Hyperbilirubinemia

The clinical condition caused by an increase in the blood level of the bile pigment bilirubin is defined as hyperbilirubinemia, which is usually a sign of an underlying disease or pathology.

In ICD-10, hyperbilirubinemia in adults has the code E80.7 - unspecified bilirubin metabolism disorder (in the section Metabolic disorders); in infants - in the section Certain conditions arising in the perinatal period (code P59.0 - neonatal jaundice). And hyperbilirubinemia without mention of jaundice is classified as a deviation from the norm detected during a blood test (code R17.9).

Epidemiology

According to some clinical studies, the prevalence of synonymous hyperbilirubinemia of jaundice is estimated to be approximately 4-12% of the general population.

In 46% of cases it is associated with viral hepatitis; in 30% of cases – with alcoholic liver disease; in 2% of cases – with hemolytic anemia and in 2% of cases – with Gilbert's syndrome.

Increased levels of bilirubin in the blood caused by viral hepatitis are usually observed in young patients, and in liver cirrhosis and liver cancer – in the elderly.

In the first days of life, some degree of hyperbilirubinemia develops in approximately 60-80% of all healthy newborns born at term, and in two-thirds of cases – for physiological reasons.

And nearly 10% of breastfed babies experience persistent jaundice (Lucy-Driscoll syndrome) during the first few weeks after birth.

Causes hyperbilirubinemia

During the natural metabolic breakdown of “expired” red blood cells – physiological hemolysis – the oxygen-carrying blood pigment hemoglobin, consisting of protein and heme (an iron-containing non-protein component), is also destroyed. During the breakdown of heme, the bile pigment biliverdin is first formed, and then, with the help of enzymes from macrophages of the mononuclear phagocytic system, bilirubin is formed in the liver. It enters the bile, and with it into the intestine; an insignificant part enters the blood, where its content normally does not exceed 1-1.2 mg/dl (17 μmol/liter).

But in certain diseases and pathologies, this indicator can be abnormally high. That is, an elevated level of bilirubin in the blood is not a disease, but a sign of a pathological process - a violation of bilirubin metabolism.

Its causes are usually divided into extrahepatic and intrahepatic. Intrahepatic causes include:

• viral (A, B, C, D, E, HSV), alcoholic, autoimmune, drug-induced hepatitis;
• intrahepatic cholestasis - bile stagnation;
• alcoholic liver disease;
• dystrophic changes in the liver and its dysfunction, in particular, in fatty liver disease, as well as liver cirrhosis and tumors;
• sarcoidosis and liver amyloidosis.

Experts attribute the following to extrahepatic causes of hyperbilirubinemia:

• inflammation of the bile ducts, leading to their stenosis;
• cholelithiasis – gallstone disease;
• common bile duct stones (choledochus);
• extrahepatic bile stasis, which occurs due to a cyst of the common bile duct or pancreas, as well as due to dysfunction of the sphincters of the biliary tract;
• acute and chronic inflammation of the pancreas – pancreatitis;
• malignant neoplasms of the gallbladder, bile ducts or pancreas;
• hemolytic anemia (associated with increased destruction of red blood cells);
• drug-induced hemolytic anemia.

Hyperbilirubinemia during pregnancy, two thirds of which occur in the third trimester, can be the result of both the presence of stones in the gallbladder and slow bile outflow - intrahepatic cholestasis of pregnancy, and accelerated hemolysis of red blood cells in HELLP syndrome - a complication of preeclampsia.

Also read:

• Causes of increased bilirubin in the blood
• Causes of Jaundice

Risk factors

The risk of bilirubin metabolism disorders with an increase in its level in the systemic bloodstream is increased by:

• inflammatory processes in the liver of parasitic etiology (in case of infection by cat fluke, echinococcus, fasciola, leishmania, schistosomes, etc.);
• alcohol abuse;
• malignant tumors of the gallbladder or liver, as well as leukemia;
• hereditary hemolytic anemia, autoimmune hemolytic anemia and sickle cell anemia;
• violation of acid-base balance in the body - metabolic acidosis;
• a decrease in the level of albumin synthesized by the liver in the blood – hypoalbuminemia;
• hemolytic transfusion reaction;
• sepsis;
• rejection syndrome in liver transplantation.

In children, such factors may include: congenital hepatitis B; congenital liver fibrosis; Caroli syndrome or disease (congenital enlargement of the lumen of the intrahepatic bile ducts); metabolic diseases; ineffective erythropoiesis and bone marrow hyperplasticity (for example, in myelodysplastic syndrome).

Pathogenesis

The development of hyperbilirubinemia is based on a disturbance in bilirubin metabolism, and the pathogenesis of this clinical condition is caused either by the inability to properly transform the product of red blood cell breakdown, or by problems with its removal from the body (due to obstruction of the bile ducts or damage to liver cells), or by accelerated destruction of red blood cells (increased hemolysis).

Total bilirubin in the blood is represented by indirect (free, unbound or unconjugated) and direct (bound or conjugated) bilirubin. And depending on which of them is abnormally high in the blood, there are different types of this clinical condition:

• indirect hyperbilirubinemia or unconjugated hyperbilirubinemia (with a free bilirubin content of more than 85%);
• direct hyperbilirubinemia or conjugated hyperbilirubinemia.

