The disorder usually presents in the form of unconjugated hyperbilirubinemia. Clinically, apart from jaundice, patients have normal physical examination. In diseased children or adults, the condition usually manifests under stressful conditions like fasting, exposure to cold, dehydration or infections.

Newborns with GS experience more severe and longer lasting form of neonatal jaundice shortly after birth. As the condition is  benign, it usually goes undetected until it is accidentally found in the form of elevated blood levels of bilirubin during a routine check up. In such individuals, bilirubin levels are elevated and fluctuates between 34 and 86 μmol/L (2 and 5 mg/dl). They tend to rise under stressful conditions like fasting. The bilurubin level in diagnosed cases of Gilbert syndrome is defined to be lower than 6 mg/dl, though, most patients have levels lower than 3 mg/dl. Approximately 30% of the patients are asymptomatic. Besides jaundice, they don't show any other symptom. Certain non-specific symptoms like fatigue, malaise and abdominal cramps can occur in these patients. 

In some cases, mild stomach ache and nausea may be present during the episode of hyperbilirubinemia. However, presence of gastrointestinal ailments listed above is not directly related to increased levels of bilirubin in blood. It is often manifested as a psychological side effect in patients following the diagnosis of the disease. The bilirubin levels may show daily and seasonal fluctuations and in nearly one third patients the levels may occassionally be found to be normal.

Gilbert syndrome may become apparent immediately after the birth, however, it may take several years to recognize this condition. Jaundice episodes are more common in males than females. In many individuals, it becomes prominent only under certain triggering conditions such as dehydration, fasting, stress, infection, strain or exposure to cold. Some of the patients complain about stomach cramps, exhaustion and slight depression. However, there is no scientific evidence to connect these ailments. Anesthesia and surgery are the other two stressful events which can possibility bring about a hike in bilirubin levels post operation [11].

• Fatigue

  Chronic Fatigue Syndrome anyone with thyroid issues been diagnosed with Chronic Fatigue Syndrome? My doctor just diagnosed me... [healthunlocked.com]

  In a small study, the most common symptom was chocolate and sweet craving followed by fatigue. [diagnose-me.com]

  We ask about general symptoms (anxious mood, depressed mood, fatigue, pain, and stress) regardless of condition. Last updated: May 13, 2019 [patientslikeme.com]

  GS is regarded as common and harmless, but is associated with numerous unpleasant symptoms, including fatigue, itching, gastrointestinal symptoms, and increased risk for gallstones. [thepaleodiet.com]

  Was diagnosed with chronic fatigue since then and am still now battling with my health (inc. chronic fatigue)... [web.archive.org]

• Pain

  I have just found a FB Gilbert's syndrome site, and a lot of people on there are complaining about joint and muscle pain, eye pain, insomnia, extreme fatigue etc etc the list of symptoms go on and on. They all sound like thyroid problems to me! [healthunlocked.com]

  TENS has also been applied in the postoperative period for pain relief. [apicareonline.com]

  Gilbert's syndrome benign hereditary hyperbilirubinemia of humans marked by mild intermittent jaundice and often by fatigue, weakness and abdominal pain. A comparable disease has been identified in mutant Southdown sheep. [medical-dictionary.thefreedictionary.com]

  The pain may spread to the area around the right shoulder. Nausea, vomiting and sweating often follow. The pain may gradually go away or decrease, becoming a less severe but persistent abdominal pain. [web.archive.org]

• Weakness

  In some cases, jaundice is triggered or made worse by stress, exercise, fasting, dehydration, drinking alcohol, or illness. [1] [2] Some people with Gilbert syndrome have reported other symptoms such as fatigue, weakness, nausea, or diarrhea. [rarediseases.info.nih.gov]

  Gilbert's syndrome benign hereditary hyperbilirubinemia of humans marked by mild intermittent jaundice and often by fatigue, weakness and abdominal pain. A comparable disease has been identified in mutant Southdown sheep. [medical-dictionary.thefreedictionary.com]

  Other symptoms may include lack of concentration, generalized weakness, tea-colored urine, light-colored stools, lack of appetite, loss of weight, stomach pain and itching. [highrisklifeinsuranceagency.com]

