Gilbert's syndrome

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Gilbert's syndrome
Other namesGilbert syndrome, Meulengracht syndrome, Gilbert-Lereboullet syndrome, hyperbilirubinemia Arias type, hyperbilirubinemia type 1, familial cholemia, familial nonhemolytic jaundice [1] [2]
Bilirubin.svg
Bilirubin
Pronunciation
Specialty Gastroenterology
Symptoms Usually none, still, abdominal pain, nausea, tired and weak feeling, slight jaundice may present [1]
Complications Usually none [1]
Causes Genetic [1]
Differential diagnosis Crigler–Najjar syndrome, Rotor syndrome, Dubin–Johnson syndrome [2]
TreatmentNone typically needed [1]
Frequency~5% [3]

Gilbert syndrome (GS) is a syndrome in which the liver of affected individuals processes bilirubin more slowly than the majority. [1] Many people never have symptoms. [1] Occasionally jaundice (a slight yellowish color of the skin or whites of the eyes) may occur. [1]

Contents

Gilbert syndrome is due to a genetic variant in the UGT1A1 gene which results in decreased activity of the bilirubin uridine diphosphate glucuronosyltransferase enzyme. [1] [3] It is typically inherited in an autosomal recessive pattern and occasionally in an autosomal dominant pattern depending on the type of variant. [3] Episodes of jaundice may be triggered by stress such as exercise, menstruation, or not eating. [3] Diagnosis is based on higher levels of unconjugated bilirubin in the blood without either signs of other liver problems or red blood cell breakdown. [2] [3]

Typically no treatment is needed. [1] Gilbert syndrome is associated with decreased cardiovascular health risks. [4] If jaundice is significant phenobarbital may be used, which aids in the conjugation of bilirubin. [1] Gilbert syndrome affects about 5% of people in the United States. [3] Males are more often diagnosed than females. [1] It is often not noticed until late childhood to early adulthood. [2] The condition was first described in 1901 by Augustin Nicolas Gilbert. [5] [2] [6]

Signs and symptoms

Jaundice

Gilbert syndrome produces an elevated level of unconjugated bilirubin in the bloodstream, but normally has no consequences. Mild jaundice may appear under conditions of exertion, stress, fasting, and infections, but the condition is otherwise usually asymptomatic. [7] [8] Severe cases are seen by yellowing of the skin tone and yellowing of the conjunctiva in the eye. [9]

Gilbert syndrome has been reported to contribute to an accelerated onset of neonatal jaundice. The syndrome cannot cause severe indirect hyperbilirubinemia in neonates by itself, but it may have a summative effect on rising bilirubin when combined with other factors, [10] for example in the presence of increased red blood cell destruction due to diseases such as G6PD deficiency. [11] [12] This situation can be especially dangerous if not quickly treated, as the high serum bilirubin can cause irreversible neurological disability in the form of kernicterus. [13] [14] [15]

Detoxification of certain drugs

The enzymes that are defective in GS – UDP glucuronosyltransferase 1 family, polypeptide A1 (UGT1A1) – are also responsible for some of the liver's ability to detoxify certain drugs. For example, Gilbert syndrome is associated with severe diarrhea and neutropenia in patients who are treated with irinotecan, which is metabolized by UGT1A1. [16]

While paracetamol (acetaminophen) is not metabolized by UGT1A1, [17] it is metabolized by one of the other enzymes also deficient in some people with GS. [18] [19] A subset of people with GS may have an increased risk of paracetamol toxicity. [19] [20]

Cardiovascular effects

The mild increase in unconjugated bilirubin due to Gilbert syndrome is closely related to the reduction in the prevalence of chronic diseases, especially cardiovascular disease and type 2 diabetes, related risk factors, and all-cause mortality. [21] Observational studies emphasize that the antioxidant effects of unconjugated bilirubin may bring survival benefits to patients. [22]

Several analyses have found a significantly decreased risk of coronary artery disease (CAD) in individuals with GS. [23] [24]

Specifically, people with mildly elevated levels of bilirubin (1.1 mg/dl to 2.7 mg/dl) were at lower risk for CAD and at lower risk for future heart disease. [25] These researchers went on to perform a meta-analysis of data available up to 2002, and confirmed the incidence of atherosclerotic disease (hardening of the arteries) in subjects with GS had a close and inverse relationship to the serum bilirubin. [23] This beneficial effect was attributed to bilirubin IXα which is recognized as a potent antioxidant, rather than confounding factors such as high-density lipoprotein levels. [25]

