1. The document discusses the physiology of hepatic microcirculation including the dual blood supply from the portal vein and hepatic artery. 2. It describes techniques to study hepatic microcirculation such as radioactive microspheres and various imaging modalities. 3. Modes of microvascular inflammation and dysfunction in liver injury are explained involving Kupffer cell activation, leukocyte recruitment, and endothelial dysfunction.

1. Microcirculation in liver
transplant
Dr. Rohit Saini
Moderator: Dr. Neha

2. Topics
1. Physiology of hepatic microcirculation
2. Techniques to study hepatic microcirculation
3. Microvascular inflammation in liver injury
4. Microvascular dysfunction in liver injury
5. Modes of cell death in liver injury
6. Measures targeting hepatic microvascular disorders

3. Physiology of hepatic microcirculation
• Dual blood perfusion:
1. Portal vein – valveless afferent vessel, 75 – 80% blood supply
2. Hepatic artery - 20 - 25% blood supply
• Hepatic oxygenation almost equally by both afferent vessels
• Efferent vessel – Hepatic vein
• Hepatic artery is a vessel of resistance, whereas the portal
and hepatic veins are vessels of capacitance.

4. “Hepatic arterial buffer response”
(HABR)
• Burton-Opitz observed this response in 1911, the term HABR
was stamped in 1981 by Wayne Lautt
• Ability of hepatic artery to produce compensatory flow
changes in response to changes in portal venous flow

5. HABR
• Adenosine: putative mediator in space of Mall driving the
communication between hepatic artery and portal vein
• Other mediators: NO,CO, H2S
• capable of buffering 25– 60% of the decreased portal flow
Cirrhosis Normal

6. HABR
Importance?
• In cirrhosis and liver transplants, HABR is maintained
• Split liver transplant (Small-for-size grafts): due to intact
HABR, poor hepatic arterial flow with vasospasm occurs and if
severe, leads to functional dearterialization, ischemic
cholangitis, and parenchymal infarcts

7. Anatomy of hepatic vasculature

8. Anatomy of hepatic vasculature

9. Anatomy of hepatic vasculature

10. Regulation of the hepatic
microvascular blood flow

12. Regulation of the hepatic
microvascular blood flow

13. Techniques to study hepatic
microcirculation
1. Radioactive microspheres technique
2. Hydrogen, Xenon and ICG technique
3. Laser doppler flowmetry
4. Near-Infrared spectroscopy
5. In Vivo fluorescence microscopy
6. Orthogonal polarized spectral imaging
7. Sidestream dark-field imaging
8. Incidental dark-field imaging

17. Microvascular inflammation in liver
injury
A. Kupffer cell activation, oxidative stress, mediator release
B. Leukocyte recruitment within hepatic microvasculature
C. Leukocyte transendothelial migration and parenchymal cell
killing
D. Platelet adhesive interactions
E. Sinusoidal cell plugging

19. It is the global mismatch and the
imbalance of pro- and anti-
inflammatory substances that cause
a disease

20. Microvascular dysfunction in liver
injury
Sinusoidal endothelial cell activation
Sinusoidal vasomotor dysfunction
Sinusoidal perfusion failure and hypoxic cell injury
Sinusoidal endothelial capillarization

21. Microvascular dysfunction in liver
injury
• Imbalance between vasoconstrictive ET-1 and vasodilative
molecules NO, CO with a shift towards ET system:
1. Increased ET-1 production by HSC, KC and SEC
2. Increased expression and sensitivity of ET-B2 receptor on
HSC
3. The increased expression of iNOS further stimulates ET-1
production, most probably through the excessive NO release

24. Modes of cell death in liver injury

25. Measures targeting hepatic
microvascular disorders

26. Radical scavengers and antioxidants
• Superoxide dismutase
• N acetyl cysteine
• Tocopherol
• Allopurinol
• Glutathione
• Glutamine
• NADPH oxidase
inhibitor
• Selenium
1. Inhibition of intrahepatic
leukocyte accumulation
2. Inhibition of lipid peroxidation
3. Increase of hepatic
microvascular blood flow
4. Attenuation of sinusoidal
perfusion failure
Mechanism of
action