• Asymptomatic

  The symptoms, which were extremely vague, included the following: recurrent asymptomatic jaundice in 74%, malaise in 66%, asthenia in 65%, and vague abdominal distension in 52% of patients. Eight per cent of patients were totally asymptomatic. [ncbi.nlm.nih.gov]

  In asymptomatic individuals, UGT1A1 enzyme maintains one third of its activity to detoxify enough uncongugated bilirubin so that no symptoms develop. [symptoma.com]

  […] check your overall health status understand what's happening to your body let The Analyst™ find what's wrong Signs and Symptoms The condition is usually asymptomatic, although some patients do complain about anorexia, malaise, and fatigue. [diagnose-me.com]

  Presentation usually asymptomatic, with mild icterus (jaundice) seen during times of fasting or physiological stress. No treatment is needed since there is no liver injury or progression to end stage liver disease. [bestpractice.bmj.com]

• Pallor

  Examination Pt was conscious, dehydrated, and had icterus without pallor BP - 90/60 mmHg Fetal HR - 148/mt Urine ketone bodies 4+ RBS 54 mg/dL Liver Function test normal with exception of serum bilirubin - 6mg/dL Hepatitis test - negative Liver - normal [physio-pedia.com]

• Abdominal Pain

  Asthenia, fatigue, anxiety, nausea, and abdominal pain occur in most cases. The symptoms may be precipitated by exertion, alcohol, or infection. It is most commonly diagnosed by chance investigation. [web.archive.org]

  Gilbert's syndrome benign hereditary hyperbilirubinemia of humans marked by mild intermittent jaundice and often by fatigue, weakness and abdominal pain. A comparable disease has been identified in mutant Southdown sheep. [medical-dictionary.thefreedictionary.com]

  Many people report diffuse symptoms related to Gilberts Syndrome such as feeling tired, poor concentration, abdominal pain etc., but no clear adverse symptoms related to Gilbert’s Syndrome in adults have been found in scientific studies. [newcastle-hospitals.org.uk]

  Symptoms that have been associated with Gilbert’s include fatigue, weakness, and abdominal pain, but these aren’t common. The bottom line is that Gilbert’s syndrome isn’t dangerous. It won’t harm your liver, make you sick, or shorten your life. [drweil.com]

• Nausea

  Asthenia, fatigue, anxiety, nausea, and abdominal pain occur in most cases. The symptoms may be precipitated by exertion, alcohol, or infection. It is most commonly diagnosed by chance investigation. [web.archive.org]

  In some cases, jaundice is triggered or made worse by stress, exercise, fasting, dehydration, drinking alcohol, or illness. [1] [2] Some people with Gilbert syndrome have reported other symptoms such as fatigue, weakness, nausea, or diarrhea. [rarediseases.info.nih.gov]

• Constipation

  She also exhibited persistent fatigue, constipation, and yellowing of the eyes. In 2010, she began with the Paleo diet, excluding dairy, grains, legumes, refined carbohydrates, and vegetable oils. [thepaleodiet.com]

  […] problems during episodes of jaundice, including: abdominal (tummy) pain feeling very tired ( fatigue ) loss of appetite feeling sick dizziness irritable bowel syndrome (IBS) – a common digestive disorder that causes stomach cramps, bloating, diarrhoea and constipation [nhs.uk]

  Her additional symptoms included fatigue, constipation and unclassified granulomatosus dermatitison both legs. Dermatitis was present for 10 years. No biopsy was taken to specify histology. [pubs.sciepub.com]

  The wide range of digestive symptoms include everything from canker sores to diarrhea to constipation to nausea. [web.archive.org]

• Hypotension

  Preloading was done with Ringer’s lactate solution to avoid any episode of hypotension. TENS was added in the postoperative period to avoid the use of narcotics for adequate pain relief to avoid any kind of stress. [apicareonline.com]

  Symptoms include a sudden increase in heart rate upon standing, often accompanied by hypotension, and associated with dizziness, fatigue, and nausea. About 80 percent of patients diagnosed with POTS are female and of menstruating age. [web.archive.org]

