Association between Serum GGT and Acute stroke
Among all the neurologic diseases of adult life, stroke ranks first in frequency and importance. The common mode of expression of stroke is a relatively sudden occurrence of a focal neurologic deficit. Strokes are broadly categorized as ischemic or hemorrhagic. Ischemic stroke is due to occlusion of a cerebral blood vessel and causes cerebral infarction.
Ischemic strokes are classified by the underlying cause of the vascular occlusion. One of three main processes is usually operative:
There are many other pathologic processes that lead to ischemic brain damage, not all associated with occlusion of cerebral vessels, including arterial dissection, inflammatory conditions such as vasculitis, thrombosis of cerebral veins and dural sinuses, in situ thrombosis of large or small cerebral vessels due to hypercoagulable conditions, vasospasm from any of several mechanisms, unusual types of embolic materials such as fat, tumor, cholesterol, and several unique diseases that involve the cerebral vasculature. Closely allied with ischemic strokes is the transient ischemic attack (TIA), a temporary neurologic deficit caused by a cerebrovascular disease that leaves no clinical or imaging trace. The definition of TIA requires that all neurologic signs and symptoms resolve within 24 hours without evidence of brain infarction on brain imaging. (HARRISON’S). If there is evidence of a brain infarction or the neurologic signs and symptoms persist for more than 24 hours, stroke has occurred.
The second broad category consists of hemorrhage, which occurs either within the substance of the brain, called intracerebral hemorrhage; or blood contained within the subarachnoid spaces, called subarachnoid hemorrhage. The causes of the first category are numerous and include chronic hypertension, coagulopathies that arise endogenously or because of anticoagulant medications, vascular malformations of the brain, cranial trauma, and hemorrhage that occurs within the area of an ischemic stroke. (ADAM AND VICTOR’S PRINCIPLES OF NEUROLOGY 11TH ED).
Ischemic strokes, accounting for approximately 87% of all strokes, occur when a blood clot obstructs a blood vessel supplying blood to the brain. Haemorrhagic strokes, which make up the remaining 13%, occur when a blood vessel in the brain bursts, leading to bleeding in or around the brain.1 Both types of stroke lead to rapid loss of brain function and can result in permanent neurological deficits or death. (Vascular occlusion, the fundamental underlying cause of ischemic stroke, can be from embolic matter originating in the cardiovascular system distant from the region of the stroke (cardio-embolic) or from within the arteries (arterio-arterial), or thrombotic, in which a clot forms within a vessel in proximity to the area of infarction. Most embolic strokes occur suddenly and the deficit reaches its peak almost at once. Thrombotic strokes tend to evolve somewhat more slowly over a period of minutes or hours and occasionally days; in the latter case, the stroke usually progresses in a saltatory fashion, that is, in a series of steps rather than smoothly. ) Adams
Ischemic strokes result from severe occlusion and reduction in cerebral perfusion, leading to cerebral hypoxia, irreversible damage, and necrosis of brain tissue Additionally, conditions such as hemodynamic instability, inflammatory cascades, and increased permeability of the blood-brain barrier, along with infiltration of leukocytes, activation of glial cells and oxidative stress can further contribute to the narrowing of cerebral vasculature and result in ischemic strokes.4
Atherothrombosis is the usual underlying pathology for local vascular thrombosis. Atheromatous plaques preferentially form at branching sites and curves of the cerebral arteries. The most frequent sites are (1) in the internal carotid artery at its origin and as it enters the skull; (2) in the cerebral part of the vertebral arteries or at their origins in the subclavian vessel, and at their junction to form the basilar artery; (3) at the origins of the major branches of the middle cerebral arteries (4) in the main bifurcation of the middle cerebral arteries as they pass anteriorly and curve over the corpus callosum. Atherothrombosis may cause stroke by an occlusive plaque or a thrombus formed on a plaque which occupies the lumen of a major intracerebral vessel, such as the middle cerebral artery, and stops flow to the areas of the brain supplied by the vessel. A variation of this mechanism is one of occlusion by atherosclerosis of a more proximal vessel, such as the distal carotid artery. This may lead to infarction in the territory between major branches of the internal carotid circulation that are most susceptible to reduced blood flow—termed “borderzone,” or “end-arterial,” or less accurately, “watershed infarction,” depending on the richness of collateral vessels. Or, an atherothrombotic lesion in a proximal vessel may serve as the nidus for the formation of an embolus that manifests itself as a stroke in one of the territories of that vessel—called “artery-to-artery” embolism.
In haemorrhagic stroke bleeding in brain from ruptured vessel is the major pathology. Among the haemorrhagic stroke types, intracerebral haemorrhage (ICH) is more common than subarachnoid Haemorrhage. The arachnoid membrane is a thin layer of tissue that is named for the spiderweb-like pattern on its surface; if a vessel ruptures due to an AV malformation, this can result in stroke. Other less frequent causes of Haemorrhagic stroke include hemangiomas, dura fistulas, arteriovenous malformations, cavernous malformations, and venous malformations. Aronowski J, Zhao X. Molecular pathophysiology of cerebral hemorrhage: secondary brain injury. Stroke. 2011;42(6):1781-6.
