Hyperbilirubinemia– a group of diseases and syndromes characterized by icteric staining of the skin and mucous membranes, hyperbilirubinemia with normal other indicators of liver function and (in the main forms) the absence of morphological changes in the liver, a benign course. These include posthepatitis hyperbilirubinemia and functional congenital hyperbilirubinemia.
Causes of hyperbilirubinemia
Functional congenital hyperbilirubinemias are a group of hereditarily transmitted (genetically determined) non-hemolytic hyperbilirubinemias. The diseases are caused by a disruption in the processes of hepatocytes capturing free bilirubin from the blood, binding it to glucuronic acid to form bilirubin glucuronide (bound bilirubin) and its subsequent release into bile.
Symptoms of hyperbilirubinemia
In all cases, hyperbilirubinemia and jaundice are detected from early childhood, in most cases (except for Crigler-Nayjar syndrome) they are insignificant, and can be intermittent (intensified under the influence of errors in diet, alcohol intake, intercurrent diseases, physical fatigue and other reasons). Mildly expressed dyspeptic symptoms, mild asthenia, weakness, and fatigue are not uncommon.
The course is benign, the prognosis is favorable; ability to work, as a rule, is preserved.
Diagnosis of hyperbilirubinemia
The liver is usually not enlarged, soft, painless, liver function tests (with the exception of Hyperbilirubinemia) are not changed. Radioisotope hepatography does not reveal any changes. The spleen is not enlarged. The osmotic resistance of erythrocytes and their life expectancy are normal. A puncture biopsy in all forms (except Dubin-Johnson syndrome) does not reveal any changes.
Treatment of hyperbilirubinemia
Patients, as a rule, do not need special treatment, only during the period of increased jaundice they are prescribed a gentle diet No. 5, vitamin therapy, and choleretic agents. It is prohibited to consume alcoholic beverages, spicy and fatty foods, and physical overload is not recommended.
Hyperbilirubinemia in the ICD classification:
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Specialization: Gastroenterologist
Christina: 02/13/2016
Hello. FGDS and FCS diagnosed the following: erosive gastropathy, urease test colonization of the gastric mucosa with H. pylori (+++), colon atony. I am worried about loose stools, abdominal pain, flatulence. I’ll go to a gastroenterologist, but not soon, is all this serious?
Treatment of hyperbilirubinemia primarily depends on its pathogenetic variant, symptoms and should be aimed at treating the underlying disease that caused the symptoms of hyperbilirubinemia. Patients with symptoms of hyperbilirubinemia are immediately hospitalized in order to definitively clarify the diagnosis and carry out active treatment. An exception to this rule is patients with Gilbert's syndrome with hyperbilirubinemia, in whom it is not necessary to specifically reduce hyperbilirubinemia. In these patients, the main focus is on preventing symptoms of liver disease, as well as reducing physical and neuropsychic stress. For the treatment of hyperbilirubinemia, it is recommended to eat 4 full meals a day and 1-2 times a year monthly courses of treatment with choleretic tea.
All other patients with hyperbilirubinemia are prescribed diet No. 5, which limits fats but contains carbohydrates, proteins and vitamins in sufficient quantities. Drinking plenty of water is beneficial, especially mineral waters (“Borjomi”, “Essentuki” No. 4, No. 17, etc.). Food should be taken at least 5 to 6 times a day when treating hyperbilirubinemia.
Hyperbilirubinemia - treatment in the clinic
The regime of patients with hyperbilirubinemia should be bed or semi-bed. The toxic effect of high concentrations of bilirubin during hyperbilirubinemia can be reduced by including antioxidant drugs (tocopherol, ascorbate, cystamine, ionol, etc.) in the complex of drug treatment of symptoms of hyperbilirubinemia. In severe forms of hyperbilirubinemia, intravenous glucose, sometimes in combination with subcutaneous insulin injections, is recommended to treat symptoms; hemodesis.
To prevent and treat symptoms of hemorrhagic syndrome, vitamin K, vikasol, ascorbic acid, B vitamins, and calcium chloride are administered. For symptoms of parenchymal and intrahepatic hyperbilirubinemia caused by an immunoinflammatory process, a relatively short course of treatment with glucocorticosteroids (12–30 days) in small doses (30 mg/day) is administered.
In the absence of symptoms of mechanical hyperbilirubinemia, choleretic agents (holosas, etc.) can be prescribed for treatment, and in the presence of infection in the biliary tract, antibiotics can be prescribed to treat hyperbilirubinemia. Bile secretion can be improved with duodenal intubation. Such a symptom as painful and persistent skin itching in patients with cholestatic jaundice is alleviated by treatment with warm baths with the addition of vinegar, soda, carbolic acid; rubbing with a weak solution of carbolic acid or camphor alcohol. For the same purpose, bromine preparations, atropine, and pilocarpine can be prescribed internally.
