The liver is the largest digestive gland organ in the human body and has important functions in synthesis, detoxification and metabolism, and plays a very important role in the life activities of the human body, including digestion, absorption, excretion, biological transformation and metabolism of various substances. Therefore, liver damage caused by hepatitis B virus, hepatitis C virus, alcoholic hepatitis, steatohepatitis, drug-related hepatitis, etc., more or less affects the performance of these functions. In the early stage or compensated stage of liver disease, it may manifest as various types of clinical discomfort, and in the late stage or decompensated stage, it will seriously threaten the life of patients. However, because many patients with liver function impairment have mild clinical discomfort, many patients may not have any clinical discomfort for a long time, or even have developed serious liver diseases such as cirrhosis or liver cancer without any clinical discomfort, which makes many patients with liver diseases ignore the screening and treatment of liver diseases, and also easily leads clinicians to miss the diagnosis of many potential liver diseases in their clinical work. And in some cases, some physicians or patients see mild changes in liver enzymology and abnormalities in viral markers and are unable to properly assess whether or not liver impairment is occurring or the extent of liver impairment. Either the significance of long-term monitoring and appropriate treatment is overlooked and the condition is delayed. Either unnecessary or over-treatment measures were taken, resulting in unnecessary damage and waste. Either over-reliance on tests and screening measures fails to monitor changes in the condition in a timely manner. To this end, this article provides an overview of the clinical manifestations and findings of patients with potentially impaired liver function, in order to guide physicians or patients to correctly determine whether damage to the patient’s liver has occurred and the severity of their damage, so as to better make correct and reasonable judgments in clinical decision-making. I. Clinical manifestations of patients with impaired liver function The specific causes of clinical discomfort caused by impaired liver function are not known, and due to differences in individual tolerance, some patients with mild abnormalities in liver function indicators can show significant weakness, anorexia and other manifestations, while many patients do not have any clinical discomfort even if they develop severe liver disease. The presence of clinical discomfort is often the main reason for patients to seek medical advice, mainly in the following cases. Fatigue. Fatigue caused by disease is an irresistible exhaustion, tiredness to perform daily activities, a multidimensional symptom that includes a range of discomforts such as weakness, fatigue, lethargy, and lack of energy, often accompanied by sleep disturbances and autonomic dysfunction, but not relieved by sleep, and is an interactive manifestation of biopathology, psychology, spirituality, and activity. Fatigue is a common mainstay of discomfort in many patients with impaired liver function disorders. It is particularly common in primary biliary cirrhosis and primary sclerosing cholangitis leading to cholestatic disease, seen in 78% of patients with primary biliary cirrhosis, and some quantitative fatigue assessment scales have been used as one of the prognostic indicators for this disease. The mechanisms that cause fatigue in patients with liver disease are not well understood and are related to central neurological factors in the brain and peripheral musculo-articular factors. However, it can be manifested in a variety of other diseases, lacking specificity and lacking a linear relationship with enzymatic indicators of liver function and histological changes. There is also a relationship between fatigue and the patient’s psychology. Fatigue is more prominent in women than in men with liver disease. And a certain stage for individual patients can be used as a good subjective evaluation indicator for the onset of relapse or not and prognosis, for example, in patients with slow plus acute liver failure. Several studies [1] have done some work on the mechanisms, degree, grading, gender relations, psychological relations, comorbid symptoms, and duration of fatigue in patients with liver disease. Autonomic dysfunction (AD). In chronic liver disease, heart rate and blood pressure, which are regulated by the autonomic nervous system, can be disturbed, and this is called autonomic dysfunction, which is a systemic symptom of liver disease along with fatigue, sleep disturbance, and cognitive impairment [2]. Although this syndrome has been described in the literature for decades, it has been considered as one of the idiopathic manifestations of severe cirrhosis or as a complication associated with underlying diseases (e.g. alcoholic neuropathy, diabetic autonomic neuropathy in non-alcoholic adipose patients). Recent studies have confirmed that autonomic dysfunction can also occur early in many liver diseases. In patients with alcoholic liver disease, alcohol directly exacerbates the autonomic dysfunction, sometimes with manifestations such as increased heart rate, large fluctuations in blood pressure, increased urine output, involuntary sweating, and even complications with alcohol withdrawal syndrome. The degree of autonomic dysfunction is closely related to the prognosis of the condition, and may be associated with falls, blackouts or poor upright tolerance, postural hypotension, bowel disturbances, and sudden cardiac death. Disordered sleep (DSS). Sleep abnormalities, especially excessive daytime