The multicenter Trial of Acute Stroke Treatment (TOAST) categorizes ischemic stroke into five types:
1.Large vessel stroke
2.Small vessel stroke (Lacunar stroke)
3.Cardioembolic stroke
4.Stroke of other determined etiology
5.Stroke of undetermined etiology
Strokes involving large arteries may occur due to thrombotic or embolic occlusion of major brain arteries, such as the internal carotid, middle cerebral, anterior cerebral, or vertebrobasilar arteries. In contrast, lacunar strokes affect smaller, perforatingvessels that supply deeper structures of the brain.
The serious complication of ischemic stroke is haemorrhagic transformation, sometimes referred to as ischemia-related bleeding, is a serious and sometimes fatal consequence of acute ischemic stroke. It is believed that cerebral ischemia caused by artery occlusions leads to necrosis and disturbance of cerebral metabolism, which constitutes the pathophysiological mechanism of haemorrhagic transformation. Hong JM, Kim DS, Kim M. Hemorrhagic Transformation After Ischemic Stroke: Mechanisms and Management. Front Neurol. 2021;30;12:703258.
(In cerebral hemorrhage, also abrupt in onset, the deficit may be virtually static or steadily progressive over a period of minutes or hours, while subarachnoid hemorrhage is almost instantaneous. It follows that gradual downhill course over a period of several days or weeks will usually be traced to a nonvascular disease. There are, however, many exceptions, such as the additive effects of multiple vascular occlusions and the progression that is caused by secondary brain edema surrounding large infarctions and cerebral hemorrhages. A focal stroke syndrome that reverses itself entirely and dramatically over a period of minutes or up to an hour is called a TIA. The first distinction is to separate ischemic from hemorrhagic stroke; features that are characteristic of the latter such as headache and vomiting at the onset, rapid progression to coma, and severe hypertension. ) Adams
The World Health Organization (WHO) identifies stroke as the second leading cause of death globally, responsible for approximately 11% of all deatnhs. World Health Organization. The Top 10 Causes of Death. https://www.who.int/news-room/fact-sheets/detail/the-top-10-causes- of-death (2020). The Global Burden of Disease (GBD) study highlights that stroke was accountable for over 6.6 million deaths and 143 million disability-adjusted life years (DALYs) in 2019. GBD 2019 Stroke Collaborators. Global, regional, and national burden of stroke and its risk factors, 1990–2019: A systematic analysis for the Global Burden of Disease Study 2019. Lancet Neurol. 20, 795–820 (2019).
In India, the burden of stroke is substantial and growing, with profound implications for the healthcare system and public health. Stroke ranks as the fourth leading cause of death and the fifth leading cause of disability in the country.IndiaState-LevelDiseaseBurdenInitiativeStrokeCollaborators.TheburdenofstrokeinIndia:Asystematicreviewofpopulation-
based studies. Lancet Glob. Health 6, e662–e671 (2018). The incidence of stroke in India ranges from 119 to 145 per 100,000 population annually, with a higher prevalence observed in urban areas compared to rural regions.Banerjee,T.K.&Das,S.K.FiftyyearsofstrokeresearchinIndia.Ann.IndianAcad.Neurol.19,1–8(2016).
A significant proportion of strokes occur in individuals younger than 65 years, with approximately 20–30% of cases occurring in those under 50. Gupta, R. & Xavier, D. Hypertension: The most important non-communicable disease risk factor in India. Indian Heart J. 70,565- 572(2018).8.InternationalDiabetesFederation.IDFDiabetesAtlas9thedn.(InternationalDiabetesFederation,2019).The gender distribution shows a higher prevalence in males, although this disparity varies by region and age group.Prabhakaran,D.,Jeemon,P.&Roy,A.CardiovasculardiseasesinIndia:Currentepidemiologyandfuturedirections.Circulation 133, 1605–1620 (2016).
In a recent report titled "India: Health of the Nation's States," published by the ICMR, stroke ranked fifth in terms of Disability Adjusted Life Years (DALY) and fourth in terms of overall mortality in 2016.National Programme for Prevention and Control of Cancer, Diabetes, Cardiovascular Diseases & Stroke (NPCDCS). Guidelines for Prevention and Management of Stroke, MOHFW. Between 2018 and 2019, the US spent almost $56.5 billion on stroke-related expenses which include the price of medical services, stroke medications, and lost workdays. One of the main causes of significant, long-term disability is stroke. In over half of stroke survivors 65 years of age and older, the stroke reduces their mobility. Center for Disease Control and Prevention. “Stroke Prevention” CDC.
Stroke has major global health impact and is a big challenge, attributing to its disabilities and effect on cognitive functions. Stroke survivors has significantly affected quality of life and face chronic disabilities. It also has significant impact on financial cost which includes both acute and post stroke treatments including hospital services and rehabilitation. Tiwari S, Joshi A, Rai N, Satpathy P. Impact of Stroke on Quality of Life of Stroke Survivors and Their Caregivers: A Qualitative Study from India. J Neurosci Rural Pract. 2021;22;12(4):680-688.
Around 25% of people who have had a stroke will experience another stroke within five years of their first event. The risk of recurrence is highest immediately following the initial stroke but gradually decreases over time. Each additional stroke further increases the likelihood of severe disability and the risk of death. Within the first 30 days after a stroke, about 3% of patients suffer a second stroke, and nearly one-third experience a recurrence within two years. Prasad K, Vibha D, Meenakshi. Cerebrovascular disease in South Asia - Part I: A burning problem. JRSM Cardiovasc Dis. 2012;1:20.