The concentration of bile acids in the blood with symptoms of hyperbilirubinemia can be tried to be reduced by influencing the mechanism of their hepatic-intestinal circulation. For this, patients are prescribed drugs that bind bile acids in the intestines - cholestyramine 12 - 16 g per day, bilignin 5 - 10 g (1 - 2 teaspoons) 3 times a day 30 - 40 minutes before meals, washed down with water. Treatment of patients with obstructive jaundice is usually surgical.
Gilbert's syndrome in the treatment of symptoms of hyperbilirubinemia
Among enzymatic hyperbilirubinemias, the most common is Gilbert's syndrome (disease) and the adjacent Calque's syndrome (post-hepatitis variant of Gilbert's syndrome). This syndrome (disease) with symptoms of hyperbilirubinemia occurs more often in men in the second and third decades of life. It is characterized by symptoms: a periodic increase in the content of unconjugated plasma bilirubin to 85 - 140 µmol/l and in most cases appears for the first time in acute diseases of various nature (acute viral hepatitis, infectious mononucleosis, toxic liver damage of various etiologies, malaria, etc.), as well as after significant physical or emotional stress, hypothermia, injury, surgery, etc.
Symptoms of hyperbilirubinemia due to inflammatory (hepatitis, cirrhosis) or toxic (chemical poisoning, drug intolerance, etc.) hepatocellular damage is called hepatic (hepatocellular), or parenchymal. Damaged hepatocytes are not able to fully capture bilirubin from the blood, bind to glucuronic acid and release it into the bile ducts and require treatment.
As a result, without treatment, the content of unconjugated (indirect) bilirubin increases in the blood serum. In addition, with symptoms of liver cell dystrophy, reverse diffusion of conjugated (direct) bilirubin from the bile canaliculi into the blood capillaries is observed. This pathological mechanism causes an increase in the level of conjugated (direct) bilirubin in the blood serum, as well as symptoms of hyperbilirubinuria and a decrease in the excretion of stercobilin in feces.
In total, when liver parenchyma cells are damaged, the content of unconjugated and conjugated bilirubin in the blood serum can increase 4–10 times or more. With parenchymal lesions of the liver, the ability of liver cells to capture bile acids from the blood sharply decreases, as a result of which they accumulate in the blood and are excreted in the urine.
Hyperbilirubinemia - symptoms of the disease
Development of symptoms of hyperbilirubinemia
Symptoms of hyperbilirubinemia occur when there is increased formation of bilirubin, as well as when its transport into liver cells and excretion by these cells is impaired, or when the binding processes of free bilirubin are impaired (glucuronidation, sulfurization, etc.). Free (unconjugated) bilirubin in hyperbilirubinemia is poorly soluble and toxic; it is neutralized in the liver by the formation of soluble diglucuronide - a paired compound of bilirubin with glucuronic acid (conjugated, or direct bilirubin).
High concentrations of bilirubin with symptoms of hyperbilirubinemia inhibit the processes of oxidative phosphorylation and reduce oxygen consumption, which leads to tissue damage and the need for treatment. The toxic effect of high concentrations of bilirubin is manifested by symptoms of damage to the central nervous system, the occurrence of foci of necrosis in parenchymal organs, suppression of the cellular immune response, the development of anemia due to hemolysis of red blood cells, etc.
Symptoms of hyperbilirubinemia due to increased formation of bilirubin are observed with excessive hemolysis (for example, with hemolytic anemia during a hemolytic crisis, extensive hemorrhages, heart attacks, lobar pneumonia). This form of hyperbilirubinemia is called suprahepatic or hemolytic hyperbilirubinemia. If it causes symptoms of jaundice, then the latter has similar names.
| Pathogenetic variants of jaundice | Skin coloring | Itchy skin | Blood bilirubin | Urobilin urine | Urine bilirubin | Stercobilin |
|
| conjugated | unconjugated |
||||||
| 1. Suprahepatic (hemolytic) | Pale yellow with lemon tint | Absent | |||||
| 2. Constitutional (enzymatic) | Absent | ||||||
| 3. Hepatocellular (parenchymal) | Orange, bright yellow | Unstable, lightweight | |||||
| 4. Cholestatic | |||||||
| 4.1. Intrahepatic (parenchymal with cholestasis syndrome) | Reddish-greenish | Steady torturous | |||||
| 4.2. Subhepatic (mechanical, obstructive) | Dark gray-greenish (earthy) fading to black | Steady torturous | |||||
Stages of hemolysis of hyperbilirubinemia
In the initial stage of hemolysis, there may be no symptoms of hyperbilirubinemia, since the liver is able to metabolize and secrete bilirubin into bile in an amount that is 3 to 4 times greater than its production under physiological conditions. Overhepatic (hemolytic) hyperbilirubinemia develops when the reserve capacity of the liver is exhausted. With moderate hemolysis, the symptoms of hyperbilirubinemia are caused mainly by unconjugated bilirubin, and with massive hemolysis - by unconjugated and conjugated bilirubin. The latter can cause symptoms of hyperbilirubinuria. Unconjugated bilirubin does not pass through the healthy kidney filter and does not appear in the urine.
