Hepatobiliary MRI contrast agents

Last revised by Mohammad Taghi Niknejad on 16 Oct 2022

Hepatobiliary MRI contrast agents are specialized contrast agents used to aid diagnosis in MRI.

They are separated into three categories: gadolinium-based agents, manganese-based agents and superparamagnetic iron oxide particles. 

Gadolinium (Gd) based contrast agents are classified into:

  1. non-specific extracellular gadolinium chelates (do not bind to serum proteins)
  2. high relaxivity agents (bind to serum proteins)

Hepatobiliary specific gadolinium agents include two of the high relaxivity agents: gadobenate dimeglumine (Gd-BOPTA) and gadoxetate disodium (Gd-EOB-DTPA).

Biochemically, these agents are linear ionic molecules and show higher T1 relaxivity (>6.5 L/mmol/s at 1.5 T) as compared to the other Gd chelates (<4.8 L/mmol/s at 1.5 T).

These agents initially act like non-specific extracellular gadolinium chelates post bolus injection and show three primary phases of vascular and tissue enhancement (arterial, blood pool and extracellular phases). However, in the delayed (hepatobiliary) phase, they are taken up by the liver as their excretion is not only through the renal but the hepatic route as well.

The absorption by hepatocytes is via the OATP1 transporter (polypeptide adenosine triphosphate-dependent organic anion transporter), the same as the bilirubin transporter. Thus, the enhancement of lesions in the hepatobiliary phase depends on the expression and activity of these transporters, depending on the presence or absence of functioning hepatocytes.  

During the hepatobiliary phase, they selectively increase the liver signal intensity and aid the in the detection of small tumors. Additionally, the biliary excretion enables biliary ductal mapping (post-contrast MRCP/ functional MRCP) using 3D T1 weighted fat-saturated GRE images.

a.       Gadobenate dimeglumine (Gd-BOPTA): weak and transient protein bonding (<5%) and only 2-4% of it is taken up by the liver cells. It goes by the trade name MultiHance (Bracco). Its delayed imaging time is between 90 to 120 minutes.

b.      Gadoxetate disodium (Gd-EOB-DTPA): has protein binding of <10%. It has almost equal biliary and renal excretion (~50% each). Compared to gadobenate, it has more intense liver parenchymal enhancement. The delayed imaging time is also more convenient (10-20 minutes). It goes by the trade name Primovist (Eovist/Bayer).

Mangafodipir trisodium (Mn-DPDP) is specifically taken up by hepatocytes due to its chemical similarity to vitamin B6. This property results in the increase in signal intensity of normal hepatic parenchyma. Thus, in the presence of a focal liver lesion, the increased signal of normal parenchyma gives a high lesion-to-liver contrast and hence provides improved detection, characterization and evaluation of liver lesions.

During the later phases, mangafodipir trisodium is excreted into the biliary system and provides a post contrast MRCP in the detection of biliary pathologies (~50% biliary excretion). It goes by the trade name Teslascan.

Unlike the gadolinium agents, mangafodipir trisodium readily dissociates to yield free manganese ions. This in vivo instability of the chelate rose concerns about potential toxicity.

Free manganese, in chronic exposure, causes a parkinsonism-like syndrome due to accumulation in the brain (manganism). Furthermore, a significant neurological risk is associated with manganese intoxication in subjects with liver dysfunction/hepatic encephalopathy whose ability to eliminate manganese is reduced. It can also have a depressive action on heart function.

Hence, mangafodipir trisodium was effectively withdrawn from the market.

Mn-based nanoparticles are under research for its use as high-performance contrast agents with reduced toxicity.

Superparamagnetic iron oxide particles such as magnetite (Fe3O4) or maghemite (γ-Fe2O3) contain a crystalline core of iron oxide crystals which are water-insoluble with the diameter of its core in the range of 4 to 10 nm.

These crystals are coated with dextran or other biodegradable polysaccharide which prevents particle aggregation. This modifies their biological behavior and makes the total size of the iron oxide particle substantially larger.

Superparamagnetic iron oxide particles do not leak into the interstitium. They, therefore, act as intravascular contrast agents or blood pool agents as long as the vessel endothelium is intact and unaltered by any pathological process. Their elimination from the blood is by uptake into the reticuloendothelial system cells in liver, spleen, bone marrow and lymph nodes and are phagocytosed by macrophages throughout the body.

The superparamagnetic iron oxide particles agents are preferentially entrapped by the Kupffer cells in the liver and spleen and reduce their T2 relaxation time. Thus, normal liver appears dark on T2 weighted images. Most liver tumors which are usually deficient in Kupffer cells, do not exhibit superparamagnetic iron oxide particles agent uptake and appear relatively hyperintense. However, well-differentiated tumors which have not lost all their Kupffer cells, will take up superparamagnetic iron oxide particles agents and exhibit reduced signal intensity.

Two superparamagnetic iron oxide particles have been approved for MR imaging:

  1. Ferumoxide:
    • particle size of 50 to 180 nm with a thin, incomplete dextran coating that causes individual particles to form polycrystalline aggregates. These aggregates behave in solutions or within cells as large particles.
    • administered as a slow IV infusion over 30-60 minutes with imaging typically performed 1 to 4 hours after infusion
    • liver appears darkest on T2*/T2 weighted images in the first 24 hours post infusion. The liver signal intensity returns to normal within 7 to 14 days in most cases; however, complete metabolism requires 14 to 28 days
    • most common complication is an acute severe low back pain, which can be minimized with a slow infusion
  2. Ferucarbotran: 
    • particle size ~60 nm and is coated with low molecular weight carboxydextran
    • provided as a ready to use formulation and is administered as a rapid bolus. It is thus used with both dynamic and delayed imaging
    • most common reported adverse events are vasodilation and paresthesias

Hepatobiliary-specific MRI contrast agents prolong the apparent "hepatobiliary phase", therefore there is no precise time requirement for imaging in this phase. High-spatial-resolution sequences in separate breath holds can complete imaging and longer imaging time can be used if needed, for example to study bile leak or contrast agent washout.

These features, combined with advances in MR imaging hardware and software, allow high-resolution images of the liver to be obtained.

  1. T1-weighted in and opposed-phase GRE
  2. T2-weighted FS fast SE
  3. T2-weighted MRCP
Post contrast imaging
  1. dynamic Imaging (in the case of Gd chelates)
  2. hepatobiliary phase imaging
  • parenchymal assessment: Axial and/or coronal 2D or 3D T1-weighted FS spoiled GRE
  • functional MRCP: Axial and oblique coronal 2D or 3D T1-weighted FS GRE

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