New advances in cirrhosis research
Introduction: The morbidity and mortality of cirrhosis have been increasing in recent years, and it has been ranked as the 14th most common cause of death in the world, and the 4th most common cause of death in Central Europe.
The morbidity and mortality of cirrhosis have been increasing in recent years, and it is the 14th most common cause of death worldwide, and the 4th most common cause of death in Central Europe. Tsochatzis et al. from the United Kingdom reviewed recent studies on cirrhosis as a dynamic process, summarizing its clinical stages and strategies for the management of important complications, and published a review in the January 27, 2014 issue of The Lancet. Based on a large amount of literature from 2000 to 2013, the authors, taking into account the clinical features of the disease, mainly described the following aspects.
1. epidemiological characteristics of cirrhosis 2. pathophysiological mechanisms associated with cirrhosis
3. updated points of clinical diagnosis of cirrhosis 4. new theories of the natural course of cirrhosis
5. Strategies for prevention and treatment of important complications of cirrhosis and clinical ideas for comprehensive diagnosis and treatment of cirrhosis 6. Outlook for the future
Nowadays, cirrhosis should be viewed not only as a single end-stage disease, but also as a group of systemic diseases that can be staged according to significant clinical symptoms. Cirrhosis can be seen as a dynamic evolutionary process and is mainly classified according to prognosis as
Stage 1 – in the compensated stage, before the appearance of esophageal varices, with a one-year mortality rate of about 1%;
Stage 2 – still in the compensated stage but with esophageal varices, with a one-year mortality rate of 3-4%;
Stage 3 – decompensated stage with ascites, with a one-year mortality rate of 20%;
Stage 4 – decompensated stage with ruptured esophagogastric fundic varices and bleeding, with a one-year mortality rate of 57%;
Stage 5 – severe decompensation with infection and renal dysfunction, the one-year mortality rate can reach 67%.
In the diagnosis of liver cirrhosis, the diagnostic model of liver fibrosis established by combining various serum indicators has become a hot research topic in recent years. Among a series of non-invasive diagnostic indexes of liver fibrosis proposed at home and abroad, the more representative ones are Fibro Test (FT), Forns Index, APRI Index and Hepascore. It must also be combined with ultrasound, CT, MRI and acoustic radiation force pulsed imaging techniques to make a comprehensive assessment of the disease in patients with cirrhosis. In contrast to the previous traditional pathological classification, a new assessment method has recently been introduced, namely the quantitative assessment of liver fibrosis in combination with collagen area ratio (CPA), which is closely related to hepatic venous pressure gradient (HVPG) and clinical outcome prediction.
Cirrhosis often leads to death due to serious complications, including portal hypertension, varices and bleeding from ruptured varices, ascites, infection, hepatic encephalopathy, and hepatocellular hepatocellular carcinoma, so this article focuses on the analysis of strategies to prevent and treat important complications, as well as clinical ideas for comprehensive diagnosis and treatment of cirrhosis.
There are numerous hotspots in exploring the pathophysiological mechanisms associated with cirrhosis, with decompensated liver function and portal hypertension being the two major endpoints in the development of cirrhosis. Portal vein pressure depends on portal blood flow and portal vein resistance. Increased portal vein resistance in cirrhosis is the initiating factor for the development of portal hypertension, while increased portal blood flow is an important factor in maintaining and exacerbating portal hypertension.
Pathophysiological mechanisms of portal hypertension
1.Increased portal vein resistance: anatomical factors such as hepatic fibrosis generation, angiogenesis, injurious loss of liver parenchyma, regenerative nodules compressing the hepatic sinusoids and hepatic venous system leading to obstruction of the hepatic sinusoids and their outflow tracts can cause increased portal vein vascular resistance and capillary vascularization of the hepatic sinusoids, ultimately causing liver dysfunction.
Functional abnormalities are mainly caused by vascular endothelial dysfunction, including decreased N0, increased thromboxane A2, and dysregulation of vasoactive substances such as increased norepinephrine, angiotensin 2 and endothelin. The increased responsiveness to vasoconstrictor factors causes increasing hepatic vascular tension.
2.Increased portal blood flow: Due to the decreased liver function, the body’s ability to clear substances such as norepinephrine decreases, and sympathetic excitation, which in turn increases cardiac contraction and cardiac output. As the organism exhibits an increase in NO, CO, endogenous cannabinoids or glucagon in an adaptive response, its vasodilatory effect and impairment of the G protein-dependent conduction pathway of the vasoconstrictor substances cause hyporesponsiveness of the vessels to the vasoconstrictor substances.
Combined with vascular endothelial growth factor (VEGF)-driven angiogenesis, this leads to dilation of small visceral arteries, creating a visceral hyperdynamic circulation in patients with cirrhosis. At this time, visceral vascular congestion, increased portal venous blood flow, and sustained elevation of venous pressure.
3, the consequences of portal hypertension, namely varices and the formation of collateral circulation: local anatomical factors and VEGF-driven angiogenesis, coupled with the increasing portal pressure, resulting in the formation of collateral circulation between the portal body to reduce portal pressure, so that many traffic branches are formed between the portal vein and the vena cava. After the opening of these traffic branches, changes in the direction of blood flow, venous dilatation and tortuosity occur.
4. The development of portal shunt encephalopathy: Due to the reduced first-pass effect and the decreased action of the reticuloendothelial system, the opening of the interportal collateral circulation allows portal blood to return directly to the right heart via the side branches instead of the liver, eventually causing a rise in blood ammonia and the accumulation of toxins in the body.
The authors also provide an in-depth analysis outlining strategies for the prevention and treatment of complications of cirrhosis, with the following clinical response guidelines for portal hypertension and ascites, respectively.