Hyperbilirubinemia caused by genetic defects in liver enzymes involved in the elimination from plasma and glucuronidation of free bilirubin are called enzymopathic (constitutional). They usually occur without symptoms of liver damage and hemolysis, are not accompanied by loss of ability to work and do not end in death with adequate treatment.
For quotation: Delyagin V.M., Urazbagambetov A.U. Medical support for patients with familial benign hyperbilirubinemia // RMZh. 2008. No. 18. S. 1194
Introduction Familial benign hyperbilirubinemia (idiopathic non-hemolytic hyperbilirubinemia, benign hyperbilirubinemia, pigmentary hepatosis) is a group of diseases without pronounced changes in the structure and function of the liver and without obvious signs of hemolysis and cholestasis, caused by impaired bilirubin metabolism (E 80 according to ICD-10), which is manifested by persistent or intermittent jaundice. Idiopathic non-hemolytic hyperbilirubinemia constitutes a large group of conditions, the development of which is caused by a violation of the intracellular transport of bilirubin. There are no signs of hemolysis or liver disease. Most of them (the most important exception is Crigler-Najjar syndrome) are benign. These hyperbilirubinemias occur due to both indirect and direct bilirubin.
Familial benign hyperbilirubinemia (idiopathic non-hemolytic hyperbilirubinemia, benign hyperbilirubinemia, pigmentary hepatosis) is a group of diseases without pronounced changes in the structure and function of the liver and without obvious signs of hemolysis and cholestasis, caused by impaired bilirubin metabolism (E 80 according to ICD-10), which manifests itself as persistent or intermittent jaundice. Idiopathic non-hemolytic hyperbilirubinemia constitutes a large group of conditions, the development of which is caused by a violation of the intracellular transport of bilirubin. There are no signs of hemolysis or liver disease. Most of them (the most important exception is Crigler-Najjar syndrome) are benign. These hyperbilirubinemias occur due to both indirect and direct bilirubin.
Indirect (unconjugated) hyperbilirubinemias include Gilbert syndrome (E 80.4), Crigler-Najjar syndrome (E 80.5), Driscol syndrome, and primary familial hyperbilirubinemia. Direct (conjugated) hyperbilirubinemias include Dabin-Jones and Rotor syndromes.
The most common condition in this group of diseases is Gilbert's syndrome (GS). GS is observed in 3-7% of Europeans, 3% of Asians and 36% of Africans. Among the carriers of the trait, there are 2-7 times more men than women. Despite the widespread prevalence of GS in the population, this syndrome is not always taken into account when carrying out differential diagnosis (DD) of jaundice, and if it is detected, many questions arise regarding the determination of medical tactics.
GS is inherited in an autosomal recessive (a/r) manner and is characterized by intermittent jaundice without signs of hemolysis or liver disease. Hyperbili-rubinemia is moderate (not higher than 6 mg%, in most - less than 3 mg%), varies by day of the week, time of year, presence or absence of dehydration, fasting, physical activity, intercurrent diseases, menstruation. Often no explanation can be found for the appearance of jaundice. Episodes of jaundice end on their own. An increase in bilirubin is not observed in more than 1/3 of gene carriers.
Pathogenesis
Unconjugated hyperbilirubinemia in GS is caused by a decrease in the activity of enzymes of the bilirubin-uridine diphosphate glucoronyl transferase (BUDGT) system. BUDGT is located in the endoplasmic reticulum of hepatocytes and converts bilirubin into bilirubin monoglucuronide and diglucorohydride. BUDGT is only one of the isoforms of uridine glucoronyl transferases (UGTs), responsible for the conjugation of hormones, neurotransmitters, carcinogens and many other compounds.
The uridine glucoronyl transferase gene is located on chromosome 2 and contains 5 exons. Exons 2–5 are constant components of all UGT isoforms. Exon 1 encodes specific regions of the enzyme and has the base base TATAA. Exons 1a and 1d encode the BUDGT 1A1 and BUDGT 1A2 regions, respectively. BUDGT 1A1 is responsible for the complete conjugation of bilirubin. The metabolic significance of BUDGT 1A2 is small. Expression of BUDGT 1A1 depends on the promoter at position 5’. Thus, disruption of bilirubin glucuronidation depends on a mutation in exon 1A, its promoter, or in the common exon. A mutation in an exon consists of the appearance of two additional bases (TA). The addition of new bases to the previous TATAA disrupts the interaction with transcription factor IID, and BUDGT expression decreases by 30%. In homozygous cases, bilirubin monoglucuronide predominates over diglucoronide in bile.