27. Heat shock proteins and metabolites
• Heme oxygenase 1
• Carbon monoxide
• Bilirubin and biliverdin
1. Antioxidant
2. Anti inflammatory
3. Anti apoptotic
4. Reduction in adhesion
molecule expression
5. Vasodilatory effect
Mechanism of
action

28. Antiapoptotic agents:
• PARP inhibitors
• Caspase inhibitors.
Adhesive molecule antibodies
• Anti-ICAM-antibodies
• Anti-P-selectin antibodies
Vasoactive agent:
• NO
• ET receptor antagonist
• CO
• PGE2
Measures Targeting Microvascular
Disorders.

29. Immunomodulatory and pleotropic drugs
• Statins  prevents lipid peroxidation, antioxidant, anti-
inflammatory
• Erythropoietin(EPO) antioxidant; reduces apoptosis,
cytokine release and leukocyte infiltration.
• L-Glycine  Downregulation of TLR4 signaling, decrease TNF
alpha, inhibit lipid peroxidation
• ANP  Anti apoptotic, vasodilatory
• Melatonin  Increase of NO bioavailability, inhibit lipid
peroxidation
Measures Targeting Microvascular
Disorders.

32. Ischemia-reperfusion injury

33. Ischemic preconditioning:
reduces organ IRI by brief period of organ ischaemia
• Reduces neutrophil specific oxidant stress
• Improves hepatic microcirculation
• Attenuates apoptosis and necrosis
Mechanism: Increases vasodilators (NO, adenosine),
antioxidants, heat shock proteins.
Preconditioning manuevers

34. H. Hirao, et al. Heme Oxygenase-1 in liver transplant ischemia-reperfusion injury; Free
Radical Biology and Medicine (2020)

36. Preconditioning manuevers
In human trials, most meta-analyses, systematic reviews, and
Cochrane reports provide no evidence to support or refute
the use of ischemic preconditioning in donor liver retrievals
and to recommend it as a standard procedure for hepatic
resection
Gurusamy KS, et al., 2008
Rahbari NN, et al. Br J Surg. 2008

37. Small-for-size syndrome
Increased portal venous flow & high PVP
Shear stress in hepatic microcirculation
Sinusoidal endothelial cell injury & vascular occlusion
Hepatocellular necrosis and graft failure.
Compensatory hepatic arterial vasoconstriction ischemic
cholangitis and centrilobular necrosis.

38. Mainly to prevent portal overflow
• Splenic artery ligation or embolization
• Splenectomy
• Portocaval or hemi-portocaval shunt.
Surgical procedures

39. Immunomodulatory effect

40. •Sevoflurane protected liver from IRI by increasing miR-9-5p
expression in rat liver model
•Increased miR-9-5pexpression inhibited NF-κB signaling
pathway activation, a cytokine storm and apoptotic cell death
•Further, it decreased IL-1, IL-6 and TNF-α levels

42.  Study on 61 patients with HCC undergoing hepatectomy
under GA or combined epidural and GA showed that patients
receiving neuraxial blockade had a more favorable Th1/Th2
lymphocyte ratio and potentially benefiting HCC patients by
promoting anti-tumor Th polarization.

43.  Study in surgical treatment of GB cancer found that addition
of RA in GA resulted in improved immune cell function
 The survival rate of CD3+, CD4+, and CD4+/CD8+
lymphocytes was signifi cantly higher, which improve patients’
postoperative immunological condition and their long-term
prognosis
2017

44.  However, these positive effects of volatile anesthetics are
very difficult to identify or evaluate in clinical practice
 Data from reported clinical trials, as well as the in vitro and
in vivo experimental studies, have often reported conflicting
statements regarding the impact of inhalation anesthetics on
outcomes of surgical procedures.