Liver Damage And Stroke: Is There A Link?

Liver damage is associated with an increased risk of stroke, particularly haemorrhagic stroke. This is due to the mixed coagulopathy observed in cirrhosis, which can lead to both thrombotic and haemorrhagic processes.

Studies have shown that patients with cirrhosis had a higher risk of stroke, with the magnitude of association appearing to be higher for intracerebral haemorrhage and subarachnoid haemorrhage than for ischaemic stroke.

The risk of cerebrovascular complications in patients with liver damage is comparatively less understood. Early studies reported a reduced prevalence of stroke in patients with cirrhosis, while more recent studies found a reduced risk of all stroke and ischaemic stroke. However, these studies had small and narrowly defined study cohorts.

The cerebrovascular complications of cirrhosis warrant further investigation to yield opportunities for stroke risk reduction and prevention.

Liver damage can cause inflammation, which is a risk factor for stroke

Acute ischaemic stroke is associated with a high risk of non-neurological complications, including respiratory failure, cardiovascular dysfunction, kidney and liver injury, and altered immune and endocrine function. The brain controls various body functions through complex neurohumoral mechanisms. Therefore, any severe cerebral insult, such as an acute ischaemic stroke, can induce several changes in specific neurosensory or neuromotor pathways, enhance the systemic response to local injury, and cause secondary peripheral organ damage.

Inflammation is a recognised important cause of anaemia, deriving from at least three different mechanisms mediated by inflammatory cytokines: inhibited production of erythropoietin, reduced response of the erythroid progenitors to erythropoietin, and reduced iron release from stores caused by the polypeptide hormone hepcidin. In addition, unconjugated bilirubin is a heme by-product, so it is directly proportional to haemoglobin. Therefore, the significant fall in unconjugated bilirubin in acute stroke seems to be a simple epiphenomenon of haemoglobin fall.

Liver cirrhosis is an end-stage liver disease characterised by diffuse fibrosis within hepatic tissue, false lobular formation, and regenerative nodules. Patients with liver cirrhosis often have coagulopathy, hypoperfusion, cardiac diseases, diabetes, and dyslipidaemia, which are associated with the development of stroke. A nationwide population-based study suggests an increased risk of atrial fibrillation development in cirrhosis. Up to 70% of cirrhotic patients develop diabetes or impaired glucose tolerance. Evidence also suggests an association of hepatogeneous diabetes with higher portal pressure and increased risk of hepatocellular carcinoma, hepatic encephalopathy, and mortality in cirrhosis.

In a study of 1,618,059 Medicare beneficiaries, patients with cirrhosis faced an increased risk of stroke, and associations appeared stronger for haemorrhagic stroke than for ischaemic stroke. The incidence of stroke was 2.17% per year in patients with cirrhosis and 1.11% per year in patients without cirrhosis. After adjustment for demographic characteristics and stroke risk factors, patients with cirrhosis had a higher risk of stroke (hazard ratio [HR], 1.4). The magnitude of association appeared to be higher for intracerebral haemorrhage (HR, 1.9) and subarachnoid haemorrhage (HR, 2.4) than for ischaemic stroke (HR, 1.3).

In a study by St Michael's Hospital and the London Health Sciences Centre, researchers found high levels of enzymes known to be markers of liver disease in adults who had an acute stroke. The study is the first to find a link between nonalcoholic fatty liver disease and stroke.

Liver cirrhosis is associated with an increased risk of stroke

A study of 1,618,059 Medicare beneficiaries found that patients with cirrhosis had a 40% higher risk of stroke than those without cirrhosis. The annual incidence of stroke was 2.17% for patients with cirrhosis and 1.11% for patients without. The study also found that cirrhosis was associated with a higher risk of intracerebral haemorrhage and subarachnoid haemorrhage, with hazard ratios of 1.9 and 2.4, respectively, compared to 1.3 for ischemic stroke.

Another study of 6,944 adults in Taiwan found that the incidence of stroke was 6.1 per 1,000 person-years for people with cirrhosis and 4.3 per 1,000 person-years for those without. The adjusted hazard ratio of stroke was 1.55 for people with cirrhosis.

The exact mechanisms underlying the association between liver cirrhosis and stroke are not fully understood, but several factors have been proposed, including coagulopathy, hypoperfusion, cardiac diseases, diabetes, and dyslipidaemia.

Coagulopathy, or impaired blood clotting, is common in people with liver cirrhosis due to an imbalance between coagulation and anticoagulation factors. This can lead to both bleeding and thrombotic events. Hypoperfusion, or reduced blood flow, can occur in cirrhosis due to ascites, decreased serum albumin levels, and gastrointestinal bleeding. Cardiac diseases, such as cirrhotic cardiomyopathy and atrial fibrillation, are also more common in people with liver cirrhosis and can increase the risk of stroke. Additionally, diabetes and dyslipidaemia, which are risk factors for stroke, are more prevalent in people with cirrhosis.