Additional mutations have been described in the promoter region (Gly71Arg, Pro364Leu, Tyr468Asp). In carriers of these mutations, the concentration of bilirubin in the blood significantly exceeds normal levels.
The degree of hyperbilirubinemia and clinical manifestations of GS depend not only on the decrease in BUDGT activity, but also on associated factors: latent hemolysis, impaired intrahepatic transport. For example, many people with a TATAA defect do not have unconjugated hyperbilirubinemia, just like patients with granulomatous liver disease and decreased BUDGT activity.
Clinical picture
The clinical picture of GS is variable. The syndrome is often associated with generalized connective tissue dysplasia of the Marfan or Ehlers-Danlos syndrome type. In infants who are homozygous for GS and are breastfed, newborn jaundice is more pronounced and lasts longer than in children without GS. Typically, GS is detected during puberty. Apparently, manifesting icterus is provoked by additional inhibition of glucuronidation of bilirubin by sex hormones. At older ages, GS is detected during the period of intercurrent diseases. In this case, it is necessary to carry out DD with posthepatic hyperbilirubinemia. Asking the patient about jaundice in relatives can help in establishing the diagnosis.
Many patients are emotional and note hypersensitivity of the skin. During the examination, moderate jaundice is revealed (usually icteric sclera against the background of dull-icteric skin, especially the face). Sometimes partial staining of the nasolabial triangle, palms, armpits, and feet is observed. Jaundice increases with dehydration, fasting, infection (including viral), drinking alcohol, heavy physical and mental work, and stress. They describe flaming and pigmented nevi, pigmentation of the eyelids, asthenic syndrome (depression, inability to concentrate, increased fatigue, weakness, poor sleep, etc.). Very often, patients complain of abdominal pain. Abdominal syndrome is often multifactorial and is often associated with general anxiety. There is no correlation between the presence or severity of abdominal syndrome and the degree of hyperbilirubinemia. In 50% of patients, latent hemolysis is diagnosed (a risk group for cholelithiasis!) (Fig. 1). In our experience, gallstones can form very quickly in such patients.
The sizes of the liver and spleen remain, as a rule, normal. There is no bilirubinuria. The study of liver enzymes does not have a decisive diagnostic value, although in rare cases an increase in serum alkaline phosphatase has been described. As with other types of benign hyperbilirubinemia, the histological structure of the liver is close to normal. Signs of dysproteinosis and necrosis of liver cells are usually not detected. But around the terminal hepatic venules an accumulation of lipofuscin-like pigment is detected.
Laboratory and differential diagnosis of Gilbert's syndrome
Laboratory diagnosis of GS is based on biochemical studies. Genetic studies are expensive and not widely available.
Fasting test. A sharp restriction of the energy value of food for 48 hours causes an increase in the level of unconjugated bilirubin. For 48 hours, the patient receives food with an energy value of 400 kcal/day. On the day the test starts, in the morning on an empty stomach and two days later, serum bilirubin is determined. When it rises by 50-100%, the test is considered positive. Within 24 hours of resuming normal nutrition, unconjugated bilirubin levels return to normal. The reasons for the increase in the concentration of unconjugated bi-lirubin during fasting have not yet been established. The concentration of unconjugated bilirubin during fasting also increases in patients with hemolytic anemia or liver disease, but the degree of increase is much less. An increase in bilirubin concentration is also observed with a normal calorie diet, but with limited fat. After taking fat, the bilirubin concentration quickly returns to normal. In modern conditions, the fasting test is rarely used.
Nicotinic acid at a dose of 50 mg when administered intravenously over the next 3 hours leads to a 2-3-fold increase in the concentration of unconjugated bilirubin. The mechanism of action is reduced to osmotic destruction of erythrocytes, increased formation of bilirubin in the spleen, reversible inhibition of BUDGT. The specificity of the sample is not high enough. A similar reaction can occur with hemolytic anemia and liver diseases.
Phenobarbital and other BUDGT inducers normalize plasma bilirubin concentrations.
Thin-layer chromatography allows us to detect an increase in the concentration of bilirubin monoglucuronide relative to diglucoronide, which is characteristic of SG.
The clearance of drugs, determined by the bromosulfophthalein test, and indocyanine green is reduced.
Differential diagnosis is carried out with other variants of familial hyperbilirubinemia (Table 1).
Crigler-Najjar syndrome = familial non-hemolytic jaundice of newborns. First described in 1952. Some believe that Krieg-le-ra-Nayar syndrome is a variant of more severe mutations in the same TATAA segment as in SG. This explains the intermediate concentrations of bilirubin in relatives of patients with Crigler-Najjar syndrome. There are two genetically heterogeneous forms of the disease.