This association was also seen in long-term data from the Framingham Heart Study. [26] [4] [ non-primary source needed ] Moderately elevated levels of bilirubin in people with GS and the (TA)7/(TA)7 genotype were associated with one-third the risk for both coronary heart disease and cardiovascular disease as compared to those with the (TA)6/(TA)6 genotype (i.e. a normal, nonmutated gene locus).[ citation needed ]

Platelet counts and MPV (mean platelet volume) are decreased in patients with Gilbert's syndrome. The elevated levels of bilirubin and decreasing levels of MPV and CRP in Gilbert's syndrome patients may have an effect on the slowing down of the atherosclerotic process. [27]

Other

Symptoms, whether connected or not to GS, have been reported in a subset of those affected: fatigue (feeling tired all the time), difficulty maintaining concentration, unusual patterns of anxiety, loss of appetite, nausea, abdominal pain, loss of weight, itching (with no rash), and others, [28] such as humor change or depression. But scientific studies found no clear pattern of adverse symptoms related to the elevated levels of unconjugated bilirubin in adults. However, other substances glucuronidized by the affected enzymes in those with Gilbert's syndrome could theoretically, at their toxic levels, cause these symptoms. [29] [30] Consequently, debate exists about whether GS should be classified as a disease. [29] [31] However, Gilbert syndrome has been linked to an increased risk of gallstones. [28] [32]

Cause

Mutations in the UGT1A1 gene lead to Gilbert Syndrome. [33] The gene provides instructions for making the bilirubin uridine diphosphate glucuronosyltransferase (bilirubin-UGT) enzyme, which can be found in the liver cells and is responsible for preparing bilirubin for removal from the body. [34]

The bilirubin-UGT enzyme performs a chemical reaction called glucuronidation. Glucuronic acid is transferred to unconjugated bilirubin, which is a yellowish pigment made when your body breaks down old red blood cells, [35] and then being converted to conjugated bilirubin during the reaction. Conjugated bilirubin passes from the liver into the intestines with bile. It's then excreted in stool.[ citation needed ]

People with Gilbert syndrome have approximately 30 percent of normal bilirubin-UGT enzyme function, which contributes to a lower rate of glucuronidation of unconjugated bilirubin. This substance then accumulates in the body, causing mild hyperbilirubinemia. [34]

Genetics

Gilbert syndrome is a phenotypic effect, mostly associated with increased blood bilirubin levels, but also sometimes characterized by mild jaundice due to increased unconjugated bilirubin, that arises from several different genotypic variants of the gene for the enzyme responsible for changing bilirubin to the conjugated form.[ citation needed ]

Gilbert's syndrome is characterized by a 70–80% reduction in the glucuronidation activity of the enzyme (UGT1A1). The UGT1A1 gene is located on human chromosome 2. [36]

More than 100 polymorphisms of the UGT1A1 gene are known, designated as UGT1A1*n (where n is the general chronological order of discovery), either of the gene itself or of its promoter region. UGT1A1 is associated with a TATA box promoter region; this region most commonly contains the genetic sequence A(TA)6TAA; this variant accounts for about 50% of alleles in many populations. However, several allelic polymorphic variants of this region occur, the most common of which results from adding another dinucleotide repeat TA to the promoter region, resulting in A(TA)7TAA, which is called UGT1A1*28; this common variant accounts for about 40% of alleles in some populations, but is seen less often, around 3% of alleles, in Southeast and East Asian people and Pacific Islanders.[ citation needed ]

In most populations, Gilbert syndrome is most commonly associated with homozygous A(TA)7TAA alleles. [37] [38] [39] In 94% of GS cases, two other glucuronosyltransferase enzymes, UGT1A6 (rendered 50% inactive) and UGT1A7 (rendered 83% ineffective), are also affected.[ citation needed ]

However, Gilbert syndrome can arise without TATA box promoter polymorphic variants; in some populations, particularly healthy Southeast and East Asians, Gilbert's syndrome is more often a consequence of heterozygote missense mutations (such as Gly71Arg also known as UGT1A1*6, Tyr486Asp also known as UGT1A1*7, Pro364Leu also known as UGT1A1*73) in the actual gene coding region, [20] which may be associated with significantly higher bilirubin levels. [20]