In the last decades, imaging technology has been refined and allows the physician to make physiologic distinctions among normal, ischemic, and infarcted brain tissue. This approach to stroke will likely guide the next generation of treatments and has already had a profound influence on the direction of research in the field. Salvageable brain tissue in the acute phase of stroke is thought to reside in a “penumbra,” the area which is ischemic and not yet infarcted. To identify such tissue but not yet infarcted tissue is a major goal of modern acute stroke medicine. ADAMS
One of essential feature of stroke is its focal signature. Most typical sign of stroke is hemiplegia, whether in cerebral hemisphere or brainstem. Other features may include paralysis, numbness, and sensory deficits of many types on one side of the body, aphasia, visual field defects, diplopia, dizziness, dysarthria.
The long term effects of a stroke can vary based on factors such as the type, severity, location, and number of strokes. The common long term physical effects include muscle weakness and paralysis in involved body parts, difficulty in moving or performing daily activities, challenges with eating and swallowing, trouble in maintaining balance and coordination. With respect to communication difficulty in speaking, understanding language or finding words, difficulty in reading or writing or vision loss in specific field and change in emotional and behaviour effects like mood swings, depression, altered behaviour, inappropriate actions. In cognition there is memory loss, challenges with thinking, reasoning and judgement. Loscalzo J, Fauci A, Kasper D, Hauser S, et al. Harrison's Principles of Internal Medicine, 21e.
Multiple risk factors attribute to development of stroke which include modifiable and non modifiable risk factors. Non modifiable risk factors, also known as, age, sex, race-ethnicity, and genetics. Modifiable risk factors for the causation of ischemic stroke include hypertension, current smoking, waist-to-hip ratio, diet risk score, regular physical activity, diabetes mellitus, binge alcohol consumption, psychosocial stress and depression, cardiac disease, and ratio of apolipoprotein B to A1. Risk factors for intracerebral hemorrhage included hypertension, smoking, waist-to-hip ratio, diet, and heavy alcohol consumption. https://www.ahajournals.org/doi/epub/10.1161/CIRCRESAHA.116.308398
Modifiable | Non modifiable |
Hypertension | Genetic factors |
Diabetes mellitus | Increasing age |
Dyslipidemia | Low birth weight |
Obesity and body fat distribution | Race/ethnicity |
Physical inactivity | Low socioeconomic status |
Tobacco use | Male gender |
Cardiac diseases such as RHD |
|
Carotid stenosis |
|
Finally, in keeping with the emerging field of genetic risk factors in human disease, several genetic loci have been found that putatively impart a risk of stroke in various populations. Single gene disorders which may cause stroke include, Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (NOTCH3/NOTCH3 gene mutation), Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (HTRA1/HtrA serine peptidase-1), Familial amyloid angiopathy (APP/β-amyloid precursor protein), Collagen 4 (COL4A1) mutations. Genetic disorders that include stroke as manifestation includes, Ehlers–Danlos type 4, Fabry disease, Marfan Sundrome, Mitochondrial encephalopathy with lactic acid and stroke-like episodes, Sickle cell disease, Smooth muscle α-actin mutation–associated disorders. Common genetic variants include TSPAN2, FOXF2, ABO, HDAC9, PITX2, ZFHX3.
Pathophysiology of ischemic infarction involves two processes: Loss of supply of oxygen and glucose secondary to vascular occlusion and array of changes in cellular metabolism due to collapse of energy-producing processes. Other mechanisms involve loss of cellular ion homeostasis, acidosis, increased intracellular calcium levels, excitotoxicity, free radical-mediated toxicity, cytokine-mediated cytotoxicity, complement activation, BBB disruption, glial cell activation, and leukocyte invasion. These interrelated events can lead to ischemic necrosis in severely affected ischemic core regions. O'Donnell ME, Yuan JX. Pathophysiology of stroke: the many and varied contributions of brain microvasculature. Am J Physiol Cell Physiol. 2018 Sep 1;315(3):C341-C34212.
When an intracranial vessel becomes acutely blocked, blood flow to the brain area it supplies is significantly reduced. The extent of this reduction depends on the availability of collateral blood flow, which is influenced by the vascular structure of the specific vessel (which may be affected by disease), the location of the occlusion, and systemic blood pressure. A decrease in cerebral blood to zero can cause brain tissue death within 4–10 minutes. If blood flow drops below 16-18 ml/100g of tissue per minute, infarction can occur within an hour. Flow rates under 20 ml/100g may cause ischemia without infarction unless the condition lasts for hours or days. If blood flow is restored to the affected tissue before extensive infarction occurs, the patient may experience only transient symptoms, known as a transient ischemic attack (TIA).
Ischemic penumbra refers to the region of ischemic but potentially salvageable tissue surrounding the core infarct area. Without intervention to restore blood flow, the penumbra is likely to progress to infarction. There are two main pathways by which focal cerebral infarction occurs:
1.Necrotic Pathway: Energy failure in the cell leads to rapid cytoskeletal breakdown.
2.Apoptotic Pathway: Cells are programmed to die in a regulated manner.