In the first form, the syndrome is inherited a/r. Caused by the almost complete absence of BUDGT. Intense, often kernicterus is caused by a 20-30-fold increase in indirect bilirubin in the blood serum. Develops in the first hours and days of a child’s life. Symptoms of central nervous system damage come to the fore: muscle hypotonia, nystagmus, opisthotonus, athetosis, tonic and clonic convulsions, retardation in physical and mental development. Hemato-logical parameters remain within normal limits. There is no bi-rubinuria, the number of urobilin bodies in urine and feces is small. There is no success with the use of phenobarbital or glutethimide, inducers of microsomal enzymes. Patients rarely survive beyond 1.5 years.
In the second form, the syndrome is inherited a/d. BUDGT is present, although enzyme activity is significantly reduced. The intensity of jaundice is less pronounced. Kernicterus does not develop. The effect of phototherapy and microsomal enzyme inducers is good. The level of indirect fraction of serum bilirubin increases 5-20 times. The bile is colored, and a large amount of urobilinogen is detected in the feces. Patients live up to 50 years or more, but in the long term, especially with late treatment, deafness, choreathetosis, neuromuscular and personality abnormalities, and dental hypoplasia are common.
Driscoll syndrome is a familial form of transient hyperbilirubinemia of newborns due to steroid bodies in the maternal plasma that block the conjugation of bilirubin. A related (but not familial) condition is known in some breastfed infants, which may contain an unspecified factor that interferes with the glucuronidation of bilirubin.
Dubin-Johnson syndrome. Described in 1954. Transmitted by a/r. It manifests itself as chronic non-hemolytic jaundice with an increase in the level of conjugated bilirubin in the blood serum. It often begins during puberty, but can begin at any age. Jaundice is chronic or intermittent; the bilirubin content does not exceed 0.06 g/l. Exacerbation of jaundice is manifested by pain in the right hypochondrium, general weakness, and is observed with the accumulation of infections. During remission, jaundice almost completely disappears. The liver is moderately enlarged and has a dense consistency. In half of all cases, the spleen is palpable. Serum enzyme activity and liver function tests remain normal. Bile pigments are found in the urine. There are no signs of hemolysis. The bromsulfalein test has been changed. When bromsulfalein is prescribed, its content in the blood quickly drops, only to then rise again; at the 90th and 120th minutes the concentration exceeds that at the 45th minute, that is, normal uptake of the dye occurs with difficulty in release from the liver cells. A definitive diagnosis can be made with a puncture biopsy, which reveals the deposition of coarse-grained melanin-like pigment of a dark brown color in the liver cells. At laparoscopy, the liver is greenish-brown, the gallbladder is unchanged.
A variant of Dubin-Johnson syndrome (or an independent entity?) is Burk syndrome. It also reveals lipochromic hepatosis, but WITHOUT jaundice, although with significant hepatosplenomegaly.
Rotor syndrome was described in 1948. It is transmitted by a/r. Occurs with a predominant increase in the level of conjugated bilirubin in the blood serum with a normal histological picture of the liver. The disease occurs as prolonged jaundice with a moderate increase in conjugated bilirubin with normal liver function tests and good contrast of the gallbladder during cholecystography. DD with Dubin-Johnson syndrome is performed on the basis of a needle biopsy, since in Rotor syndrome dark pigment is never detected in the liver cells.
Along with these syndromes, DD of Gilles-bert syndrome is carried out with a general syndrome of jaundice, including hemolysis, hematomas, acute and chronic liver diseases, rhabdomyolysis, ineffective erythropoiesis, and side effects of drugs.
Treatment of Gilbert's syndrome
The patient should be informed that GS is a benign hyperbilirubinemia, life expectancy on average does not differ from the general population. However, cholelithiasis or the above-mentioned somatic and psychosomatic disorders may occur, which requires adjustment of the regimen and, in some cases, drug intervention.
Hospitalization is not required for uncomplicated cases. The vaccination calendar does not change. Physical activity should be normal. You should not take long breaks from eating. Fluid restriction is unfavorable.
Phenobarbital or glutethemide induce BUDGT activity and can be used in short courses in unfavorable situations.
Considering that in GS, along with biochemical disorders, the uptake of molecules by hepatocytes and transport throughout the cell suffers, and there is a risk of cholelithiasis, we used the drug LIV.52K in 15 of our patients.