• Jaundice

  Approach to the patient with jaundice or abnormal liver test results. In: Goldman L, Schafer AI, eds. Goldman-Cecil Medicine. 25th ed. Philadelphia, PA: Elsevier Saunders; 2016:chap 147. Lidofsky SD. Jaundice. [nlm.nih.gov]

  Extended periods of fasting induce jaundice due to the presence of fatty acids that hinder the normal bilirubin excretory mechanism. In some cases jaundice is accompanied by mild abdominal pain and fatigue. [symptoma.com]

  When to see your GP See your GP if you experience an episode of jaundice for the first time. The jaundice of Gilbert's syndrome is usually mild, but jaundice can be associated with more serious liver problems, such as cirrhosis or hepatitis C. [nhs.uk]

  The role of GS in neonatal jaundice is unknown. [ncbi.nlm.nih.gov]

• Scleral Icterus

  It is postulated that the defect responsible for the inadequate bilirubin conjugation which is characteristic of Gilbert's Disease may also Keywords Morphine Morphine Sulfate Cephaloridine Scleral Icterus Morphine Glucuronide These keywords were added [link.springer.com]

• Yellow Discoloration of the Skin

  High levels of bilirubin in the blood may produce jaundice (a yellow discoloration of the skin and/or eyes), and in the urine may produce a tea-coloured appearance. Who is at risk? Gilbert’s syndrome is an inherited disorder. [liver.ca]

• Asthenia

  The symptoms, which were extremely vague, included the following: recurrent asymptomatic jaundice in 74%, malaise in 66%, asthenia in 65%, and vague abdominal distension in 52% of patients. Eight per cent of patients were totally asymptomatic. [ncbi.nlm.nih.gov]

  Asthenia, fatigue, anxiety, nausea, and abdominal pain occur in most cases. The symptoms may be precipitated by exertion, alcohol, or infection. It is most commonly diagnosed by chance investigation. [web.archive.org]

• Headache

  I was a professional football player and didn't understand why i was having episodes of sickness and fatigue, headaches, nausea and more. [letsrun.com]

  Studies of people with Gilbert’s syndrome also reveal they are particularly prone to vague symptoms such as extreme tiredness, headaches, dizziness and nausea, stomach and abdominal discomfort. They often experience anxiety symptoms and insomnia. [thelondonclinic.co.uk]

  A Case Report [10] Authors: Mohan M, Sailaja LP, Narasimha PV Journal: Journal of Clinical & Diagnostic Research Date, Volume, Pages: 2014Jun;8(6):1-2 History Patient was a female who presented to the emergency room with severe vomiting, myalgia, headache [physio-pedia.com]

  Jaundice Fatigue Brain fog, poor concentration Nausea Feeling antisocial, anxiety, poor memory, irritability Difficulty digesting fatty foods (but see Remedies below), pale stools that float Loose stools / diarrhoea Symptoms - less frequent Insomnia Headaches [growyouthful.com]

  Any exercise seems to leave me exhausted, I have an almost constant headache, and my yellow eyes hurt a little too... [web.archive.org]

• Insomnia

  I have just found a FB Gilbert's syndrome site, and a lot of people on there are complaining about joint and muscle pain, eye pain, insomnia, extreme fatigue etc etc the list of symptoms go on and on. They all sound like thyroid problems to me! [healthunlocked.com]

  They often experience anxiety symptoms and insomnia. All of these symptoms occur in most people at some time, so it is difficult to know how they are actually related to the syndrome. [thelondonclinic.co.uk]

  common Jaundice Fatigue Brain fog, poor concentration Nausea Feeling antisocial, anxiety, poor memory, irritability Difficulty digesting fatty foods (but see Remedies below), pale stools that float Loose stools / diarrhoea Symptoms - less frequent Insomnia [growyouthful.com]

  […] brain fog, headaches, poor memory, dizziness, depression, irritability, anxiety, nausea, loss of appetite, irritable bowel syndrome (IBS), stomach pain & cramping, liver/gallbladder pain, abdominal pain, tremors, itchiness, jaundice Commonly Reported : insomnia [web.archive.org]

Diagnosis of Gilbert syndrome is made from thorough history and physical examination and is confirmed by specific blood tests. Clinical features, triggering factors and disease duration helps in making the diagnosis clinically. Frequently the diagnosis is made following blood tests during a routine health check up or another medical illness.