Because of its effects on drug and bilirubin breakdown and because of its genetic inheritance, Gilbert's syndrome can be classed as a minor inborn error of metabolism.[ citation needed ]

Diagnosis

People with GS predominantly have elevated unconjugated bilirubin, while conjugated bilirubin is usually within the normal range or is less than 20% of the total. Levels of bilirubin in GS patients are reported to be from 20 μM to 90 μM (1.2 to 5.3 mg/dl) [38] compared to the normal amount of < 20 μM. GS patients have a ratio of unconjugated/conjugated (indirect/direct) bilirubin commensurately higher than those without GS.[ citation needed ]

The level of total bilirubin is often further increased if the blood sample is taken after fasting for two days, [40] and a fast can, therefore, be useful diagnostically. A further conceptual step that is rarely necessary or appropriate is to give a low dose of phenobarbital: [41] the bilirubin will decrease substantially.

Tests can also detect DNA variants of UGT1A1 by polymerase chain reaction or DNA fragment sequencing.[ citation needed ]

Differential diagnosis

While Gilbert syndrome is considered harmless, it is clinically important because it may give rise to a concern about a blood or liver condition, which could be more dangerous. However, these conditions have additional indicators:[ citation needed ]

Treatment

Typically no treatment is needed. [1] If jaundice is significant phenobarbital may be used. [1]

Research directions

Vitamin levels

Studies conducted so far suggest that subjects with GS may have lower levels of vitamin D and folic acid than control subjects, having these levels inversely correlated with bilirubin levels. It may be that GS may impair the metabolism or absorption of these vitamins, or that these vitamins may affect the expression or activity of the UGT1A1 enzyme that is responsible for bilirubin conjugation. However, these studies had limitations, such as the small sample size, the lack of a standardized definition of GS, the possible confounding factors of diet, lifestyle, and medication use, and the cross-sectional and observational design that does not allow for causal inference. [43]

The role of bilirubin in health and disease

Ongoing studies suggest that mild hyperbilirubinaemia in GS may have beneficial effects, probably due to the antioxidant and anti-inflammatory properties of bilirubin. Hyperbilirubinaemia in GS may protect against oxidative stress and inflammation-related diseases, such as cardiovascular diseases, cancers, diabetes, and neurodegenerative disorders. However, the mechanisms and pathways of bilirubin protection are not fully elucidated, and the optimal level and range of bilirubin are unknown. The genetic and environmental factors that influence UGT1A1 expression and activity are also poorly characterized and may affect the variability and penetrance of GS. [44] Despite the fact that hyperbilirubinemia in GS is associated with reduced incidence of cardiovascular diseases, [45] diabetes, and metabolic syndrome, [46] the clinical significance and implications of these GS research findings are unclear, and can not yet be translated into preventive or therapeutic strategies. [44]

History

Gilbert syndrome was first described by French gastroenterologist Augustin Nicolas Gilbert and co-workers in 1901. [6] [5] In German literature, it is commonly associated with Jens Einar Meulengracht. [47]

Alternative, less common names for this disorder include:[ citation needed ]

Society and culture

Notable cases

Related Research Articles

<span class="mw-page-title-main">Jaundice</span> Abnormal pigmentation symptom for disease of the liver

Jaundice, also known as icterus, is a yellowish or greenish pigmentation of the skin and sclera due to high bilirubin levels. Jaundice in adults is typically a sign indicating the presence of underlying diseases involving abnormal heme metabolism, liver dysfunction, or biliary-tract obstruction. The prevalence of jaundice in adults is rare, while jaundice in babies is common, with an estimated 80% affected during their first week of life. The most commonly associated symptoms of jaundice are itchiness, pale feces, and dark urine.

<span class="mw-page-title-main">Bilirubin</span> Red pigment of the bile

Bilirubin (BR) is a red-orange compound that occurs in the normal catabolic pathway that breaks down heme in vertebrates. This catabolism is a necessary process in the body's clearance of waste products that arise from the destruction of aged or abnormal red blood cells. In the first step of bilirubin synthesis, the heme molecule is stripped from the hemoglobin molecule. Heme then passes through various processes of porphyrin catabolism, which varies according to the region of the body in which the breakdown occurs. For example, the molecules excreted in the urine differ from those in the feces. The production of biliverdin from heme is the first major step in the catabolic pathway, after which the enzyme biliverdin reductase performs the second step, producing bilirubin from biliverdin.