LIV.52K is widely used in gastroenterology and hepatology, in pediatrics (in children over 2 years old, 10-20 drops 2 times a day) for chronic and acute hepatitis, dysfunction of the biliary system and many other conditions. LIV.52K is a combined herbal preparation. The drug is available in tablets and drops, is easily tolerated by children, and has hepatoprotective, antitoxic, anti-inflammatory, choleretic, antioxidant, and antianorexic effects. The hepato-protective effect of LIV.52K is due to the antioxidant and membrane-stabilizing properties of its constituent components. LIV.52K stimulates the biosynthesis of proteins and phospholipids, promotes the restoration of hepatocytes, reduces degenerative, fatty and fibrotic changes, and enhances intracellular metabolism. The drug regulates the level of plasma proteins in the blood, normalizing the albumin/globulin ratio. Provides normalization of the level of plasma transaminases, cholesterol, triglycerides, reducing the manifestations of dyslipidemia. Reduces bilirubin and alkaline phosphatase levels. Increases the liver's ability to store glycogen. It is very valuable that the drug improves the colloidal properties of bile, prevents the formation of gallstones and helps normalize the contractile function of the gallbladder.
With the use of the drug, the general condition of the children improved. Appetite normalized, skin hyperesthesia disappeared. During the period of viral infections, no disturbances in bilirubin metabolism were noted. Over the next few days after starting to take LIV.52K, the pain in the right hypochondrium disappeared. According to ultrasound studies, the phenomenon of sludge in the gallbladder disappeared.
Mandatory studies for hyperbilirubinemia:
- General blood analysis
General urine test (additionally urobilinogen, bile pigments)
Biochemical blood test: total bilirubin with fractions, AST, ALT, ALP, GGTP, LDH;
Markers of viral hepatitis (HbsAg, anti HCV, anti HGV)
Stool test for stercobilin;
Test with fasting and/or
Test with phenobarbital and/or
Sequential application of a fasting test and phenobarbital and/or
Test with nicotinic acid and/or
Test with cordiamine;
Test with bromsulfalein;
Ultrasound of the abdominal organs;
Oral cholecystography or intravenous cholegraphy.
Additional tests for hyperbilirubinemia:
- Blood reticulocytes
Proteinograma;
Coagulogram;
Coombs test;
Fecal urobilinogen;
Test with rose bengal 13IJ;
Endosonographic studies of the hepatopancreatobiliary zone;
CT scan of the hepatopancreatobiliary zone;
Liver puncture biopsy with histological examination of the biopsy;
Molecular diagnostics: DNA analysis of the UDFGT gene (TUGT 1A1). Consultations with specialists for hyperbilirubinemia:
- Hematologist;
Infectious disease specialist;
Surgeon;
Clinical geneticist.
Differential diagnosis of functional hyperbilirubinemia
If hyperbilirubinemia is detected in a serviceman, it is necessary to study the patient’s medical history in detail, clarify the presence of jaundice syndrome in close relatives (burdened heredity), pay attention to the time of the first episode of jaundice, if it occurred earlier (after birth, puberty or previous diseases), determine the severity icteric syndrome and disorders of general health. At the same time, past or existing diseases of the hepatopancreatobiliary zone are specified (acute or chronic hepatitis, acalculous or calculous cholecystitis, cholangitis, pancreatitis), congenital or acquired hemolytic anemia, contact with toxic substances, especially hepatotropic poisons (carbotetrachloride, yellow phosphorus, mitotoxin), and the epidemiological medical history (malaria) and bad habits of the patient (alcohol, drugs).
Unconjugated hyperbilirubinemia may be caused by excess production and delivery of such an amount of bilirubin to the liver that exceeds its ability to accept and conjugate it, for example, with hemolysis, ineffective erythropoiesis, resorption of hematomas, and the presence of artificial heart valves. First of all, functional unconjugated hyperbilirubinemia must be separated from hereditary or acquired hemolytic anemias. The main supporting points of the differential diagnosis are anemia, splenomegaly, reticulocytosis, a decrease in the osmotic and mechanical resistance of erythrocytes, a change in their morphology, an increase in the excretion of urobilinogens in the bodies and a shortening of the lifespan of erythrocytes, determined using a radioactive label, accumulation of hemosiderin in hepatocytes - are not typical for PC. For the diagnosis of autoimmune hemolytic anemia, it is important to identify a positive direct Coombs test. To exclude Zieve syndrome, indications of alcohol abuse and the typical picture of alcoholic liver disease help.
Conjugated hyperbilirubinemia should be separated from chronic intrahepatic (liver cirrhosis, hepatitis, primary biliary cirrhosis, drug-induced hepatitis) and extrahepatic (biliary tract obstruction due to choledocholithiasis, benign strictures, bile duct atresia, neoplasms of the digestive system, sclerosing cholangitis) cholestatic jaundice. It is taken into account that, along with a predominant increase in bound bilirubin in the blood serum, cholestatic diseases are characterized by clinical and laboratory symptoms of cholestasis: skin itching, high activity of alkaline phosphatase, GGTP, bile acids, hypercholesterolemia, hyper-β-lipoproteinemia. Of course, obstructive jaundice caused by choledocholithiasis is excluded, taking into account the presence of pain, cholestatic, dyspeptic syndromes, a significant increase in the level of conjugated bilirubin, the presence of cholelithiasis, detection of violations of the passage of bile through the ductal system in the form of dilation of the common bile duct and / or intrahepatic bile ducts. It is rarely necessary to differentiate conjugated FG from Caroli syndrome (against the background of cystic dilatation of the intrahepatic bile ducts). The differential diagnosis of FH and chronic diffuse liver diseases such as chronic hepatitis and cirrhosis is usually not difficult. This takes into account the presence of cytolytic, autoimmune, cholestatic, hepatodepressive, edematous-ascitic syndromes and/or markers of viral hepatitis B, C, D, G.
