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| REVIEW ARTICLE |
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| Year : 2023 | Volume
: 3
| Issue : 2 | Page : 39-43 |
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Clinical encounters with kupffer cells while managing patients with liver diseases: Part 1 (Focus on Liver Imaging)
Vijay Alexander, Kovi Sai Lakshmi, CE Eapen
Department of Hepatology, Christian Medical College, Vellore, Tamil Nadu, India
| Date of Submission | 02-Dec-2022 |
| Date of Decision | 02-Jan-2023 |
| Date of Acceptance | 16-Jan-2023 |
| Date of Web Publication | 09-Mar-2023 |
Correspondence Address:
C E Eapen
Department of Hepatology, Christian Medical College, Vellore (Ranipet Campus), Tamil Nadu
India
 Source of Support: None, Conflict of Interest: None
DOI: 10.4103/ghep.ghep_36_22
Reticuloendothelial cells such as tissue-resident macrophages have an important function of clearing unwanted material from our bloodstream. Kupffer cells residing in liver sinusoids comprise the largest contingent of tissue-resident macrophages in our body. Different radiological techniques used to diagnose and treat patients with liver diseases employ the scavenging function of Kupffer cells to clear the contrast agents administered into peripheral vein or hepatic artery. It is useful for the clinician to understand the utility of these “unsung heroes” in liver microcirculation: The Kupffer cells act as scavengers removing waste material from bloodstream and work silently to maintain homeostasis.
Keywords: Kupffer cell, lipiodol, macrophages, reticuloendothelial system
How to cite this article:
Alexander V, Lakshmi KS, Eapen C E. Clinical encounters with kupffer cells while managing patients with liver diseases: Part 1 (Focus on Liver Imaging). Gastroenterol Hepatol Endosc Pract 2023;3:39-43 |
How to cite this URL:
Alexander V, Lakshmi KS, Eapen C E. Clinical encounters with kupffer cells while managing patients with liver diseases: Part 1 (Focus on Liver Imaging). Gastroenterol Hepatol Endosc Pract [serial online] 2023 [cited 2023 Mar 27];3:39-43. Available from: http://www.ghepjournal.com/text.asp?2023/3/2/39/371278 |
| Reticuloendothelial System and Vital Staining: Historical Perspective | |  |
For elucidating the phenomenon of phagocytosis, Metchnikoff was awarded the Nobel Prize more than a century ago. He categorized phagocytes into macrophages (“large eaters”) and microphages (“small eaters,” later renamed as polymorphonuclear leukocytes).[1]
The term “reticuloendothelial system” (RES) was coined in 1924 by Ludwig Aschoff.[2] The RES cells appeared to ingest and remove vital dyes from the circulation. These cells tend to form a reticulum or network by cytoplasmic extensions (referred to as “reticulo”), and “endothelial” referred to their close proximity to vascular endothelium, from which they were believed to originate. Scavenging of foreign particulate matter from blood was considered the major function of the RES.
“Vital” dyes/stains are applied to living cells without causing cell death. In contrast, supravital stains are applied to cells taken out of the body. The uptake of vital dye by phagocytosis was used to identify RES cells. Some of the intravenous contrast agents used during magnetic resonance imaging (MRI) are taken up by Kupffer cells, and are examples of vital dyes. Stains applied onto a liver biopsy specimen are an example of supravital stain.
In 1969, RES was renamed as “mononuclear phagocyte system.”[2] RES and MPS refer to overlapping parts of the human immune system. MPS refers to macrophages, monocytes, and dendritic cells with the exclusion of endothelial cells.[3] The term RES emphasizes the anatomical proximity and interdependent functioning of the tissue-resident macrophages and endothelial cells.
