, Chen YW, Lin CY, et al. Variable uptake feature of focal nodular hyperplasia in Tc-99m phytate hepatic scintigraphy/single-photon emission computed tomography — A parametric analysis. Kaohsiung Journal of Medical Sciences. 2015;31(12):621-625. doi:10.1016/j.kjms.2015.09.010. PubMed
6. Schmidt E, Udvaros E, Szabó Z, Zámbó K. Varying appearance of focal nodular hyperplasia in nuclear medicine imaging. Clinical Nuclear Medicine. 2008;33(1):71-73. doi:10.1097/RLU.0b013e318148b229. PubMed
7. D'Souza VJ, Sumner TE, Watson NE, Formanek AG. Focal nodular hyperplasia of the liver imaging by differing modalities. Pediatric Radiology. 1983;13(2):77-81. doi:10.1007/BF02390106. PubMed
8. Tong EC, Son YO, Lee CH. A simplified method of assessing hemodynamics in technetium-99m sulfur colloid liver imaging. Clinical Nuclear Medicine. 1987;12(9):723-728. doi:10.1097/00003072-198709000-00011. PubMed
9. Phillips WT, Andrews T, Liu H, et al. Evaluation of [99mTc] liposomes as lymphoscintigraphic agents: comparison with [99mTc] sulfur colloid and [99mTc] human serum albumin. Nuclear Medicine and Biology. 2001;28(4):435-444. doi:10.1016/s0969-8051(01)00198-6. PubMed
10. International Commission on Radiological Protection. ICRP Publication 128: Radiation Dose to Patients from Radiopharmaceuticals — A Compendium of Current Information Related to Frequently Used Substances. Annals of the ICRP. 2015;44(2S). icrp.org