In case of isolated hyperbilirubinemia, its nature is clarified: the predominance of the indirect (unconjugated, free) bilirubin fraction may indicate Gilbert, Meulengracht, Calque syndrome. In practice, the need to establish a diagnosis of Crigler-Nayjar syndrome types I and II in a military personnel does not arise, since these diseases debut in newborns. If the direct (conjugated, bound) fraction of bilirubin predominates, the diagnostic search is conducted in the direction of Dubin-Johnson syndrome, Rotor (Table 1.6).
Verification of the diagnosis of Gilbert's syndrome
1. When the level of indirect bilirubin is less than 30 µmol/l, the use of a fasting test with xanthinol nicotinate and nicotinic acid is justified. At the same time, an increase in the bilirubin level by more than 1.5 times, mainly due to the unconjugated fraction, indicates Gilbert's syndrome. Lower increases may also be observed in healthy individuals.
2. Carrying out a test with rose bengal, labeled with 13IJ, there is an extension of the half-life of clearance to an average of 28 minutes by 13 minutes in practically healthy people and the time of maximum absorption is 56 minutes versus 25 minutes normally, as well as a slowdown in dye expression - 4.2 hours versus 1.5 hours, respectively. The bromsulfalein test for FG is not very informative; considered positive when the release of bromsulfalein is reduced by 20%.
3. For hyperbilirubinemia more than 30 µmol/l, the use of tests with phenobarbital and cordiamine is optimal. A significant decrease or normalization of blood bilirubin levels indicates in favor of PC. In this case, a test with phenobarbital helps reduce the level of bilirubin to 23.6 µmol/l. It is advisable to use a test with cordiamine when diagnosing Gilbert's syndrome in military personnel due to the sufficient sensitivity of the test and the presence of cordiamine at the stages of medical support.
4. Recently, when diagnosing FG, incl. Gilbert's syndrome, it is considered advisable to use two tests sequentially, when first a test with a low-calorie diet is carried out, and then a phenobarbital test is prescribed. The test is considered positive when the bilirubin level decreases by more than 3 times from its values determined after a test with a low-calorie diet.
5. In complex differential diagnostic cases, dynamic observation, genetic counseling and liver biopsy are carried out, followed by histological examination of hepatobiopsy specimens. In Gilbert's syndrome, hepatobiopsy specimens are characterized by a normal particle structure, absence of inflammatory changes and necrosis, absence of signs of connective tissue development and fibrotization, accumulation of fine golden and yellow-brown pigment in the liver cells along the bile capillaries, and rarely activation of Kupffer cells.
Verification of the diagnosis of Meulengracht syndrome, Kalka
To verify the disease, a test with phenobarbital or sequential use of two tests is indicated: a test with a low-calorie diet and a phenobarbital test.
Verification of the diagnosis of Dubin-Johnson syndrome
1. Test with bromsulfalein. Late repeated increase in bromsulfalein concentration in the blood 2 hours after the start of observation.
2. Test with rose bengal, labeled with 13IJ. An increase in the half-life of excretion to 7 hours is observed.
3. oral cholecystography or intravenous cholegraphy. Lack of contrast or late and weak filling of the gallbladder and biliary tract.
4. Examination of liver biopsy. Accumulation of pigment in hepatocytes in the form of amorphous granules with a diameter of 0.5 to 4 microns, containing lipofuecin.
Verification of the diagnosis of Rotor syndrome
1. Test with bromsulfalein. Increased retention of dye in the blood 45 minutes after the start of observation.
2. Sample with rose bengal, labeled 131J. There is a moderate decrease in the absorption and release of the drug.
3. oral cholecystography or intravenous cholegraphy. Filling the gallbladder is enough. The biliary tract does not fill after intravenous administration of a contrast agent.
4. Examination of liver biopsy. Lack of accumulation of lipofuscin in hepatocytes.
Noticeable yellowing of the skin, mucous membranes and eye sclera will alert anyone. After all, almost every person knows that such symptoms indicate disturbances in the liver. Such ailments can be caused by many factors, and their treatment is carried out exclusively under the supervision of a doctor. The yellowing of the skin itself occurs when the amount of bilirubin in the blood serum increases; doctors classify this condition as hyperbilirubinemia. Let's talk about what benign hyperbilirubinemia is, the symptoms, its treatment, and the causes in a little more detail.
