Systemic disorders in liver disease

Liver diseases often present with general symptoms and disturbances.

Circulatory disturbances

Arterial hypotension with progressive liver failure may contribute to renal dysfunction. The pathogenesis of hyperdynamic circulation (increased cardiac output and heart rate) and arterial hypotension that develop with progressive liver failure or liver cirrhosis is not fully understood. However, these disorders may be caused by peripheral arterial vasodilation. Specific circulatory disorders in the liver (e.g., Budd-Chiari syndrome).

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Endocrine disorders

Glucose intolerance, hyperinsulinism, insulin resistance, and hyperglucagonemia are common in patients with cirrhosis; elevated insulin levels reflect a decrease in the rate of insulin breakdown in the liver rather than an increase in secretion, while the opposite is more typical of hyperglucagonemia. Changes in thyroid function parameters reflect disturbances in the metabolism of thyroid hormones in the liver and disturbances in the binding of hormones to plasma proteins rather than disturbances in the function of the thyroid gland itself.

Chronic liver disease commonly causes menstrual and fertility disturbances. Men with cirrhosis, particularly those with alcoholism, often have hypogonadism (including testicular atrophy, erectile dysfunction, decreased spermatogenesis) and feminization (gynecomastia, effeminacy). The biochemical mechanisms for these changes are not well understood. The hypothalamic-pituitary gonadotropin reserve is often decreased. Circulating testosterone levels are decreased mainly because of decreased synthesis but also because of increased peripheral conversion to estrogens. Levels of estrogens other than estradiol are usually increased, but the relationship between estrogenemia and feminization is complex. These disturbances are more pronounced in alcoholic liver disease than in cirrhosis of other etiologies. It is assumed that alcohol itself, rather than liver disease, is the cause of these changes. Alcohol itself has been shown to be toxic to the testicles.

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Hematological disorders

Anemia is common in patients with liver disease. It is promoted by bleeding, folate deficiency, hemolysis, alcohol-induced hematopoiesis suppression, and the direct effect of chronic liver disease. Leukopenia and thrombocytopenia are often associated with splenomegaly as portal hypertension progresses.

Coagulation disorders are characteristic, the mechanism of their occurrence is complex. Hepatocellular dysfunction and decreased absorption of vitamin K disrupt the synthesis of coagulation factors in the liver. Depending on changes in PT or INR values and the severity of hepatocellular dysfunction, there may be a different response to parenteral administration of phytonadione (vitamin K 5-10 mg once a day for 2-3 days. Thrombocytopenia, disseminated intravascular coagulation and fibrinogen levels also affect hemostasis in most patients.

Renal and electrolyte disturbances

Renal and electrolyte disturbances are common, especially in patients with ascites.

Hypokalemia may result from urinary potassium loss due to elevated blood aldosterone, renal retention of ammonium ions in exchange for potassium, secondary renal tubular acidosis, or diuretic therapy. Treatment includes potassium chloride and potassium-sparing diuretics.

Hyponatremia is common even when the renal Na-retaining function is preserved; hyponatremia is usually seen in advanced hepatocellular disorders and is difficult to correct. It is due to a relative water excess rather than to total sodium losses; potassium depletion is also important. Fluid restriction and potassium supplementation may be effective; the use of diuretics, which increase free water clearance, is controversial. Intravenous saline is indicated only when hyponatremia is severe enough to cause paroxysms or if total sodium depletion is suspected; it should be avoided in patients with cirrhosis with fluid retention because it worsens ascites and only temporarily increases serum sodium.

Progressive liver failure may alter the acid-base balance, usually resulting in metabolic alkalosis. Blood urea concentrations are usually low because of impaired hepatic synthesis; gastrointestinal bleeding is associated with increased enteral load rather than with deterioration in renal function. In the latter case, normal creatinine concentrations confirm normal renal function.

Renal failure in liver disease may reflect rare disorders that directly affect both the kidney and liver (eg, carbon tetrachloride poisoning); circulatory failure with decreased renal perfusion, with or without visible acute tubular necrosis; or functional renal failure, often referred to as hepatorenal syndrome. Hepatorenal syndrome consists of progressive oliguria and azotemia in the absence of structural renal damage; it typically occurs in patients with fulminant hepatitis or progressive cirrhosis with ascites. The mechanism probably involves marked vasodilation of splanchnic arterial vessels, resulting in decreased effective arterial blood flow. There is a decrease in neurogenic or humoral regulation of renocortical blood flow, leading to decreased glomerular filtration. Low urinary sodium concentration and normal urinary sediment usually differentiate it from tubular necrosis, but this condition is difficult to differentiate from prerenal azotemia; in equivocal cases, renal response to fluid loading can be assessed. Renal failure due to hepatorenal syndrome is generally rapidly progressive and fatal (hepatorenal syndrome type 1), but some cases are more favorable, with stable renal failure (type 2). Liver transplantation is the only treatment for patients with hepatorenal syndrome type 1; transjugular intrahepatic portosystemic shunt (TIPS) and vasoconstrictors have shown encouraging results but require more follow-up.

Asymptomatic course with altered laboratory test results

Because aminotransferases and alkaline phosphatase are routine laboratory tests, abnormalities are often seen in patients without signs or symptoms of liver disease. In such cases, the physician should obtain information about possible liver toxicities, including alcohol use; use of prescription and over-the-counter drugs, herbal products, and home remedies; and exposure to an industrial or other chemical. Moderate elevations in ALT or AST (< 2 times ULN) require only repeat testing; they occur in approximately one-third of cases. If abnormalities are seen in other laboratory tests and are significant or persist on repeat testing, further evaluation is necessary.

If aminotransferase levels are elevated, fatty liver disease, which is often suspected on clinical examination, should be excluded. If fatty liver disease is excluded, screening for hepatitis B and C should be performed. Patients over 40 years of age should be tested for hemochromatosis; patients under 30 years of age, for Wilson's disease. Most patients, especially young or middle-aged women, should be tested for autoimmune diseases. Certain groups of patients (risk groups) should be tested for malaria and schistosomiasis. If the results are negative in such cases, testing for alpha-antitrypsin deficiency is indicated. If the cause is not established, liver biopsy is recommended.

In the case of asymptomatic isolated elevation of alkaline phosphatase, it is necessary to confirm the liver origin of this phenomenon (this is confirmed by elevated levels of 5'-nucleotidase or gamma-glutamyl transpeptidase). If the presence of liver pathology is confirmed, instrumental examination of the liver is indicated, usually using ultrasonography or magnetic resonance cholangiopancreatography. If no structural abnormalities are detected, intrahepatic cholestasis can be considered and toxic effects of drugs or hepatotoxic poisons can be assumed. Infiltrative changes and metastases to the liver (e.g., colon cancer) require clarification.

In women, determination of antimitochondrial antibodies is necessary. Constant unexplained increases in indicators or suspicion of intrahepatic cholestasis are indications for liver biopsy.

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