Kupffer cells, the most abundant tissue macrophages in the body, reside in the liver adjacent to sinusoidal endothelial cells. Both liver sinusoidal endothelial cells and Kupffer cells filter out waste products from the blood traversing the liver sinusoids. While Kupffer cells remove insoluble particulate matter by phagocytosis, the liver sinusoidal endothelial cells remove soluble macromolecules and colloids by pinocytosis.
| Clinical Applications of Phagocytosis of Vital Dyes used in Hepatic Diagnostic and Therapeutic Radiological Techniques | | |
A variety of contrast agents are injected into a peripheral vein during imaging studies of the liver such as computed tomography (CT) scan, MRI scan, or contrast-enhanced ultrasound (CEUS). Less often, contrast agents (e.g., lipiodol) are infused directly into the hepatic artery to detect hepatocellular carcinoma during lipiodol CT. These parenterally administered contrast agents reach the liver sinusoids.
The route taken by these parenterally administered contrast agents in the liver to be removed from the bloodstream is analyzed to assess different focal and diffuse liver pathologies by imaging studies. Commonly used intravenous contrast agents during CT scan (like iodixanol) and MRI scan (like gadolinium) traverse from the liver sinusoid to the extravascular space (termed space of Disse or interstitium). Other contrast agents administered through the peripheral vein or into hepatic artery (Lipiodol) do not traverse from the liver sinusoid into the interstitium (space of Disse) and hence are cleared by scavenging cells (Kupffer cells) [Table 1]. | Table 1: Sites of clearance (marked as +) in the liver of radiological contrast agents administered intravascularly after they reach the hepatic sinusoid
Click here to view |
Many factors determine the clearance route of unwanted material such as contrast agents used in diagnostic radiological tests, from the bloodstream. The liver sinusoidal endothelial cells have pores or fenestrae (diameters of ~100–150 nm). The size of the fenestra and factors influencing the dynamic changes in the size of these fenestrae can influence which of the unwanted material can traverse the sinusoidal endothelial cells. The presence of receptors to remove unwanted material from the bloodstream (“scavenger receptors”) on macrophages determine which substances are phagocytozed by these cells. At least ten classes of scavenger receptors are now described on the surface of macrophages and liver sinusoidal endothelial cells.[4]
| Diagnostic and Therapeutic Radiological Techniques Used in Patients with Liver Disease Which Utilize Clearance of Contrast Agents by Kupffer Cells | | |
The following sections briefly discuss the relevance of clearance of parenterally administered contrast agents during liver imaging studies and during radiological interventions for focal liver lesions. Contrast agents administered through the peripheral vein (during contrast-enhanced MRI scan of the liver and CEUS of the liver) and through a hepatic artery (during lipiodol CT scan) are of interest to the clinician in this regard.
Contrast-enhanced magnetic resonance imaging scans of the liver
Contrast agents increase the sensitivity and specificity of MRI by changing T1 and T2 relaxation rates; this results in increased signal intensity on T1-weighted images or decreased signal intensity on T2-weighted images, or both.[5] Low concentrations of gadolinium diethylenetriamine penta-acetic acid shorten T1 relaxation times. Superparamagnetic agents such as ferrite shorten T2 relaxation times, resulting in a loss of signal in the liver with all commonly used pulse sequences. Superparamagnetic iron oxide particles for parenteral use are coated with substances such as albumin, starch, or dextran to facilitate uptake by RES.
Examples of MRI hepatobiliary contrast agents are gadolinium-based agents and superparamagnetic iron oxide agents.