When neurons are deprived of oxygen and glucose, ischemia induces necrosis by halting ATP production in mitochondria. Neuronal depolarization and failure of membrane ion pumps can lead to increased intracellular calcium. During cellular depolarization, glutamate is also released from synaptic terminals. Excess glutamate in the extracellular space triggers neurotoxicity by activating postsynaptic glutamate receptors, leading to increased calcium entry into neurons. Ischemia also damages or destroys axons, dendrites, and glial cells in brain tissue. Lipid membrane degradation and mitochondrial dysfunction result in free radical formation, which can cause membrane breakdown and disrupt other crucial cellular processes. In regions with less severe ischemia, such as the ischemic penumbra, cells are more likely to undergo apoptosis, with cell death occurring days to weeks later. Fever and high blood sugar levels (glucose >11.1 mmol/L or 200 mg/dL) worsen brain injury during ischemia, making it essential to control fever and prevent hyperglycemia as much as possible.Hui C, Tadi P, Khan Suheb MZ, Patti L. Ischemic Stroke. 2024 Apr 20. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024.
In haemorrhagic cerebrovascular accidents, most bleeding episodes are primarily caused by cerebral amyloid angiopathy (CAA), coagulopathy, sympathomimetics (such as cocaine and methamphetamine), and hypertension. Major risk factors include older age, excessive alcohol intake, low-dose aspirin in people without symptomatic cardiovascular conditions, and sympathomimetic use, especially among younger individuals.
Intracerebral Hemorrhage (ICH) typically arises from the spontaneous rupture of a small, penetrating artery deep within the brain. Common sites for these hemorrhages are the thalamus, cerebellum, pons, and basal ganglia, particularly the putamen, as small arteries in these areas are highly susceptible to damage from hypertension. Hemorrhages in other brain regions or in non-hypertensive individuals should prompt consideration of alternative causes, such as bleeding disorders, tumors, vascular malformations, vasculitis, and CAA. These hemorrhages can range from minor bleeds to large clots, which can exert pressure on surrounding tissue, leading to herniation and potentially fatal outcomes. Blood may also spill into the ventricular space, significantly increasing the risk of complications like hydrocephalus. Most hypertensive ICHs form within 30 to 90 minutes, but hemorrhages linked to anticoagulant use can take up to 48 hours to develop. Research shows that within the first day, about one-third of patients, even those without a bleeding disorder, may experience substantial hematoma expansion. Within 48 hours, macrophages begin to clear the hemorrhage from its outer surface, and over 1-6 months, the bleed typically resolves, leaving behind a slit-like cavity lined with glial scarring and macrophages containing hemosiderin. Magid-Bernstein J, Girard R, Polster S, Srinath A, Romanos S, Awad IA, Sansing LH. Cerebral Hemorrhage: Pathophysiology, Treatment, and Future Directions. Circulation Research.2022;130(8), 1204–1229.
Subarachnoid Hemorrhages are primarily caused by the rupture of saccular aneurysms located at the branching points of large and medium-sized intracranial arteries, with bleeding into the subarachnoid space of the basal cisterns and occasionally into nearby brain tissue. About 85% of these aneurysms are located in the anterior circulation, typically around the circle of Willis, with roughly 20% of affected patients having multiple aneurysms, often symmetrically positioned on both sides. Aneurysms consist of a neck and a dome, with significant variations in neck length and dome size—both crucial factors in planning surgical or endovascular treatment. The internal elastic layer of the artery diminishes at the base of the aneurysm’s neck, and the middle layer thins, with connective tissue replacing smooth muscle cells. The aneurysm wall, particularly at the dome, becomes thin and prone to tearing, allowing bleeding to occur. The size and location of an aneurysm influence its rupture risk, with those exceeding 7 mm in diameter and located at the basilar artery apex or at the origin of the posterior communicating artery carrying higher rupture risks. Ziu E, Khan Suheb MZ, Mesfin FB. Subarachnoid Hemorrhage. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-.
At the center of an ischemic stroke is a zone of infarction. The necrotic tissue swells rapidly, mainly because of excessive intracellular water content (cytotoxic edema). Because anoxia also causes necrosis and swelling of cerebral tissue, oxygen lack must be a factor common to both infarction and anoxic encephalopathy. The effects of ischemia, whether functional and reversible or structural and irreversible, depend on its degree and duration. The margins beyond the infarct are hyperemic, being supplied by meningeal collaterals, and here there is only minimal or no parenchymal damage. (ADAMS) The neurons in the penumbra are considered to be physiologically "stunned" by moderate ischemia and subject to salvage if blood flow is restored in a certain period of time.
Technological advances enhance the clinical study of stroke patients and allow for demonstratin of both the cerebral lesion and affected blood vessel. CT demonstrates and accurately localizes even small hemorrhages, hemorrhagic infarcts, subarachnoid blood, clots in and around aneurysms, arteriovenous malformations, and established regions of infarction. Due to bone artifact, small ischemic strokes in the posterior fossa and small infarcts on the cortical surface may not be visible on CT. By demonstrating the contrast enhancement of subacute infarcts and enabling the visualization of venous structures, contrast-enhanced CT scans increase specificity. National Guidelines Center (UK), 2019. National Institute for Health and Care Excellence. On the other hand, Magnetic resonance imaging is able to reveal flow voids in vessels, hemosiderin and iron pigment, and the alterations resulting from ischemic necrosis and gliosis. MRI is particularly advantageous in demonstrating small lacunar lesions deep in the hemispheres and abnormalities in the brainstem (a region obscured by adjacent bone in CT). Arteriography, enhanced by digital processing of images, accurately demonstrates stenoses and occlusions of the intracranial and extracranial vessels as well as aneurysms, vascular malformations, and other blood vessel diseases such as arteritis and vasospasm. The extracranial internal carotid arteries and large intracranial vessels can be highly sensitively detected by MR angiography. Kakkar P, Kakkar T, Patankar T, Saha S. Current approaches and advances in the imaging of stroke. Dis Model Mech. 2021;14(12).