Bilirubin is essentially a bile pigment that has a yellow-red color. This substance is produced from hemoglobin of erythrocytes, which disintegrate due to involutive changes inside the cells of the spleen, liver, bone marrow, as well as inside the connective tissues of organs.
What is benign hyperbilirubinemia?
This pathological condition is an independent disease, which makes itself felt by constant or periodic jaundice, while the structure and functions of the liver remain normal, and there is no increase in hemolysis and cholestasis.
Why does benign hyperbilirubinemia occur, what are the reasons for its appearance?
As practice shows, benign hyperbilirubinemia in most cases is familial in nature - transmitted by a dominant type.
Posthepatitis hyperbilirubinemia also occurs as an outcome of acute viral hepatitis. The causes of benign hyperbilirubinemia can be attributed to infectious mononucleosis, since sometimes a similar condition is observed after it.
With benign hyperbilirubinemia, the patient experiences disruptions in bilirubin metabolism. Thus, an increase in this substance in the serum may be explained by a violation of the uptake or transfer of free bilirubin from plasma into liver cells.
Also, a similar condition can occur when the processes of binding bilirubin with glucuropic acid are disrupted, which is explained by a temporary or permanent deficiency of the enzyme glucuronyl trapsferase. A similar mechanism of hyperbilirubinemia is characteristic of Crigler-Najjar, Gilbert syndromes, as well as posthepatitis hyperbilirubinemia.
Symptoms of benign hyperbilirubinemia
This condition in most cases is diagnosed in adolescence and can last for many years, including throughout life. Most often, this disease affects men. The classic manifestation of benign hyperbilirubinemia is yellowing of the sclera, and a corresponding coloration of the skin is observed only in isolated cases.
This manifestation of the disease is usually intermittent and only in rare cases is it permanent.
The appearance or intensification of jaundice can be provoked by severe fatigue (nervous or physical), exacerbation of infectious lesions of the biliary tract, and drug intolerance. Yellowing can also be caused by colds, various surgical interventions, alcohol intake, etc.
In parallel with the staining of the sclera (skin) in characteristic yellowish tones, many patients experience a feeling of heaviness in the area of the right hypochondrium. They may also be bothered by a number of dyspeptic symptoms, represented by nausea, vomiting, lack of appetite, stool disturbances and increased gas formation in the intestines.
Hyperbilirubinemia leads to the appearance of some asthenovegetative disorders, namely depression, fatigue and weakness.
During the examination, doctors first of all pay attention to dull yellow skin and pronounced yellowness of the sclera. Sometimes the skin color remains completely normal. The liver may be palpated at the edges of the costal arch or not be felt at all. Sometimes the organ slightly increases in size, while it has a soft consistency, and palpation itself is painless.
The spleen with benign hyperbilirubinemia remains not enlarged. Its size can change only in patients with the posthepatitis form of this disorder.
How is benign hyperbilirubinemia corrected, and what is its effective treatment?
During remission of benign hyperbilirubinemia of the liver, patients are usually prescribed diet No. 15, and during an exacerbation they are recommended to adhere to treatment table No. 5 (diet 5 according to Pevzner).
With such a health problem, patients are not indicated for any special treatment. They do not need special “liver” therapy. Taking multivitamins and choleretic drugs will be beneficial. As for sanatorium-resort treatment, it is not indicated. And carrying out thermal and electrical procedures on the liver area can be harmful.
In the case of a congenital form of the disease, as well as during exacerbations, doctors may prescribe the use of sorbents, for example, Sorbovit-K.
With a benign form of hyperbilirubinemia, the prognosis is completely favorable. With this disorder, patients remain able to work, but they are strongly advised to limit physical and nervous stress.
Folk treatment of benign hyperbilirubinemia with folk remedies
Choleretic compounds can be used as folk remedies for benign hyperbilirubinemia. It would be a good idea to discuss the advisability of their use with your doctor.
So, as a good choleretic agent, you can use such a common herb as knotweed (instructions, the use of the drug before using it should be studied personally from the official annotation included in the package!). You will need the roots of this plant. Clean them, dry them and chop them well. Pour a tablespoon of the resulting raw material into a glass of cool, pre-boiled water. Place the container with this product in a boiling water bath and leave for half an hour. Afterwards, infuse the medicine for fifteen minutes. Take the strained broth one tablespoon three or four times a day.
Corn silk also gives a remarkable effect (the properties they possess are very useful in this case). Brew a tablespoon of crushed raw materials with a glass of boiling water. Infuse the medicine for an hour, then strain and take a tablespoon at an interval of three hours.