sleepiness, are associated with fatigue due to liver disease. In patients with primary biliary cirrhosis, daytime sleep status can be a good identifier for fatigue-related status as a condition assessment and the need to improve it with the application of stimulants such as modafinil in appropriate amounts. In patients with NAFLD, sleep abnormalities and obstructive sleep apnea and: pushing 7 beaks around the boil and striking the nucleus to the nasal region of the liver. There are no nerves in the liver, so even after severe liver injury, cirrhosis, or liver cancer, many patients do not experience any pain in the liver area, and may not feel pain even if a knife is struck in the liver parenchyma. The nerves in the liver are located outside the liver in the peritoneum. Discomfort in the liver may occur when hepatitis causes enlargement of the liver, when inflammation reaches the peritoneum, when adhesions occur between the peritoneum and surrounding tissue, or when liver cancer tissue invades the peritoneum. Some patients describe this discomfort as simple discomfort in the right upper abdomen and right lower back, foreign body sensation, numbness, or in severe cases, mild to moderate pain, while severe pain is only seen in patients with liver rupture or advanced hepatocellular carcinoma. It is important to note that many gastric and duodenal disorders can also present with discomfort in the liver and lower back. These can be identified by gastroscopy, and some patients with unexplained liver discomfort found by negative gastroscopy can even be relieved by direct administration of acid-suppressing drugs. Chronic cholecystitis and cholelithiasis are also disorders that need to be differentiated from parenchymal liver disease and need to be further investigated by imaging. Oral problems. The oral cavity can reflect liver impairment, mainly in the form of yellow staining of the oral mucosa, bleeding gums, easy damage to the mucosa, gingivitis, liver odor (the peculiar odor of advanced or severe liver disease), labyrinthitis, smooth or atrophic tongue, oral lichen planus, oral dryness, bitter mouth, nocturnal teeth grinding syndrome, and crusty perioral rash [3]. Chronic periodontal disease can often be present in patients with liver disease. Patients with alcoholic hepatitis may present with tongue inflammation, angular labyrinthitis, and gingivitis, especially when combined with nutritional deficiencies. Some patients with chronic and heavy alcohol consumption may present with salivary adenopathy, which may be associated with abnormal salivary metabolism and secretion due to peripheral autonomic neuropathy triggered by chronic alcohol stimulation. Patients with advanced cirrhosis often present with oral hygiene and health problems, especially in those associated with alcoholism, and correlate with the extent of the disease, affecting the patient’s quality of life. Respiratory symptoms. Respiratory problems are common in patients with liver disease, but are often easily overlooked by patients and clinicians. In acute viral infections resulting in liver impairment, such as hepatitis A virus, hepatitis E virus, and EBV, the initial manifestations are often chills, fever, cough, sore throat, and other upper respiratory tract infection-like symptoms, which are closely related to viral invasion of cells outside the liver, and these symptoms often serve as an important differentiator from chronic liver. In severe and long-term liver disease, some patients may also develop severe respiratory complications of hepato-pulmonary syndrome and portopulmonary hypertension. Hepato-pulmonary syndrome can occur in 8-24% of patients with cirrhosis and presents as intrapulmonary vasodilatation accompanied by a decrease in intrapulmonary arterial oxygenation. It can also be seen in some cases of non-sclerotic portal hypertension, acute liver injury (e.g. viral hepatitis, ischemic hepatitis). Its symptoms are not specific and may present as dyspnea with an insidious onset after long-term liver disease, which may present with oblique breathing (Platypnea), often with pestle finger and cyanosis. Portal pulmonary hypertension is defined as a syndrome associated with pulmonary hypertension in the setting of portal hypertension, with or without liver disease, and can depend on hemodynamic indices to make the diagnosis [4]. Symptoms in patients with portal pulmonary hypertension are not specific and may present as extreme weakness, progressive dyspnea, peripheral hemoedema, syncope, and chest pain. Digestive system symptoms. As an important component of the human digestive system, the most prominent and major manifestations of impaired liver function are mainly in the digestive system, including symptoms of digestive discomfort such as decreased appetite, aversion to greasy foods, nausea, acid reflux, abdominal distention, and diarrhea. Most often occur in acute liver injury, liver failure, long-term cirrhosis and other severe end-stage liver symptoms, where the liver lacks the ability to effectively process the food it consumes and will conditionally trigger the above non-specific symptoms. These symptoms are closely related to the state of liver function, and with the recovery of liver function, these can mostly be relieved rapidly and effectively. Abnormalities in stools and urine. In many patients with acute liver function injury, it may be the deepening change in urine color that prompts the patient to seek medical attention. The life span of human red blood cells is usually 120 days. After the death of red blood cells, they turn into bilirubin, which is converted into bile in the liver and excreted into the bile duct and finally through the stool, hence the yellow color of the stool. When