Tissue enhancement after intravenous gadolinium-based contrast may be due either intravascular enhancement or interstitial enhancement. The enhancement of liver lesions in the hepatobiliary phase with gadolinium-based agents depends on the presence of functioning hepatocytes. Hence, these contrast agents are specific to hepatocyte function.[6] Hepatocyte-specific MRI contrast agents are taken up by functioning hepatocytes and excreted through the biliary system. They can help differentiate focal liver lesions of hepatocellular origin from those of nonhepatocellular origin. They can be used to evaluate the biliary tree[6] and improve sensitivity to detect hepatocellular carcinoma using the hepatobiliary phase.[7]
Iron oxide particles do not leak into the interstitial compartment, hence they act as intravascular contrast agents (when vascular endothelium is intact). They are taken up by Kupffer cells and reduce T2 relaxation time; hence, the normal liver appears dark on T2-weighted images with this contrast administration. Some hepatic tumors are deficient in Kupffer cells; hence, these tumors do not take up this contrast and appear relatively hyperintense. However, well-differentiated tumors with intact native Kupffer cells take up iron oxide particles and exhibit reduced signal intensity.[8]
MRI-based in vivo macrophage imaging is also used in animal experiments to study immune response in the liver.[9]
| Toxicity of Gadolinium-Based Contrast Agents is Mediated by Macrophages | | |
The most gadolinium-based contrast media distribute primarily in extracellular fluid have little protein binding and are mainly excreted in urine by glomerular filtration.
Gadolinium-based contrast MRI agents when administered to patients with chronic kidney disease can cause a systemic fibrosing illness (nephrogenic systemic fibrosis). The release of labile iron from iron-recycling CD163 macrophages and ferroportin-expressing macrophages may mediate the contrast agent toxicity.[10]
The risk of nephrogenic systemic fibrosis with the use of Group II gadolinium contrast agent is considered extremely low.[11]
| Gadolinium Chloride Used to Inactivate Kupffer Cells in Animal Models | | |
It is of interest that gadolinium is also used as an agent to inactivate/eliminate Kupffer cells in different animal experiments.[12]
Contrast-enhanced ultrasound of the liver
CEUS is used to visualize contrast enhancement patterns in real time in all vascular phases (arterial, portal venous, and late). The portal venous phase occurs 45–120 s after the injection of contrast and late phase occurs 2–5 min after the contrast injection. Enhancement patterns in portal venous and late phases provide added information to characterize liver lesions. Typically, malignant lesions are hypoenhancing, while most solid, benign lesions are isoenhancing or hyperenhancing.[13]
Contrast agents used to enhance ultrasound are microbubbles of gas stabilized by a shell. Examples are Sonazoid (perfluorobutane with a phospholipid shell) and SonoVue (sulfur hexafluoride with a phospholipid shell).
The ultrasound contrast agents can be categorized as
- Agents taken up by the RES (e.g., Sonazoid) – these have a postvascular phase after an initial intravascular phase
- Agents which remain in intravascular compartment (“blood pool agents” like Sonovue).[14]
Sonazoid is taken up by Kupffer cells; hence, there is an additional postvascular phase (or Kupffer phase) starting 10 min after contrast injection, lasting ≥1 h.[15]
What is the evidence that the late phase in CEUS of the liver is due to phagocytosis of contrast agent microbubbles by macrophages?
In vitro phase, contrast microscopy has demonstrated phagocytosis of various contrast agents by Kupffer cells. The degree of phagocytosis by Kupffer cells varied among the different ultrasound contrast agents studied, for example, 99% of Sonazoid were phagocytosed, while only 7% of SonoVue and 0% of Imavist were phagocytosed. Thus, Sonazoid can be considered a RES contrast agent.[14]
Some of the Sonovue bubbles transiently attached to the Kupffer cells (without phagocytosis). On inactivating RES by gadolinium chloride, the enhancement of the liver decreased by 13% for Sonovue and 47% for Sonazoid.[16] These studies provide the evidence that phagocytosis of the contrast agents used in ultrasound by Kupffer cells is responsible for the late-phase images on contrast ultrasound in the liver.