MRA depicts the "time of flight" of blood through vessels and is not as accurate as CT angiography in measuring the degree and morphology of changes within a cerebral or intracranial vessel.
Positron emission tomography (PET), a nuclear imaging modality, is also being studied to determine its potential for diagnosing strokes. Cerebral blood flow can be measured using both positron emission tomography (PET) and xenon techniques, primarily xenon CT. Although these instruments are primarily utilized for research, they can be helpful in assessing the importance of arterial stenosis and in the planning stages of revascularization surgery. Relative cerebral blood flow is reported by MR perfusion techniques and single-photon emission computed tomography (SPECT). Dundar A, Bold MS, Agac B, et al. Stroke detection with 3 different PET tracers. Radiology Case Reports. 2019;14:1447-1451.
The main objective in these forms of ischemic cerebrovascular disease is the amelioration of the existing deficit and the prevention of future stroke. In addition to reduction of known risk factors such as hypertension, smoking, and glucose control in diabetics, the widespread use of cholesterol-lowering statin medications has been shown in some studies to reduce the primary incidence of and recurrence of stroke.
If a patient's blood pressure is higher than 220/120 mmHg, has concurrent myocardial ischemia or malignant hypertension, or is higher than 185/110 mmHg and thrombolytic therapy is expected, their blood pressure should be lowered. Bowry R, Navalkele DD, Gonzales NR. Blood pressure management in stroke: Five new things. Neurol Clin Pract. 2014;4(5):419-426.
Intravenous (IV) recombinant tissue-type plasminogen activator (alteplase) has been approved by the United States Food and Drug Administration (USFDA) for the treatment of acute ischemic stroke within 3 hours of witnessed symptom onset or last known well. The European Cooperative Acute Stroke Study (ECASS) III trial showed that alteplase was safe and effective in this time window with strict inclusion criteria that included patients ≤ 80 years of age, without a history of both diabetes mellitus and prior stroke, with an NIHSS score ≤ 25, not taking any oral anticoagulation, and without imaging evidence of ischemic injury involving more than one-third of the middle cerebral artery (MCA) territory. https://www.banglajol.info/index.php/BCCJ/article/download/72424/48188
If vascular imaging performed during or after intravenous thrombolysis treatment shows large vessel occlusion (distal internal carotid or proximal middle cerebral arteries), the patient is eligible for endovascular thrombectomy or thrombolysis, and can be considered as an alternative or adjunctive treatment for acute stroke. (ADAMS)
When treating Haemorrhagic stroke, osmotic agents can be started in advance of ventriculostomy or parenchymal ICP monitoring if the hematoma results in a significant midline shift of structures with obtundation, coma, or hydrocephalus. Rymer MM. Hemorrhagic stroke: intracerebral hemorrhage. Mo Med. 2011;108(1):50-4.
In today’s era various biomarker panels that is group of markers are there which offer valuable insight into underlying pathophysiological process and help stratify patients based on risk and monitor the efficacy of therapeutic interventions. Some examples are 22 gene panel,18 gene panel and many more. Jickling GC, Sharp FR. Blood biomarkers of ischemic stroke. Neurotherapeutics. 2011;8:349–360.
Gamma glutamyl transferase is a peptide membrane bound enzyme containing terminal glutamate residue. Serum gamma-glutamyl transferase (GGT) has been conventionally considered a marker of excessive alcohol intake and/or liver dysfunction. There is accumulating evidence suggesting a prognostic role of GGT in cardiovascular diseases (CVD) including stroke. Akinci E, Dogan NO, Gumus H, Akilli NB. Can we use
serum gamma-glutamyl transferase levels to predict early mortality in stroke? Pak J Med Sci 2014; 30(3): 606-10.
Gurbuzer N, Gozke E. Gamma-glutamyl transferase levels in patients with acute ischemic stroke. Cardiovasc Psychiatr Neurol 2014;2014:170626. Weikert C, Drogan D, di Giuseppe R, Fritsche A, Buijsse B, Nothlings U, et al. Liver enzymes and stroke risk in middle-aged German adults. Atherosclerosis 2013;228(2):508-14.
It is located on the cell membrane and is located in many tissues such as Kidney, Canalicular portion of hepatocyte, acinar cells of pancreas, prostate and bile duct, except mucles. Frey A, Meckelein B, weiler - Guttler H, Mockel B, Pericytes of the brain microvasculature expresses Gamma -Glutamyl Transpeptidase - Eur Journal Biochem 1991, 202. It mediates intake of extracellular glutathione inside the cells which is an important anti-oxidant. Whenever oxidative stress happens, glutathione inside the cells decreases which then induce the formation of GGT to normalize glutathione levels inside the cells. GGT causes extracellular catabolism of glutathione (GSH). Arteriosclerosis, Thrombosis & Vascular Biology 2007;27:4 American Heart Association, Inc. This process helps for the precursor assimilation and recycling of amino acids which are necessary for the synthesis of intracellular glutathione.