the liver cells become diseased, they are unable to convert and excrete bile properly, and the bilirubin in the blood will rise, resulting in jaundice. Since the color of urine is greatly affected by drinking water and medication, the first urine color should be the evaluation point in the early morning. In severe liver disease, complications of portal hypertension, hypoalbuminemia, hepatorenal syndrome may be accompanied by low urine; complications of gastrointestinal bleeding may be accompanied by black stools or vomiting blood. In patients with mild or moderate hepatic impairment, physical examination often does not reveal any positive signs. In severe acute attacks or long-term chronic decompensation, especially in patients with cirrhosis, a variety of positive signs can be observed [5], mainly in the following areas. Jaundice. Jaundice is a yellow-like change triggered by abnormal bilirubin metabolism and excretion in the body leading to deposition of bile pigments in the tissues. High jaundice can lead to yellowish staining of the skin and mucous membranes throughout the body, which in itself does not cause significant damage to the organism, but can be a sensitive response to the degree of liver damage and the effectiveness of treatment. To exclude effects such as skin color, the most ideal observation is to examine the color change of the sclera or sublingual mucosa under natural light. This yellow staining is homogeneous and can be differentiated from pre-existing yellow lesions of the sclera itself. Scleral yellowing occurs when the bilirubin level exceeds 2.5 to 3 mg/dL (multiplied by 17.104 if converted to micromol/L). During the recovery period of severe acute liver injury, the scleral yellow color may vary from dark yellow, thick yellow, dark yellow, bright yellow, and pale yellow. Significant jaundice can be manifested in acute liver injury, severe cirrhosis, or liver cancer. Severe jaundice or cholestasis can trigger pruritus, which is a common manifestation of cholestatic disease of all types of etiology, often accompanied by elevated bile acid and bilirubin levels. Most are mild, while in some liver diseases can lead to intractable pruritus, affecting the quality of sleep and even leading to severe depression. Hepatic palms (Palmar erythema). Palmar erythema or palmar erythema is a widespread and intense reddish change in the skin color of the palm of the hand, mainly in the area between the large and small fissures. The color turns white when pressure is applied, and the redness returns rapidly when pressure is released. When a slide is pressed on the palm of the hand, flushing-like changes in the local skin can be observed with each pulsation of the arteries. Liver palms are mostly found in patients with long-term chronic liver disease or cirrhosis, but are not directly proportional to the disease process. White nails (Terry nails) can be seen in some patients with cirrhosis and are silvery-white like changes in the proximal nail bed, which can sometimes blur the crescent. [6] In severe cases, the entire nail bed appears white with only a reddish band 0.5 to 3 mm wide at the end, with the thumb and index finger being most frequently involved. Gynecomastia (male breast development). Gynecomastia is an enlargement or feminization change of the male breast. It is most often seen in patients with long-term and severe cirrhosis. In clinical workup, care needs to be taken to distinguish between true breast tissue enlargement and fatty tissue enlargement (e.g., breast lipoma). True breast tissue is often palpable, especially around the areola, is firmer and contains cords, unlike softer textured fatty tissue. Breast development in men is associated with an imbalance in the regulation of testosterone and estrogen by the liver, resulting in impaired estrogen inactivation and elevated estrogen levels in the body. These changes can also be accompanied by changes such as a decrease in body hair or a shrinking of the testicles. In women, this can lead to menstrual disorders. Spider nevi (spider nevus). Spider nevi consist of a clearly visible central arterial vascular lesion with numerous small radiating vessels, the latter resembling the legs of a spider, hence the name. Pressure on its central area with a match tip or pen causes the entire lesion to turn white, and after releasing the pressure object, it fills up and turns red in all directions starting from the central area. In some cases, the central pulsation can even be seen and felt, a manifestation that is more pronounced when the central area is lightly pressed with a slide. Spider nevi are usually found in the vascular distribution of the superior vena cava, especially on the face, neck, upper trunk, and arms. Although there are no clear criteria for evaluation, more than 2-3 spider nevi are usually considered abnormal. Spider nevi can also be closely associated with high estrogen levels. Other atopic skin changes such as Bier spots, Paper-money skin, Xanthelasma, Porphyria cutanea tarda, Hemochromatosis, Disseminated superficial sweat keratosis Disseminated superficial porokeratosis is also common in some specific liver diseases. These obvious cutaneous manifestations can be the first clue to the diagnosis of liver disease. Dilatation of blood vessels. Facial capillary dilation refers to superficial capillary dilation on the surface of the nose, forehead and neck and is seen in patients with severe cirrhosis. This sign is of great value in the clinical visualization of liver disease and in the assessment of acute and chronic disease. Abdominal varices occur mostly in patients with severe cirrhosis and are associated with portal hypertension and dilated collateral circulation. When significant or dilated