In vitro studies in cultured cell monolayers showed that the ultrasound contrast agents attached to mouse macrophage such as like cell lines and not to endothelial cells.[17]
Liver lesions containing Kupffer cells demonstrate late-phase binding and/or sequestration of blood pool ultrasound contrast agents. The presence and functioning of Kupffer cells in focal nodular hyperplasia in liver and in hepatic adenomas appear to be different (hepatic adenomas appear to a lack functioning Kupffer cells).[18],[19] The most focal nodular hyperplasias typically have absent washout in the late phase.[20] In contrast, hepatic adenomas often have less Kupffer cells, and sustained portal phase enhancement is less common in hepatic adenomas than in focal nodular hyperplasia.[21]
The degree of differentiation of hepatocellular carcinoma correlates with the late (Kupffer cell) phase of Sonazoid. Moderately differentiated and poorly differentiated hepatocellular carcinoma show hypoenhancement, while most well-differentiated hepatocellular carcinoma shows isoenhancement in the Kupffer cell phase.[22],[23]
Lipiodol computed tomography scan of the liver
Lipiodol is an oil-based iodinated contrast medium used initially for myelography and hysterosalpingography.
While MRI and CT scans have good sensitivity to detect hepatocellular carcinoma >2 cm sized, they are less sensitive to detect smaller-sized lesions. Performing CT after the injection of intraarterial lipiodol injection helps improve the detection of small tumors [Figure 1]. Lipiodol is also used during transarterial chemoembolization to treat hepatocellular carcinoma, for its tumor-seeking ability, for better radio-opacification, and transiently embolize tumor microcirculation.[24],[25],[26],[27] | Figure 1: (a) Digital subtraction angiogram (a) Hepatic arterial angiogram shows hypervascular nodule (arrow) (b) CT noncontrast scan done 12 days after lipiodol injection into hepatic artery shows focal intense retention of lipiodol within the hepatocellular carcinoma in the segment 5 of liver. CT: Computed tomography
Click here to view |
The addition of lipiodol to standard diagnostic modalities enables the earlier detection of primary and metastatic hepatic tumors. In a study of 22 patients with 37 nodular hepatocellular carcinoma lesions, all patients had ultrasonography, CT, MRI, digital subtraction angiography, and Lipiodol CT. All study patients had surgery eventually, and intraoperative ultrasound was taken as the gold standard to detect hepatocellular carcinoma. In this study, lipiodol CT had the highest sensitivity to detect small nodular hepatocellular carcinoma.[28] CT scan was done 3–5 weeks after lipiodol injection in 18 patients with 25 hepatocellular carcinoma lesions treated by percutaneous ethanol injections earlier showed lipiodol retention; CT had 69% sensitivity and 83% specificity to detect residual viable tumor.[29] Lipiodol CT had a high positive predictive value to detect intrahepatic metastatic nodules in patients with hepatocellular carcinoma.[30]
Selective retention of lipiodol in hepatocellular carcinoma may be caused by the siphoning effect of tumor vessels, leading to the flow of lipiodol into vessels supplying the tumor, electrostatic difference between lipiodol and tumor endothelium, and lack of clearance of lipiodol by Kupffer cells.[31] Lipiodol is normally phagocytosed by Kupffer cells and cleared within a week through lymphatic channels.[32]
On injection into the hepatic artery, lipiodol selectively can remain in tumor nodules for even up to a year, resulting in embolic effects on smaller vessels. Lipiodol also acts as a vehicle to carry chemotherapeutic agents inside a tumor.
Animal models of iodized oil injected into the hepatic artery have demonstrated Kupffer cells actively capturing and engulfing the oil droplets in the hepatic sinusoids.[33],[34]
In conclusion, it is useful for the clinician caring for patients with liver disease to be familiar with the RES in the liver and its scavenging functions. The choice of contrast agents used to enhance liver imaging studies rests with the radiologist.[35] Various diagnostic and therapeutic interventional radiological techniques used in these patients utilize the clearance of contrast agents by Kupffer cells. A better understanding of the scavenging function of Kupffer cells may help clinicians provide better care for patients with liver diseases.
Acknowledgment
We gratefully acknowledge Dr. Shyam Kumar, Interventional Radiology department, Christian Medical College, Vellore, Tamil Nadu, for his inputs.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
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[Figure 1]
[Table 1]
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