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Ischemia-Reperfusion Injury - Causes, Pathophysiology and Management

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Ischemia-Reperfusion Injury - Causes, Pathophysiology and Management

4 min read


Ischemic reperfusion is a critical medical condition that challenges physicians after successful liver transplantation. Read in detail the below article.

Medically reviewed by

Dr. Jagdish Singh

Published At July 22, 2022
Reviewed AtMay 10, 2023


Ischemic reperfusion injury is connected with serious medical conditions like myocardial infarction, cerebral dysfunction, gastrointestinal dysfunction, acute heart failure, systemic inflammatory response syndrome, and multiple organ dysfunction syndromes. Cell damage occurs by long ischemic reperfusion injury, which may lead to apoptosis (programmed cell death), autophagy (body’s mechanism to clean out body’s cells), necrosis (cell death), and necroptosis (alternative mode of mimicking cell death).

What Is Ischemia-Reperfusion Injury?

Ischemic-reperfusion injury is a blood circulation disorder caused by various factors like surgery, shock, transplantation, burns, and thrombus (blood clot). Restoration of the blood flow to the damaged myocardium shoots further ischemic cellular damage. This paradoxical effect is known as ischemic reperfusion injury.

Hepatic ischemia-reperfusion injury (IRI) is a pathophysiological process that involves complex systemic processes affecting multiple tissues and organs. Liver ischemia-reperfusion, on a serious note, impairs liver function and even causes irreversible damage to the liver. Also leads to a cascade of multiple organ dysfunction.

How Does It Occur?

  • This involves a complex interaction between the intracellular calcium and oxygen free radicals, which leads to the acceleration of myocardial damage and death, fatal arrhythmias (a condition caused by the improper beating of the heart that can be life-threatening), and microvascular dysfunction.

  • An endothelium derives the relaxing factor nitric oxide’s role as a cardioprotective agent against reperfusion injury. Nitric oxide works over inactive oxygen free radicals, thus, ameliorating the process.

  • Decreasing ATP production in mitochondria produces anaerobic metabolism, dysfunction of sodium-potassium pumps, and detachment of ribosomes. There are no specific therapies to prevent this condition.

How Does Ischemia-Reperfusion Injury Cause Necrosis?

Ischemia-reperfusion induces the cell to degenerate due to the dysfunctional ion transport mechanism. This causes cells to swell and burst, thus affecting the plasma membrane damage and causing necrosis of cells.

How and When Does Liver Ischemia-Reperfusion Injury Occur?

  • A local sterile inflammatory response by innate immunity is a primary cause of organ dysfunction after liver transplantation or liver resection surgery; this causes liver ischemia-reperfusion injury.

  • Cellular damage resulting due to this injury is an important risk factor for graft dysfunction but also acute and even chronic rejection. Hepatocytes (liver cells), liver sinusoidal (capillaries of the liver), endothelial cells (single layer cells that line the blood vessels), and kupffer cells (phagocytic cells of the liver), along with extrahepatic monocyte-derived macrophages (cells produced in response to infection), neutrophils (type of white blood cells), and platelets (thrombocytes-blood cells), are involved in this injury. This causes acute to chronic liver failure up to 30 % after liver transplantation.

What Are the Pathophysiologic Conditions of Liver Ischemia-Reperfusion Injury?

  • The restriction of blood flow has multiple effects on an organ. The primary consequences are decreased oxygen delivery (hypoxia) and reduced removal of toxic metabolites.

  • Hypoxia is the main reason which results in ischemic liver injury.

  • Hypoxia results in the depletion of adenosine triphosphate (ATP), which is required to Austin multiple cellular processes like DNA or RNA synthesis, maintenance of Na and K pumps, protein synthesis, and degradation.

  • Due to mitochondrial injury, ATP levels are adversely affected, thus decreasing mitochondrial mass and activity.

  • Mitochondria involve a major contribution to the oxidative injury occurring during ischemia injury.

  • Sterile inflammation is another characteristic feature of ischemia-reperfusion injury. This is primarily attributed to the actions of the innate immune system.

  • Neutrophil-mediated oxidative injury is the most important harming process in this.

  • Damage-associated molecular patterns (DAMPs) are released by the injured hepatocyte (liver cells) after ischemia-reperfusion.

  • DAMP’s pattern recognition receptors (PRRs) on innate immune cells are toll-like receptors (TLRs), nucleotide oligomerization domain-like receptors (NLRs), and retinoic acid-inducible gene I-like receptors (RLRs).

  • TLR 4 is a PRR that has contributed to the pathogenesis of hepatic ischemia injury.

  • In addition to innate immune response, there is growing evidence of proinflammatory adaptive immune response, with CD4T cells playing a key role.

  • Several protective mechanisms are also activated during an injury, like the activation of the autophagy salvage pathway. This autophagy targets dysfunctional organelles and large molecules for lysosomal degeneration.

  • The factors and cells implicated in the hepatic reperfusion injury are anaerobic metabolisms, oxidative stress, intracellular calcium overload, liver kupffer cells, neutrophils, cytokines and chemokines, and mitochondria.

How Is the Management of Ischemic Reperfusion Injury Done?

  • Therapeutic approaches are different based on the injured organ.

  • For a condition like sepsis, timely resuscitation with adequate fluids and vasopressors is recommended.

  • To control malignant arrhythmias, staged gradual reflow or transient acid perfusion management approaches to reduce reperfusion injury.

  • In acute myocardial infarction, reperfusion arrhythmias are common, and patients are recommended to undergo revascularization.