abdominal wall veins are seen, the direction of blood flow in both cephalad and caudal directions needs to be determined using the belly button as a stronghold. The vein on one side is closed by pressure with the first finger and the second finger slides to empty the flow on the inferior side of the closure. When the second finger is removed, the blood flow refills, suggesting that the direction of that blood flow is directed to the first finger. If the vessel is not filled or is filled only when the pressor finger is released, the suggestion is that the direction of blood flow is directed to the second finger. In patients with portal hypertension, the direction of blood flow in the abdominal wall is centered on the navel traveling up (superior vena cava) or down (inferior vena cava). In patients with inferior vena cava obstruction, all the abdominal wall veins travel in the direction of the superior vena cava (head). In patients with inferior vena cava obstruction, all lateral wall venous flow travels in the direction of the inferior vena cava (feet). Manipulation of abdominal wall venous flow direction centered on the belly button can identify different etiologies of abdominal wall varices or manifestations. Spider nevus and abdominal wall varices may improve as the disease improves. Hepatic encephalopathy. The severity of hepatic encephalopathy in the broad sense can range from simple changes in sleep patterns, altered concentration memory mental focus, cognitive impairment to coma, mostly in liver failure or in the decompensated phase after long-term cirrhosis, while recently mild hepatic encephalopathy has been studied even in many patients with chronic hepatitis. Fluttering tremor, a typical representative sign of severe hepatic encephalopathy, is a brief and sudden tremor due to involuntary muscle contraction that is not associated with rest. It can best be elicited by instructing the patient to extend the arms, dorsally bend the wrists, keep the fingers extended and abducted, and close the eyes for 30 seconds or more. Positive patients may have sudden and involuntary wrist or metacarpophalangeal flexion and extension movements, accompanied by lateral movements of the fingers, followed by a rapid return to the original position. The prognosis for hepatic encephalopathy occurring in acute liver failure is mostly poor. In contrast, in hepatic encephalopathy due to long-term cirrhosis, the patient can mostly recover rapidly after treatment, but the condition can occur several times and is better tolerated by the patient. In some patients with recurrent attacks careful observation can even directly react to the degree of hepatic encephalopathy from changes in skin texture, which of course requires an experienced and attentive physician to make a judgment. Ascites and edema. Ascites and edema are common manifestations of advanced liver disease and are due to the accumulation of fluid in the abdominal cavity and subcutaneous tissue as a result of portal hypertension and hypoalbuminemia. In the decompensated phase of severe liver disease, ascites can be common and manifests as an abdominal bulge with positive mobile turbid sounds and accompanying abdominal wall varices, the latter of which can be differentiated from other tumorigenic ascites. In hypoproteinemia, there is more fluid accumulation in the subcutaneous tissues, and edema may appear around the body, which is depressed by pressure and recovers slowly, common in both lower limbs. Albumin is synthesized by hepatocytes and is also the main substance that maintains the colloid osmotic pressure of the blood and plays an important role in maintaining blood volume. The formation of ascites depends on two main factors. Firstly, the liver cannot synthesize enough albumin and the other is the inability of blood to flow freely through the liver due to liver scarring and the body compensates by reducing the blood volume balancing pressure. In this process, plasma leaks out of the vessel wall into the abdominal cavity. Palpation of the liver and spleen. By examination of the abdomen, the liver can be palpated in acute liver disease and alcoholic liver disease, while in severe cirrhosis or liver failure, the liver tends to shrink, and overall the prognosis is better for an enlarged liver than a shrunken liver. The one exception is in the case of liver tumors. The spleen may show varying degrees of enlargement in some acute diseases or in liver damage caused by viruses such as EBV, but with a relatively soft texture. The presence of an enlarged spleen in adolescent patients with hepatitis B and C suggests the need for close follow-up and aggressive treatment. In contrast, in varying degrees of cirrhosis, the spleen can be significantly enlarged and hard in texture. Liver, spleen and abdominal organ examination can be a reference, but the specific size and fluid depth are mostly based on ultrasound, CT or MRI. In conclusion, the above overview only mentions some of the clinical discomfort and signs that may be caused by impaired liver function, but liver disease is not an isolated disease, and can cause clinical discomfort in various systems outside the liver, as well as specific and non-specific clinical signs in many parts of the liver and outside the liver, and different manifestations in the nervous system, urinary system, cardiovascular system, endocrine system, and other aspects. In clinical work, first-hand clinical data obtained through careful consultation and physical examination, coupled with meticulous analysis, can often provide a good initial assessment of whether liver impairment has occurred and the extent of the impairment, in order to guide the selection of further tests, examinations and treatment plans.