GGT mediated cleavage of glutathione on the cellular membrane or in the extracellular space results in release of the reactive thiol group from the cysteinylglyceine moiety. This reactive thiol group cause the reduction of ferric (Fe3+) to ferrous (Fe2+) ion, which in turn starts the iron dependent redox-cycling process. This process results in the production of the reactive oxygen species particularly superoxide anion and hydrogen peroxide, which are both capable of stimulating pro-oxidant reactions.
These GGT mediated prooxidant reactions catalyse the LDL lipoproteins oxidation (lipid peroxidation), that leads to the formation of inflammatory atheroma. Thus the prooxidant reactions mediated by GGT could play a major role in the pathogenesis of atherosclerotic plaque.
Emdin M, Pompella A, Paolicchi A.Gamma Glutamyl transferrase, atherosclerosis and Cardio Vascular disease, triggering Oxidative Stress within the Plague. Circulation, 2005;112:2078-2080.
Paolicchi A Et al Human Athero Sclerotic Plagues contain gamma – glutamyl transpeptidase enzyme activity Circulation, 2004;109:1440.
At time of increased oxidative stress, as in acute stroke, there is increased requirement for glutathione which exerts harmful effects on cells due to oxidative stress. Experimental studies and studies of human atherosclerotic plaques have revealed not only the presence of catalytically active GGT in atherosclerotic plaques, but also a correlation between GGT activity and indices of plaque instability, suggesting direct involvement in the pathophysiology of atherosclerosis and related clinical events via promotion of pro-oxidant reactions by the enzyme. Ndrepepa G, Colleran R, Kastrati A. Gamma-glutamyl transferase and the risk of atherosclerosis and coronary heart disease. Clinica chimica acta. 2018;476:130-8.
Higher serum GGT levels may be associated with:
• Advanced age
• Male gender
• High body mass index
• Smoking
• Metabolic syndrome
• Sedentary lifestyle.
Serum GGT is related to both risk and prognosis in cardiovascular as well as cerebrovascular diseases, since it is involved in pathogenesis of atherosclerosis through oxidative and inflammatory mechanisms. Kalirawna TR, Rohilla J, Bairwa SS, Gothwal SK, Tak P, Jain R. Increased concentration of serum gamma-glutamyl transferase in ischemic stroke patients. Brain Circulation. 2021;7(2):71.
Recent data suggest active involvement of GGT in pathogenesis of atherosclerosis through oxidative and inflammatory mechanisms. Oxidative stress predisposes to vascular injury/endothelial dysfunction, leading to atherosclerosis, cardiovascular disease and stroke. Dar UF, Ali S, Sirhindi GA. Association between Ischemic Stroke and Raised Serum Gamma-Glutamyl Transferase. Age (years). 2016;55(227):58-2.
After exclusion of alcohol consumption, a positive correlation has been demonstrated between higher GGT levels and advanced age, male gender, increases in body mass index, smoking, sedentary lifestyle, hypertension, tachycardia, hyperglycemia, increased low-density lipoprotein cholesterol, and decreased high-density lipoprotein-cholesterol levels, hypertriglyceridemia, menopause, and oral contraceptive use. Paolicchi A, Emdin M, Ghliozeni E, Ciancia E, Passino C, Popoff G, et al. Human atherosclerotic plaques contain gamma-glutamyl transpeptidase enzyme activity. Circulation. 2004;109(11):1440.
Tu WJ, Ma GZ, Ni Y, Hu XS, Luo DZ, Zeng XW, et al. Copeptin and NT-proBNP for prediction of all-cause and cardiovascular death in ischemic stroke. Neurology. 2017;88:1899–905.
REVIEW OF LITERATURE
Chun Li et al in 2024, investigated links between liver enzymes and stroke risk through meta-analyses and Mendelian randomization (MR) studies. Observational data reveal that elevated γ-glutamyl transferase (GGT) and alkaline phosphatase (ALP) levels are associated with increased stroke risk, especially ischemic and hemorrhagic stroke. This relationship varies by sex and stroke subtype. Genetic MR analyses support a causal link between liver enzyme levels and stroke risk, highlighting ALP’s predictive value for stroke. The study suggests liver enzymes could serve as biomarkers for stroke, guiding targeted prevention strategies.
Rathor Eeshan et al in 2024 conducted a study which investigated the role of gamma-glutamyl transferase (GGT) as a potential biomarker in acute ischemic stroke. Results show that serum GGT levels are significantly elevated in stroke patients compared to controls, correlating with the severity of stroke as measured by the NIH Stroke Scale (NIHSS). No significant differences in GGT levels were found when comparing age, gender, or comorbidities like hypertension and diabetes. This suggests that GGT levels may serve as a useful indicator of stroke severity, with further research needed to confirm its prognostic value.
Kanwal Sibgha et al in 2024 conducted a case control study which aimed to explore the link between high GGT levels and acute ischemic stroke (AIS). Conducted at Mayo Hospital, Lahore, it involved 310 participants aged 40–80, split equally between AIS patients and matched controls. Blood samples were analyzed, and GGT levels above 27 IU/ml were considered elevated. Results showed that 74% of AIS patients had high GGT levels compared to 20% in controls, with a significant association (p<0.00001, OR=11.5). This finding highlights GGT as a potential early marker for AIS risk, warranting further study for its role in stroke prevention and management.
