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Systemic Abnormalities in Liver Disease

By

Danielle Tholey

, MD, Sidney Kimmel Medical College at Thomas Jefferson University

Last full review/revision Jan 2021| Content last modified Jan 2021
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Liver disease often causes systemic symptoms and abnormalities.

Circulatory Abnormalities

Hypotension in advanced liver failure may contribute to renal dysfunction. The pathogenesis of the hyperdynamic circulation (increased cardiac output and heart rate) and hypotension that develop in advanced liver failure or cirrhosis Cirrhosis Cirrhosis is a late stage of hepatic fibrosis that has resulted in widespread distortion of normal hepatic architecture. Cirrhosis is characterized by regenerative nodules surrounded by dense... read more is poorly understood but is in part a compensatory mechanism for extensive peripheral splanchnic vasodilation. Factors that may contribute in cirrhosis may include altered sympathetic tone, production of nitric oxide and other endogenous vasodilators, and enhanced activity of humoral factors (eg, glucagon).

Endocrine Abnormalities

Glucose intolerance, hyperinsulinism, insulin resistance, and hyperglucagonemia are often present in patients with cirrhosis; the elevated insulin levels reflect decreased hepatic degradation rather than increased secretion, whereas the opposite is true for hyperglucagonemia. Abnormal thyroid function tests may reflect altered hepatic handling of thyroid hormones and changes in plasma binding proteins rather than thyroid abnormalities.

Sexual effects are common. Chronic liver disease commonly impairs menstruation and fertility. Males with cirrhosis, especially alcoholics, often have both hypogonadism Male Hypogonadism Hypogonadism is defined as testosterone deficiency with associated symptoms or signs, deficiency of spermatozoa production, or both. It may result from a disorder of the testes (primary hypogonadism)... read more (including testicular atrophy, erectile dysfunction, decreased spermatogenesis) and feminization (gynecomastia Gynecomastia This photo shows enlarged breast tissue in a male patient. Gynecomastia is hypertrophy of breast glandular tissue in males. It must be differentiated from pseudogynecomastia, which is increased... read more Gynecomastia , female habitus). The biochemical basis is not fully understood. Gonadotropin reserve of the hypothalamic-pituitary axis is often blunted. Circulating testosterone levels are low, resulting mainly from decreased synthesis but also from increased peripheral conversion to estrogens. Levels of estrogens other than estradiol are usually increased, but the relationship between estrogens and feminization is complex. These changes are more prevalent in alcohol-related liver disease Alcohol-Related Liver Disease Alcohol consumption is high in most Western countries. According to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), 8.5% of US adults are estimated to have... read more Alcohol-Related Liver Disease than in cirrhosis of other etiologies, suggesting that alcohol, rather than liver disease, may be the cause. In fact, evidence indicates that alcohol itself is toxic to the testes.

Hematologic Abnormalities

Anemia is common among patients with liver disease. Contributing factors may include blood loss, folate (folic acid) deficiency, hemolysis Overview of Hemolytic Anemia At the end of their normal life span (about 120 days), red blood cells (RBCs) are removed from the circulation. Hemolysis is defined as premature destruction and hence a shortened RBC life span ( read more Overview of Hemolytic Anemia , marrow suppression by alcohol, and a direct effect of chronic liver disease.

Clotting and coagulation abnormalities are common and complex. Hepatocellular dysfunction and inadequate absorption of vitamin K may impair liver synthesis of clotting factors. An abnormal prothrombin time (PT), depending on the severity of hepatocellular dysfunction, may respond to parenteral phytonadione (vitamin K1) 5 to 10 mg once/day for 2 to 3 days. Thrombocytopenia, disseminated intravascular coagulation, and fibrinogen abnormalities also contribute to clotting disturbances in many patients.

Renal and Electrolyte Abnormalities

Renal and electrolyte abnormalities are common, especially among patients with ascites.

Hypokalemia Hypokalemia Hypokalemia is serum potassium concentration 3.5 mEq/L ( 3.5 mmol/L) caused by a deficit in total body potassium stores or abnormal movement of potassium into cells. The most common cause is... read more may result from excess urinary potassium loss due to increased circulating aldosterone, renal retention of ammonium ion in exchange for potassium, secondary renal tubular acidosis, or diuretic therapy. Management consists of giving oral potassium chloride supplements and withholding potassium-wasting diuretics.

Hyponatremia Hyponatremia Hyponatremia is decrease in serum sodium concentration 136 mEq/L ( 136 mmol/L) caused by an excess of water relative to solute. Common causes include diuretic use, diarrhea, heart failure, liver... read more is common even though the kidneys may avidly retain sodium (see Ascites: Pathophysiology Pathophysiology Ascites is free fluid in the peritoneal cavity. The most common cause is portal hypertension. Symptoms usually result from abdominal distention. Diagnosis is based on physical examination and... read more ); it usually occurs with advanced hepatocellular disease and is difficult to correct. Relative water overload is more often responsible than total body sodium depletion; potassium depletion may also contribute. Water restriction and potassium supplements may help; diuretics that increase free water clearance can be used in severe or refractory cases. Saline solution IV is indicated only if profound hyponatremia causes seizures or if total body sodium depletion is suspected; it should be avoided in patients with cirrhosis Cirrhosis Cirrhosis is a late stage of hepatic fibrosis that has resulted in widespread distortion of normal hepatic architecture. Cirrhosis is characterized by regenerative nodules surrounded by dense... read more and fluid retention because it worsens ascites and only temporarily increases serum sodium levels.

Renal failure in liver disease may reflect

  • Rare disorders that directly affect both the kidneys and the liver (eg, carbon tetrachloride toxicity)

  • Circulatory failure with decreased renal perfusion, with or without frank acute tubular necrosis

  • Functional renal failure, often called hepatorenal syndrome

Hepatorenal syndrome

This syndrome consists of

  • Progressive oliguria and azotemia in the absence of structural damage to the kidneys

Hepatorenal syndrome usually occurs in patients with alcoholic hepatitis or advanced cirrhosis with ascites Ascites Ascites is free fluid in the peritoneal cavity. The most common cause is portal hypertension. Symptoms usually result from abdominal distention. Diagnosis is based on physical examination and... read more . Pathogenesis is thought to be due to extreme vasodilation of the splanchnic arterial circulation, leading to decreased central arterial volume and subsequent renal vessel vasoconstriction. Neural or humoral reductions in renocortical blood flow follow, resulting in a diminished glomerular filtration rate. Low urinary sodium concentration and benign sediment usually distinguish it from acute tubular necrosis Acute Tubular Necrosis (ATN) Acute tubular necrosis (ATN) is kidney injury characterized by acute tubular cell injury and dysfunction. Common causes are hypotension or sepsis that causes renal hypoperfusion and nephrotoxic... read more Acute Tubular Necrosis (ATN) , but prerenal azotemia may be more difficult to distinguish; in equivocal cases, response to a volume load should be assessed.

Once established, renal failure due to untreated hepatorenal syndrome is usually rapidly progressive and fatal (type 1 hepatorenal syndrome), although some cases are less severe, with stable milder renal insufficiency (type 2).

Combination therapy with vasoconstrictors (typically, midodrine, octreotide, or terlipressin) and volume expanders (typically, albumin) can be effective. Norepinephrine infusion can be used in refractory cases and titrated to urine output and mean arterial pressures.

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