Liver function tests, also referred to as a hepatic panel, are groups of blood tests that provide information about the state of a patient's liver. These tests include prothrombin time (PT/INR), activated partial thromboplastin time (aPTT), albumin, bilirubin, and others. The liver transaminases aspartate transaminase and alanine transaminase are useful biomarkers of liver injury in a patient with some degree of intact liver function.

<span class="mw-page-title-main">Kernicterus</span> Medical condition

Kernicterus is a bilirubin-induced brain dysfunction. The term was coined in 1904 by Christian Georg Schmorl. Bilirubin is a naturally occurring substance in the body of humans and many other animals, but it is neurotoxic when its concentration in the blood is too high, a condition known as hyperbilirubinemia. Hyperbilirubinemia may cause bilirubin to accumulate in the grey matter of the central nervous system, potentially causing irreversible neurological damage. Depending on the level of exposure, the effects range from clinically unnoticeable to severe brain damage and even death.

<span class="mw-page-title-main">Neonatal jaundice</span> Medical condition

Neonatal jaundice is a yellowish discoloration of the white part of the eyes and skin in a newborn baby due to high bilirubin levels. Other symptoms may include excess sleepiness or poor feeding. Complications may include seizures, cerebral palsy, or kernicterus.

<span class="mw-page-title-main">Dubin–Johnson syndrome</span> Genetic liver disease

Dubin–Johnson syndrome is a rare, autosomal recessive, benign disorder that causes an isolated increase of conjugated bilirubin in the serum. Classically, the condition causes a black liver due to the deposition of a pigment similar to melanin. This condition is associated with a defect in the ability of hepatocytes to secrete conjugated bilirubin into the bile, and is similar to Rotor syndrome. It is usually asymptomatic, but may be diagnosed in early infancy based on laboratory tests. No treatment is usually needed.

<span class="mw-page-title-main">Crigler–Najjar syndrome</span> Rare inherited disorder affecting the metabolism of bilirubin

Crigler–Najjar syndrome is a rare inherited disorder affecting the metabolism of bilirubin, a chemical formed from the breakdown of the heme in red blood cells. The disorder results in a form of nonhemolytic jaundice, which results in high levels of unconjugated bilirubin and often leads to brain damage in infants. The disorder is inherited in an autosomal recessive manner. The annual incidence is estimated at 1 in 1,000,000.

<span class="mw-page-title-main">Glucuronosyltransferase</span> Class of enzymes

Uridine 5'-diphospho-glucuronosyltransferase is a microsomal glycosyltransferase that catalyzes the transfer of the glucuronic acid component of UDP-glucuronic acid to a small hydrophobic molecule. This is a glucuronidation reaction.

<span class="mw-page-title-main">Rotor syndrome</span> Medical condition

Rotor syndrome is a rare cause of mixed direct (conjugated) and indirect (unconjugated) hyperbilirubinemia, relatively benign, autosomal recessive bilirubin disorder characterized by non-hemolytic jaundice due to the chronic elevation of predominantly conjugated bilirubin.

<span class="mw-page-title-main">Lucey–Driscoll syndrome</span> Medical condition

Lucey–Driscoll syndrome is an autosomal recessive metabolic disorder affecting enzymes involved in bilirubin metabolism. It is one of several disorders classified as a transient familial neonatal unconjugated hyperbilirubinemia.

<span class="mw-page-title-main">UDP glucuronosyltransferase 1 family, polypeptide A1</span> Enzyme found in humans

UDP-glucuronosyltransferase 1-1 also known as UGT-1A is an enzyme that in humans is encoded by the UGT1A1 gene.

Neonatal cholestasis refers to elevated levels of conjugated bilirubin identified in newborn infants within the first few months of life. Conjugated hyperbilirubinemia is clinically defined as >20% of total serum bilirubin or conjugated bilirubin concentration greater than 1.0 mg/dL regardless of total serum bilirubin concentration. The differential diagnosis for neonatal cholestasis can vary extensively. However, the underlying disease pathology is caused by improper transport and/or defects in excretion of bile from hepatocytes leading to an accumulation of conjugated bilirubin in the body. Generally, symptoms associated with neonatal cholestasis can vary based on the underlying cause of the disease. However, most infants affected will present with jaundice, scleral icterus, failure to thrive, acholic or pale stools, and dark urine.