Strategies for the management of portal hypertension and esophagogastric fundic varices
–Decide the appropriate treatment plan according to the pressure difference between the hepatic vein and the inferior vena cava, i.e., the hepatic venous pressure gradient (HVPG)
1. Portal hypertension, i.e. HVPG >5mmHg, but no clinical symptoms. It is necessary to treat the cause, change the lifestyle or apply statins and anticoagulants, etc. to carry out the corresponding treatment.
2, the emergence of clinical symptoms of portal hypertension, i.e. HVPG >10mmHg, when the risk of cirrhosis decompensation or progression to hepatocellular carcinoma increases, which is likely to cause varices in the portal collateral circulation. The main measure is to prevent variceal rupture and bleeding, and repeated endoscopic ligation is feasible until the variceal state is eradicated.
In the meantime, non-selective beta-blockers can be applied to reduce HVPG by at least 20% within the maximum tolerable dose range (control heart rate above 50 beats per minute and systolic blood pressure above 90 mmHg) or to keep HVPG below 12 mmHg, (if carvedilol is used, 6.25-12.5 mg daily is recommended).
3. When HVPG R12mmHg, it is very easy to cause bleeding from ruptured varicose veins. Once bleeding, blood should be transfused immediately until the hematocrit reaches 70-90g/L, intravenous vasoactive drugs, endoscopic ligature treatment within 12 hours, and broad-spectrum antibiotic treatment for 5 days.
If the patient has a Child classification of C or B combined with active bleeding, emergency TIPS (transjugular intrahepatic portosystemic shunt) is considered.
4. Secondary prevention of variceal rupture bleeding. Combination of endoscopic skin ring ligation and non-selective β-blockers; if this fails, consider TIPS or liver transplantation.
Strategies for prevention and treatment of ascites
1.In the early stage of portal hypertension in cirrhosis, non-selective β-blockers can be applied to prevent further endovascular and peripheral vasodilatation.
2, When the peripheral vasodilation causes a decrease in circulating blood volume, sodium retention, increased cardiac output and leads to ascites, the sodium intake should be strictly limited, diuretics such as Antiseptic and tachyphylaxis should be applied, ACEI drugs should be stopped, and NSAIDs drugs and aminoglycoside antibiotics should be avoided. The suitability of liver transplantation can be considered at this time.
3.When renal vasoconstriction and reduced cardiac output evolve into refractory ascites (type 2 hepatorenal syndrome), a large amount of ascites must be released and TIPS should be considered.
4.When it progresses to renal dysfunction (type 1 hepatorenal syndrome), all diuretics should be discontinued, and terlipressin combined with albumin infusion can be applied. Consider liver transplantation if necessary.
Liver transplantation is the only therapy that can provide long-term survival, but since there is always a shortage of donor livers, the suitability of liver transplantation for patients with cirrhosis must be critically evaluated.
Indications for liver transplantation
1. Decompensated cirrhosis: clinical stage 3 or higher, at least ascites complications, and potential abnormal complications including intractable pruritus, recurrent cholangitis and hepatopulmonary syndrome.
2. Hepatocellular hepatocellular carcinoma evolving from cirrhosis: Many medical centers use the Milan criteria to select suitable patients, i.e., a single tumor diameter Q125px or a number of less than three tumors, each Q75px in diameter, with no evidence of tumor invasion of blood vessels or the presence of extrahepatic metastases.
Contraindications to liver transplantation
1. Prohibited drug abuse: If the patient is undergoing drug replacement therapy (methadone type), it is not contraindicated.
2. AIDS: well-controlled HIV should not be considered a contraindication. If the patient is infected with HIV combined with hepatitis C, it should be considered as a contraindication.
3.Extrahepatic malignancies: excluding neuroendocrine tumors and hemangioendothelioma.
4. Sepsis: liver transplantation should only be performed after the infection has been cured.
5. Extra-hepatic organ dysfunction: such as heart and lung function. Echocardiography is essential, and cardiac catheterization is feasible for liver transplantation assessment when needed. Pulmonary artery pressure greater than 50 mmHg should be considered an absolute contraindication.
6. Extensive visceral thrombosis: has extended to the superior mesenteric vein.
7. Technical contraindications.
Clinical ideas for the prevention and treatment of early cirrhosis
1. Identify risk factors, including obesity, alcohol abuse and patients born in the United States between 1945-1965. They should be screened using non-invasive fibrosis tests and hepatitis virus tests. The first consideration is to change the patient’s lifestyle, such as weight loss, smoking and alcohol cessation, which can be complemented by the use of antioxidants and appropriate antiviral therapy.
2.If cirrhosis persists, check patients for the presence of esophagogastric fundic varices and perform primary screening for hepatocellular hepatocellular carcinoma. Further treatment can be with non-selective beta-blockers (for portal hypertension), statins (for hyperlipidemia) and avoid NSAIDs, PPIs and aminoglycosides.
3. If the patient has ascites, the treatment is a low salt diet, diuretics, stopping ACEI drugs, and liver transplantation can be considered. For spontaneous bacterial peritonitis, quinolones can be applied for secondary prevention.
4.If the variceal vein ruptures and bleeds, endoscopic skin ring ligation and non-selective beta-blockers are feasible.
5.If there is hepatic encephalopathy, the primary treatment is to control and remove the causative factors and protect liver function from further damage, and patients with mild hepatic encephalopathy must be detected early.
Early preventive intervention should be advocated for patients with cirrhosis to prevent disease progression and avoid or delay the emergence of clinical decompensation complications. A new challenge, especially for many cirrhotic patients in the 21st century, is to avoid liver transplantation whenever possible. A large number of randomized controlled clinical trials are still needed to explore and validate new treatment options for the increasing number of patients with cirrhosis.