What is bilirubin conjugation? On average, an adult produces 4 mg of bilirubin per kilogram of body weight. In liver cells, under the action of the enzyme UDP-glucuronyl transferase (uridine diphosphate glucuronosyl transferase or UDPGT), binding or conjugation (from the Latin conjugatio - connection) of insoluble in physiological fluids but fat-soluble free or indirect bilirubin with glucuronic (beta-D-glucuronic) acid occurs. This process is known as glucuronidation or glucuronic conjugation, which is not only bilirubin that undergoes: by combining with this acid (which forms soluble glucuronides), harmful substances of exogenous and endogenous origin, as well as drug metabolites, are eliminated from the body.

Thus, bilirubin from a free state passes into a bound one: the conjugated form of bilirubin - direct bilirubin in the blood (bilirubin diglucuronide) is soluble in water and less toxic to the body. With the help of the MRP2 protein (multiple drug resistance), it is transported through the plasma membranes of hepatocytes and enters the bile capillaries. From here, together with bile, conjugated bilirubin is secreted into the small intestine, where an insignificant part of it is reabsorbed and returned back to the liver, and the majority is filtered by the kidneys and excreted from the body with urine. Some of the unconjugated bilirubin with bile enters the intestine, where, under the action of intestinal microbiota enzymes, it is transformed into stercobilin (which is excreted with feces) and urobilin, which is eliminated with urine.

The pathogenesis of unconjugated hyperbilirubinemia in Gilbert and Crigler-Najjar syndromes is associated precisely with a violation of bilirubin conjugation due to a deficiency of the UDFGT enzyme.

In hepatitis, liver inflammation of various origins, intrahepatic and extrahepatic bile stasis, narrowing of the common bile duct or bile ducts, problems with the removal of conjugated bilirubin arise, which leads to conjugated (direct) hyperbilirubinemia. In addition, in these pathologies, the lysosomal enzyme beta-glucuronidase is activated, which leads to deconjugation of bilirubin glucuronides and an increase in the level of free bilirubin in the blood.

The pathophysiological mechanism of increased bilirubin levels in the blood in Dubin-Johnson and Rotor syndromes is also explained by a decrease in the body's ability to excrete bilirubin, and intermittent or chronic hyperbilirubinemia in patients with these abnormalities is conjugated. And all these syndromes are hereditary or congenital hyperbilirubinemia.

In all syndromes with a genetically determined deficiency of the liver enzyme UDFGT and mutations in the genes of transport proteins, chronic hyperbilirubinemia develops.

Unconjugated non-hemolytic hyperbilirubinemia in these same syndromes is defined as functional hyperbilirubinemia or benign hyperbilirubinemia. An increase in the level of bilirubin in the blood is accompanied by a moderate increase in the level of transaminases and alkaline phosphatase with chronic or transient jaundice without structural changes in the liver and dysfunction, as well as without bile stasis and increased breakdown of erythrocytes.

Hemolytic hyperbilirubinemia refers to indirect hyperbilirubinemia with increased bilirubin formation during accelerated or increased breakdown of erythrocytes (including due to insufficient synthesis of the above-mentioned erythrocyte enzymes - G6PD and pyruvate kinase). As in cases of hemolytic anemia, the liver simply cannot cope with glucuronic conjugation and transformation of a large amount of bilirubin, and this leads to an increase in the level of unconjugated bilirubin.

Symptoms hyperbilirubinemia

An elevated level of bilirubin in the blood (more than 2 mg/dl or 34 μmol/liter) is manifested by jaundice, the first signs of which are icterus (yellowing) of the skin, mucous membranes and whites of the eyes (due to the deposition of unconjugated bilirubin), as well as dark urine, discolored feces and itchy skin. All the details in the publication - Symptoms of Jaundice

Unconjugated hyperbilirubinemia manifests itself as suprahepatic (hemolytic) jaundice, while conjugated hyperbilirubinemia is characterized by both hepatic (parenchymatous) jaundice with impaired liver function and subhepatic (mechanical) jaundice with the presence of fat in the stool (steatorrhea), abdominal pain, nausea, vomiting, and weight loss.

The degrees of hyperbilirubinemia are determined by the peak level of total bilirubin in the blood serum:

• at the first stage, the level of total bilirubin is in the range of 12-15 mg/dl;
• at the second degree – 15-20 mg/dl;
• at the third degree – 20-30 mg/dl;
• at the fourth degree, the level of total bilirubin in the serum is ˃ 30 mg/dl.

It is best to evaluate the clinical picture of jaundice with yellowness of the sclera of the eyes when the serum bilirubin level is >2.5-3 mg/dl.

Complications and consequences

Some patients with jaundice do not experience any long-term consequences and recover completely; in others, hyperbilirubinemia and the appearance of jaundice may be the first sign of a life-threatening condition.

The type of complication and the severity of the consequences vary depending on the underlying cause of the increased bilirubin levels in the blood that caused jaundice.