<span class="mw-page-title-main">Choluria</span> Medical condition

Choluria is a symptom defining an abnormal darkness of the urine, mainly due to a high level of conjugated bilirubin. Choluria is a common symptom of liver diseases, such as hepatitis and cirrhosis. It can be described as dark or brown urine, often referred to as the color of Coca-Cola. The presence of choluria is a useful symptom to distinguish if somebody presenting with jaundice has liver disease or haemolysis. In the first case, patients have choluria due to excess conjugated ("direct") bilirubin in blood, which is eliminated by the kidneys. Haemolysis, on the other hand, is characterized by unconjugated ("indirect") bilirubin, which is not water-soluble and is bound to albumin, and thus not eliminated in urine.

<span class="mw-page-title-main">Hereditary hyperbilirubinemia</span> Medical condition

Hereditary hyperbilirubinemia refers to the condition where levels of bilirubin are elevated, for reasons that can be attributed to a metabolic disorder.

Cholestatic pruritus is the sensation of itch due to nearly any liver disease, but the most commonly associated entities are primary biliary cholangitis, primary sclerosing cholangitis, obstructive choledocholithiasis, carcinoma of the bile duct, cholestasis, and chronic hepatitis C viral infection and other forms of viral hepatitis.

<span class="mw-page-title-main">UGT1A5</span> Protein-coding gene in the species Homo sapiens

UDP-glucuronosyltransferase 1-5 is an enzyme that in humans is encoded by the UGT1A5 gene.

<span class="mw-page-title-main">UGT1A9</span> Protein-coding gene in the species Homo sapiens

UDP-glucuronosyltransferase 1-9 is an enzyme that in humans is encoded by the UGT1A9 gene.

<span class="mw-page-title-main">Bilirubin glucuronide</span> Chemical compound

Bilirubin glucuronide is a water-soluble reaction intermediate over the process of conjugation of indirect bilirubin. Bilirubin glucuronide itself belongs to the category of conjugated bilirubin along with bilirubin di-glucuronide. However, only the latter one is primarily excreted into the bile in the normal setting.

Hemolytic jaundice, also known as prehepatic jaundice, is a type of jaundice arising from hemolysis or excessive destruction of red blood cells, when the byproduct bilirubin is not excreted by the hepatic cells quickly enough. Unless the patient is concurrently affected by hepatic dysfunctions or is experiencing hepatocellular damage, the liver does not contribute to this type of jaundice.

Hyperbilirubinemia is a clinical condition describing an elevation of blood bilirubin level due to the inability to properly metabolise or excrete bilirubin, a product of erythrocytes breakdown. In severe cases, it is manifested as jaundice, the yellowing of tissues like skin and the sclera when excess bilirubin deposits in them. The US records 52,500 jaundice patients annually. By definition, bilirubin concentration of greater than 3 mg/ml is considered hyperbilirubinemia, following which jaundice progressively develops and becomes apparent when plasma levels reach 20 mg/ml. Rather than a disease itself, hyperbilirubinemia is indicative of multifactorial underlying disorders that trace back to deviations from regular bilirubin metabolism. Diagnosis of hyperbilirubinemia depends on physical examination, urinalysis, serum tests, medical history and imaging to identify the cause. Genetic diseases, alcohol, pregnancy and hepatitis viruses affect the likelihood of hyperbilirubinemia. Causes of hyperbilirubinemia mainly arise from the liver. These include haemolytic anaemias, enzymatic disorders, liver damage and gallstones. Hyperbilirubinemia itself is often benign. Only in extreme cases does kernicterus, a type of brain injury, occur. Therapy for adult hyperbilirubinemia targets the underlying diseases but patients with jaundice often have poor outcomes.

References

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  50. ↑ "Wire preaches delights of three cliffs". South Wales Evening Post . 2007-04-27. p. 3.
  51. ↑ David Cox. (19 April 2014). "A Tennis Player Learns to Be Aggressive for Health's Sake". New York Times. Monte Carlo. Archived from the original on 14 October 2016.
  52. ↑ Khorounzhiy, Valentin (2017-11-09). "Illness that 'shut down' Tech3 MotoGP rookie Jonas Folger diagnosed". Autosport.com. Motorsport Network. Archived from the original on 2017-11-10. Retrieved 2017-11-09. After visiting specialists in his native Germany, Folger has been diagnosed with Gilbert's syndrome – a genetic ailment that precludes the liver from correctly processing bilirubin.
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