In a study conducted by Mulakalapalli Vijay K. et al in 2024, association between serum gamma-glutamyl transferase (GGT) levels and acute stroke was examined, focusing on whether GGT can serve as an indicator for stroke risk. Conducted on 100 participants (50 stroke patients and 50 controls) aged 40-80 years, the research highlights that stroke patients had significantly higher mean GGT levels than controls. Hemorrhagic stroke was most prevalent, followed by ischemic and subarachnoid hemorrhage. Elevated GGT levels were notably linked to male gender, hypertension, diabetes, dyslipidemia, and smoking, while age and stroke type showed no significant association with GGT levels. This study supports previous findings suggesting GGT’s potential as a biomarker for stroke risk, especially among patients with common cardiovascular risk factors like hypertension and dyslipidemia.
In another study conducted by Rao Prakasa Surya Salla et al in 2024, the link between elevated serum gamma-glutamyl transferase (GGT) levels and the risk of cerebrovascular stroke was explored. Findings indicate that GGT levels were significantly higher in stroke patients, particularly those with ischemic stroke. Among the 50 patients studied, 64% exhibited elevated GGT levels, with a strong association observed in hypertensive patients. Elevated GGT levels are highlighted as an independent stroke risk factor, irrespective of other risk factors like diabetes and dyslipidemia. The study suggests that GGT could serve as a valuable biomarker for assessing stroke risk and prognosis, especially in older patients .
In a study conducted by Dutta et al in 2023, investigated the association between serum gamma-glutamyl transferase (GGT) levels and acute ischemic non-embolic stroke risk. Higher GGT levels, linked to oxidative stress and glutathione metabolism, were observed in stroke patients compared to controls. GGT levels correlated significantly with other risk factors like diabetes and dyslipidemia, suggesting that GGT may serve as a potential marker for stroke risk. However, its predictive value for mortality in stroke patients remains inconclusive, highlighting the need for further studies with larger sample sizes to confirm these findings.
Ismail M. Quazi et al in 2023 conducted a research which explored the relationship between serum gamma-glutamyl transferase (GGT) levels and stroke risk. Elevated GGT, an indicator of oxidative stress, was found to be higher in stroke patients, particularly those with conditions like diabetes, dyslipidemia, and hypertension. The study concludes that GGT is a potential independent risk factor for stroke, though it does not predict outcomes such as survival. Findings support GGT monitoring as a preventive measure, especially in high-risk patients, and underscore the need for further research to solidify its role as a stroke biomarker.
In another study conducted by Singh Doongar et al in 2023,Gamma-Glutamyl Transferase (GGT) levels in stroke patientswas investigated, focusing on its relationship with stroke risk factors and types. Stroke is a leading cause of death, especially rising in low- to middle-income nations. It occurs due to blood vessel issues, categorized as ischemic (caused by blockages) or hemorrhagic (due to bleeding). GGT, traditionally a marker for liver health and alcohol intake, also reflects oxidative stress and inflammation, both relevant to stroke risks. In this study, 60 stroke patients (30 ischemic and 30 hemorrhagic) and 30 controls were analyzed at SMS Hospital, Jaipur. Results showed significantly elevated GGT levels in stroke patients, correlating with factors like diabetes, hypertension, smoking, and dyslipidemia, indicating GGT’s potential as a biomarker for assessing stroke risk. However, no significant GGT difference was observed between ischemic and hemorrhagic types.
Study conducted by Lee Young et al in 2023, study examined the causal link between elevated gamma-glutamyl transferase (GGT) levels and the risk of stroke using a Mendelian randomization approach with genetic data from a European population. The findings indicate a significant association between higher GGT levels and an increased risk of stroke and specific stroke subtypes, particularly cardioembolic, small vessel, and large artery strokes. Adjusting for confounding factors such as alcohol consumption, atrial fibrillation, and body mass index strengthened the evidence of GGT as a causal risk factor for stroke. This suggests that elevated GGT could serve as a biomarker to identify individuals at increased stroke risk, emphasizing the need for early intervention and further research to validate these findings in broader populations.
In a 2022 study, Li S and Anxin Wang et al. found that elevated gamma-glutamyl transferase (GGT) levels in patients with acute ischemic stroke (AIS) or transient ischemic attack (TIA) are associated with increased risks of stroke recurrence, ischemic stroke, and combined vascular events within three months and one year. Using data from over 12,500 patients in the China National Stroke Registry-3, researchers observed that higher GGT levels consistently correlated with worse outcomes, even after adjusting for multiple risk factors. Adding GGT to conventional prediction models slightly improved the accuracy of forecasting adverse outcomes, underscoring its potential as a biomarker for stroke prognosis.
The study by Li et al. (2022) investigates the relationship between serum gamma-glutamyl transferase (GGT) levels and post-stroke cognitive impairment (PSCI). GGT, an enzyme critical for glutathione metabolism and cellular defense against oxidative stress, has been associated with cognitive decline in various conditions. The research, conducted as part of the Impairment of Cognition and Sleep (ICONS) study, followed 1,957 patients who experienced minor ischemic strokes or transient ischemic attacks. Results showed an inverse relationship between GGT levels and PSCI risk, suggesting that higher GGT may offer protective effects against cognitive impairment post-stroke. The findings highlight the potential of GGT as a biomarker for PSCI prognosis but recommend further research to clarify its mechanisms.
Similarly, Kumari N et al. (2021) investigated GGT levels and other risk factors in 100 stroke patients and 75 controls, observing higher mean GGT levels in stroke patients. This finding reinforced the connection between GGT, inflammation, oxidative stress, and infarct size, suggesting that larger infarcts correlate with elevated GGT levels.