Potential complications in adults include: anemia, chronic hepatitis, electrolyte imbalance, bleeding, liver dysfunction, and renal failure.

Among the possible complications of hyperbilirubinemia during pregnancy, experts include premature birth; vitamin K deficiency with the risk of severe bleeding during childbirth due to decreased blood clotting; fetal distress; meconium entering the amniotic fluid; breathing problems in the newborn.

In newborns, the most serious complication is impaired brain function. The fact is that unconjugated bilirubin is neurotoxic, and when its level in the systemic bloodstream increases significantly (˃ 20-25 mg / dl), it penetrates the blood-brain barrier into the brain and settles in its basal and subcortical nuclei, causing damage to the central nervous system. In newborns, this complication is called nuclear jaundice, and most survivors experience cerebral palsy, as well as hearing and vision impairment.

Diagnostics hyperbilirubinemia

Diagnosis of hyperbilirubinemia includes anamnesis (including family history) and physical examination, as well as laboratory tests: blood tests (general, hemoglobin and albumin levels, total bilirubin in the blood); blood tests for liver function tests (determining the activity of the main liver enzymes), alkaline phosphatase, UDP-glucuronyl transferase (UDP-glucuronyl transferase), hepatitis virus antigens, alpha-1 antitrypsin, Coombs antiglobulin tests.

Instrumental diagnostics are used: X-ray of the liver and bile ducts, cholescintigraphy, ultrasound cholecystography, radioisotope hepatobiliary scintigraphy, ultrasound (CT or MRI) of the abdominal cavity.

Differential diagnosis

Differential diagnosis of hyperbilirubinemia should include congenital and acquired disorders of bilirubin metabolism, its intrahepatic and extrahepatic causes, hemoglobinuria and other hemoglobinopathies, drug-induced jaundice, etc.

For more information, see – Diagnosis of Jaundice

Treatment hyperbilirubinemia

In adults, hyperbilirubinemia itself does not require treatment, and its manifestation in the form of jaundice is treated. And the treatment of jaundice largely depends on the underlying cause.

For viral hepatitis, antiviral and immunomodulatory drugs (Pegintron, Ribavirin, etc.), Ademetionine or Heptral are used; for fatty liver infiltration - Hepa-Merz; for parasitic liver invasion - anthelmintic drugs ( Mebendazole, etc.); for biliary cirrhosis of the liver - Hepalex, Essentiale Forte N, Silymarin, etc.

In case of bile stasis, cholestasis is treated with the prescription of choleretic drugs.

Phenobarbital can be used to reduce the level of indirect bilirubin in the blood of children (twice a day for a week, 1.5-2.0 mg/kg). In addition to its main action (anticonvulsant, sedative and hypnotic), this drug can stimulate the microsomal enzyme system of the liver, induce liver enzymes and accelerate the glucuronic conjugation of bilirubin.

Also, for neonatal jaundice no longer than five days (with a total daily dose of 10 mg/kg), Zixorin, a hepatoprotective agent that activates glucuronic conjugation in the liver, can be used. Among its side effects, nausea is noted.

In severe cases, immunoglobulin is administered intravenously, plasmapheresis and/or exchange blood transfusion is performed.

Phototherapy of hyperbilirubinemia is a physiotherapeutic treatment of neonatal jaundice using blue light with a wavelength of 450–470 nm. When the skin is irradiated, unconjugated bilirubin in the subcutaneous layer absorbs light waves, which leads to its photooxidation with the formation of a water-soluble isomer, which enters the bloodstream and is excreted in bile and urine.

In case of anemia due to hemolysis of red blood cells, a blood transfusion may be required. And surgical treatment may be required to remove stones in the bile ducts, to dilate them, to remove a cyst of the common bile duct or pancreas, as well as tumors that obstruct the outflow of bile.

Also recommended Diet for high bilirubin

Prevention

Is it possible to prevent hyperbilirubinemia and jaundice in adults? Vaccination can help prevent hepatitis A and B. To prevent gallstones from forming in the gallbladder, it is necessary to normalize the cholesterol level in the blood and lose extra pounds, avoid fatty and fried foods, and exercise more. If you do not abuse alcohol, there will be no threat of alcoholic hepatitis or alcoholic liver disease.

Additionally, medications should be taken when prescribed by your doctor and only as directed to prevent potential liver damage.

By following the rules of hygiene, it is easier to avoid parasitic invasion that affects the liver.

And to prevent hyperbilirubinemia and jaundice in newborns with a negative Rh factor, the mother undergoes Rh isoimmunization at certain times with the introduction of anti-Rhesus immunoglobulin.

Forecast

The prognosis for patients with hyperbilirubinemia and jaundice depends on the underlying cause of the increased bilirubin level in the blood: if the cause can be eliminated, it is favorable. But the severity of the condition, the development of complications, and the presence of other diseases can play a decisive role in determining the individual prognosis.

The prognosis for breastfeeding syndrome (Lucy-Driscoll syndrome) is favorable, since jaundice goes away on its own by the time the child is 2.5-3 months old.

With neonatal physiological jaundice, babies also recover, although about 10% of infants have persistent high bilirubin levels, which can lead to serious complications.