Coagulopathy in liver disease can lead to stroke

Coagulopathy in liver disease is a complex and multifactorial condition that can lead to both bleeding and clotting events. While the liver is the site of synthesis for most procoagulant and anticoagulant factors, it also plays a crucial role in hemostasis. Patients with a decreased liver synthetic capacity are more likely to experience bleeding, particularly gastrointestinal bleeding and coagulopathy caused by liver synthetic dysfunction. They are also at risk of thrombosis, primarily in the splanchnic circulation, particularly when platelet counts are increased by transfusion or drug therapy.

The pathogenesis of coagulopathy in liver disease involves several factors, including decreased clotting and inhibitor factor synthesis, reduced clearance of activated factors, quantitative and qualitative platelet defects, hyperfibrinolysis, and increased intravascular coagulation.

Coagulopathy in liver disease is associated with both bleeding and thrombotic complications. Bleeding events are more common than clotting events among hospitalized patients and patients with decompensated cirrhosis. The risk of post-procedure bleeding for so-called minimally invasive procedures is about 20%, which is why anyone conducting procedures in patients with liver disease will be concerned about their bleeding risk. On the other hand, the anticoagulant system that is normally present and balances clotting is also deranged in liver disease, resulting in a very low protein C level. That, together with increases in factors produced in the endothelium of the blood vessels, such as factor VIII and von Willebrand factor, lead to a relative hypercoagulable state. Coupled with relative venous stasis in cirrhosis, especially in the portal vein but also peripherally, inappropriate clot formation can result.

The diagnosis of coagulopathy in liver disease is challenging due to the limited availability of laboratory tests and the complex interplay between prohemostatic and antihemostatic drivers. Conventional coagulation tests such as the prothrombin time, international normalized ratio (INR), and activated partial thromboplastin time (aPTT) are routinely used to assess bleeding risk, evaluate unexplained bleeding, and monitor the effect of anticoagulants. However, these tests are routinely abnormal in cirrhotic patients and do not accurately measure bleeding or clotting risk. Alternative coagulation tests such as thromboelastography and thrombin generation assay (TGA) in cirrhosis have been described as potentially more accurate.

The management of coagulopathy in liver disease depends on whether the patient is at risk of bleeding or thrombosis. For bleeding complications, platelet transfusion, TPO receptor agonist, and antifibrinolytics are beneficial. For thrombosis, anticoagulation is beneficial when used therapeutically or prophylactically. Successful anticoagulation is related to a lower rate of decompensation and improved survival. Until now, treatment has consisted of low molecular weight heparins and vitamin K antagonists. According to preliminary data, novel non-vitamin K antagonist oral anticoagulants can be used safely in patients with liver cirrhosis.

Hepatic encephalopathy is a complication of liver disease that may increase the risk of stroke

Hepatic encephalopathy is a brain dysfunction caused by liver dysfunction. It is characterised by neurotoxins in the blood that are usually filtered by the liver. If the liver is not functioning properly, these neurotoxins can build up and eventually enter and affect the brain. Hepatic encephalopathy can be caused by acute liver failure, a portosystemic shunt, or chronic liver failure. Symptoms of hepatic encephalopathy can include confusion, disorientation, erratic behaviour, personality changes, and loss of consciousness.

Acquired hepatocerebral degeneration (AHCD) is a chronic progressive neurological syndrome characterised by Parkinsonism, ataxia, dementia, and other movement disorders. It is associated with cirrhosis and can be identified by bilaterally symmetric hyperintensities in the basal ganglia, especially the globus pallidus and substantia nigra, on a T1-weighted MRI.

A stroke is a sudden disruption in the blood supply to the brain, usually caused by a blockage or the bursting of a blood vessel. It can cause permanent brain damage or even death. While liver disease is not a direct cause of stroke, hepatic encephalopathy may present with stroke-like symptoms, such as dysarthria, dysphagia, and difficulty in walking. In such cases, a T1-weighted MRI may show hyperintensities in the basal ganglia, which can help distinguish hepatic encephalopathy from stroke.

Liver disease is associated with an increased risk of cerebral microbleeds

Several studies have found a positive correlation between the severity of chronic liver disease and the number of cerebral microbleeds. One study found that harder livers were associated with a higher burden of cerebral microbleeds. Another study found that liver cirrhosis patients had a higher risk of stroke, and that patients with liver cirrhosis might have an increased risk of stroke due to their concomitant high-risk factors, such as coagulopathy, hypoperfusion, cardiac diseases, diabetes, and dyslipidemia.

A study found that antidepressant use was associated with an increased risk of developing cerebral microbleeds.

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