In 2021, Kalirawna TR et al. studied 200 individuals (100 with acute ischemic stroke and 100 without) to assess GGT’s role in stroke risk and prognosis. This study investigated the association between serum gamma-glutamyl transferase (GGT) levels and ischemic stroke risk. Conducted among 100 ischemic stroke patients and 100 controls, it found significantly higher GGT levels in stroke patients. Additionally, stroke patients with diabetes, hypertension, dyslipidemia, obesity, and smoking habits had elevated GGT levels compared to those without these factors. The findings suggest that GGT could serve as a marker for stroke risk, independent of age, gender, and other risk factors, highlighting the potential of GGT in identifying high-risk individuals.
In a study conducted by Lee Min Sang et al in 2021, the link between serum gamma-glutamyltransferase (GGT) levels and the risk of cerebral infarction in the Korean population was investigated. Using data from 209,481 participants who underwent health checkups in 2009, the study followed participants for several years, identifying 2,403 cases of cerebral infarction by 2013. Results indicated that higher GGT levels were associated with an increased risk of cerebral infarction, even after adjusting for variables like age, blood pressure, cholesterol, and lifestyle factors. This study suggests that GGT, often associated with liver health and alcohol consumption, could also serve as a predictor of stroke risk, particularly cerebral infarction. It highlights GGT’s role in oxidative stress and inflammation, processes that could contribute to atherosclerosis and stroke.
R. Ganesh Shriram et al in 2021 conducted a research which examined the link between gamma-glutamyl transferase (GGT) levels and stroke severity in acute stroke patients. Conducted among 50 stroke patients and 50 control subjects, the research found that 64% of stroke patients had elevated GGT levels, with higher GGT levels correlating with ischemic strokes. Notably, 80% of stroke cases in this study were ischemic, while 20% were hemorrhagic. Elevated GGT was significantly associated with ischemic stroke, suggesting that GGT levels might serve as a valuable, accessible marker for assessing stroke severity and guiding early treatment in clinical settings.
Singh Kumar Lagendra et al in 2019 conducted a study which analyzed serum gamma-glutamyl transferase (GGT) levels in stroke patients compared to controls without stroke. Conducted on 100 stroke patients and 100 matched controls, it found that stroke patients had significantly elevated GGT levels, particularly those with diabetes, hypertension, dyslipidemia, and a history of smoking. Although GGT levels were slightly higher in hemorrhagic than ischemic stroke patients, the difference was not statistically significant. These findings indicate that GGT might serve as a potential marker for stroke risk, independent of common cardiovascular risk factors.
A 2019 study by Yao Tao et al examined the relationship between serum gamma-glutamyl transferase (GGT) levels and intracranial artery calcification (IAC) in patients with acute ischemic stroke (AIS). Results revealed that elevated GGT levels correlated with increased all-cause mortality and higher IAC scores, particularly in male patients. Logistic regression indicated that higher GGT levels were linked to both greater stroke severity, as measured by the NIH Stroke Scale (NIHSS), and increased mortality risk. However, GGT could not independently predict IAC severity. These findings suggest that GGT may act as a marker for vascular disease progression in AIS patients.
Vaid Aarti et al in 2018 conducted a study which investigated the association between serum gamma-glutamyl transferase (GGT) levels and acute stroke risk. It compared 100 acute stroke patients with a control group of 100 without cerebrovascular diseases, finding that mean GGT levels were significantly higher in the stroke group (51.74 U/L) than in controls (17.99 U/L). This suggests that elevated GGT levels may indicate increased inflammation and oxidative stress, which contribute to stroke risk. The study concludes that GGT could be a cost-effective biomarker for stroke prediction but recommends further research to solidify its role in clinical settings.
Dar UF et al. (2016) also explored the association between ischemic stroke and raised GGT levels. Conducted at Lahore General Hospital over six months in 2015, this case-control study included 195 stroke patients and 195 healthy controls, matched by age and gender. Results showed that 26.7% of stroke patients and 18.5% of controls had high GGT levels, a difference that was not statistically significant (p > 0.05). The odds ratio was 1.44, suggesting no strong association between raised GGT and stroke occurrence. Age, gender, smoking, BMI, HbA1c, and dyslipidemia did not significantly affect outcomes. The study concludes that elevated GGT levels do not correlate significantly with ischemic stroke, contradicting some previous findings.
In 2014, Gurbuzer N et al. examined GGT levels in 60 patients with acute ischemic stroke and 44 controls without cerebrovascular disease. Patients were grouped based on infarct location, with GGT levels compared across these groups. The results indicated that GGT levels were significantly higher in stroke patients, especially those with larger infarct areas. Elevated GGT levels were particularly observed in patients with hypertension, high LDL cholesterol, and triglycerides, suggesting a link between GGT, inflammation, oxidative stress, and infarct severity.
Korantzopoulos P et al. (2009) conducted a case-control study to explore the relationship between serum gamma-glutamyl transferase (GGT) and acute ischemic non-embolic stroke in elderly individuals. The study included 163 patients over 70 years (88 men) experiencing their first ischemic stroke, along with 166 controls (87 men) without cardiovascular disease. Using multivariate logistic regression, the researchers found a positive association between GGT levels and ischemic stroke, independent of cardiovascular risk factors and metabolic abnormalities.
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