  • In acute ischemic extremity injuries, the first step is shortening ischemic time, correcting metabolic acidosis, preventing acute renal injury, metabolic techniques, or anti-inflammatory treatments.

Management in Case of Liver Ischemia-Reperfusion Injury:

  • Novel therapies are needed to mitigate liver ischemia in liver transplant recipients as it is an inevitable event following surgery that affects clinical outcomes and contributes to donor shortage.
  • A mixture of cell death pathways, namely apoptosis, necrosis, necroptosis, pyroptosis, and ferroptosis, triggers hepatocellular damage and provokes an inflammatory immune cascade in the stressed liver.

  • Numerous drugs have been tried for the prevention of liver reperfusion injury.

  • Therapies like AKT activators, AMPK activators, PPARr agonists, and miRNA-based therapies have shown promising treatment strategies.

  • IPC and IPostC, with further research, are the optimized protocols to validate efficacy.

  • Machine perfusion therapies are used to preserve the organs before transplantation like HMP (hypothermic machine perfusion), HOPE (oxygenation of HMP perfusate), and NMP (normothermic machine perfusion).

  • In all these machine perfusions, NMP has the greatest strength due to an increase in utilization and preservation time, allowing the transplantation of currently deemed organs.


The liver transplant is the standard treatment in patients with end-stage liver disease and with tumors of hepatic origin. The damage incurred by organ procurement and preservation affects this condition. And in turn, this contributes to donor organ shortage and is a major risk factor for chronic and acute graft rejection. The use of steatotic organs severely limits increased susceptibility to liver ischemia-reperfusion injury. Dynamic organ preservation techniques like HOPE (additional oxygenation of HMP perfusate) hold promise to not only enhance the performance of allografts but also optimize organ pool utilization, thus improving the prognosis of patients. The use of machine perfusion offers significant potential in reconditioning liver grafts and the prevention of liver ischemia-reperfusion injury.

Frequently Asked Questions


What Are the Examples of Reperfusion Injuries?

Examples of reperfusion injuries are as follows:
- Myocardial ischemia-reperfusion injury.
- Cerebral ischemia-reperfusion injury.
- Hepatic ischemia-reperfusion injury. 


What Are the Three Components That Make Reperfusion Injury?

Reperfusion injury is composed of three components, which are:
- Oxidative stress.
- Calcium overload.
- Inflammation.


Which Reperfusion Injury Is the Most Common?

Myocardial ischemia-reperfusion injury is the most common form of reperfusion injury, which occurs when blood flow to the heart muscle is temporarily interrupted and then restored, leading to tissue damage and impaired function.


What Are the Characteristics or Features of Reperfusion Injury?

Reperfusion injury is characterized by the following features:
- Tissue damage.
- Cellular swelling.
 - Impaired mitochondrial function.
- Activation of immune cells.


What Is a Potential Complication of Reperfusion Injury?

A potential complication of reperfusion injury is the development of secondary damage to adjacent tissues, which occurs due to the spread of inflammation and oxidative stress from the primary affected area.


What Is the Mechanism of Reperfusion Injury?

The mechanism of reperfusion injury involves the following:
- Production of reactive oxygen species.
- Activation of inflammatory pathways. 
- Disruption of cellular calcium homeostasis.


How Does Myocardial Ischemia-Reperfusion Injury Occur?

Myocardial ischemia-reperfusion injury occurs when blood flow to the heart muscle is temporarily interrupted and then restored, which can lead to tissue damage and impaired function.


What Are the Indicators or Signs of Reperfusion?

Indicators or signs of reperfusion include the following:
- Changes in blood pressure.
- Heart rate
- Oxygen saturation levels.


How Can Ischemia-Reperfusion Injury Be Treated?

Treatment options for ischemia-reperfusion injury include the following:
- Anti-inflammatory drugs.
- Antioxidants.
- Calcium channel blockers. 


What Is the Role of Calcium in the Development of Ischemia-Reperfusion Injury?

Calcium has a significant role in the development of ischemia-reperfusion injury by causing the following effects.
- Cellular damage. 
- Inducing inflammation.


What Are Some Preventive Measures for Reperfusion Injury?

Preventive measures for reperfusion injury include the following:
- Optimizing blood flow to the affected tissue.
-Avoiding prolonged ischemic episodes.
- Using anti-inflammatory drugs.


Which Organ Is the Most Susceptible to Ischemia-Reperfusion Injury?

The most susceptible organ to ischemia-reperfusion injury is the liver due to its high metabolic rate and dependence on oxygen for proper function.


Which Part of the Heart Is More Prone to Ischemia?

The part of the heart that is more prone to ischemia is the left ventricle due to its high workload and dependence on oxygen-rich blood for proper function.


Can Thrombolysis Lead to Reperfusion Injury?

Yes, thrombolysis can lead to reperfusion injury in some cases, and it can occur when the sudden restoration of blood flow to the affected area leads to tissue damage and impaired function.


Which ECG Lead Is Used for Detecting Ischemia?

Lead II is commonly used for detecting ischemia on the ECG (electrocardiogram).


What Are the ECG Signs or Symptoms of Ischemia?

ECG (electrocardiogram) signs or symptoms of ischemia include the following:
- ST-segment depression or elevation.
- T-wave inversion.
- Appearance of Q waves. 
Source Article IclonSourcesSource Article Arrow
Dr. Jagdish Singh
Dr. Jagdish Singh

Medical Gastroenterology


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