Confirmation of hyperbilirubinemia by blood test along with no incidence of hemolysis (pathological destruction of erythrocytes) is suggestive of the condition. Patients have a normal liver function and hyperbilirubinemia is usually mild with a bilirubin level less than 6 mg/dl. Bilirubin level often fluctuates and  as a consequence the bilirubin level may sometimes not reflect the condition. Periodic clinical examinations and surgical procedures are not advised for disease confirmation in clinical practice. One time confirmatory test include

1. The phenobarbital test - which lowers bilurubin levels and 
2. The nicotinic acid test and rifampin test which worsen the condition [12].

These tests are not recommended for diagnosis in the newborn due to high risk of toxicity from the drugs. Developed countries follow certain specific genetic studies through laboratory investigation to confirm diagnosis of disease in suspected cases.

• Bilirubin Increased

  Because males tend to produce higher levels of bilirubin, the disorder is more likely to be detected in men. Similarly, it is rarely diagnosed before puberty because production of bilirubin increases at this point. [nuh.com.sg]

  Taking large doses of vitamin B3 (niacin) can increase bilirubin formation and can lead to a worsening of the condition. Liver disease of any kind benefits from dietary changes. [naturallysavvy.com]

  Specifically, the serum bilirubin is found to be elevated whereas the other liver tests are usually normal. Serum bilirubin may increase with fasting or during another illness such as influenza. [liver.ca]

  The association of an increased bilirubin load from chronic hemolysis and the diminished hepatic conjugation of bilirubin, increases the risk of gallstones. [bloodjournal.hematologylibrary.org]

  Beta-glucuronidase deconjugates intestinal bilirubin, increasing its ability to be absorbed (ie, increasing the enterohepatic circulation). [emedicine.com]

No medical intervention is required in the management of Gilbert syndrome. The most important part in the disease management is assuring patients regarding the benign condition of the disease and the association of normal life expectancy. Clear instructions should be given to them regarding the conditions that can trigger the symptoms i.e. jaundice such as stress, dehydration, fasting, exposure to cold, etc. Owning to benign and harmless nature of GS associated mild jaundice, the condition resolves spontaneously without any medical therapy.

GS is a commonly occurring benign condition which has an excellent prognosis. In most of the cases, the concentration of unconjugated bilirubin is found to be under normal range. Approximately one third of the normal UGT1A1 activity is retained in the patients that cause enough conjugation of bilirubin to produce any symptoms. The condition doesn't have any detrimental effect on the diseased individuals who generally lead a healthy normal life style. The benign nature of the disorder is further proved by studies on patients who underwent liver transplantation from live donors diagnosed to have Gilbert syndrome [9] [10].

GS is caused by the deficiency of the enzyme, bilirubin-UGT which is primarily present in the hepatocytes leading to improper uptake of bilirubin by liver cells [1]. 

Genetically, it develops as a result of mutations in the UGT1A1 gene in the long arm (q) of chromosome 2 (2q37) which codes for bilirubin-UGT. Gilbert syndrome is a form of non-hemolytic jaundice, which is inherited in an autosomal recessive fashion. Being recessive, it occurs when an individual acquires the mutated gene from both the parents. An individual is considered as "carrier" when he/she receive the defective gene from one parent and a normal gene from other parent. In a carrier, the disorder is not expressed and the person remains normal with full functionality of bilirubin-UGT and bilirubin metabolism. However the carrier person is capable of passing on the defective gene to his/her offspring. The probability of an offspring to inherit the defective gene from two carrier parents is about 25% and in about 50% of the cases the child ends up being a carrier like his/her parents. The risk of acquiring the disease is equal for both male and female.

GS is not an uncommon disorder that affects around 2 to 13 % of the general population [2] [3]. The disease is the mildest form of inherited nonhemolytic unconjugated hyperbilirubinemia [4]. Though the risk is the same for both sexes, it is found more commonly in males. There is no racial preponderance in GS. It is a genetic, congenital disorder which mostly remains undetected until early adulthood. Though family members may be affected, it is difficult to get a clear pattern of genetic inheritance. The condition is usually diagnosed and become evident with detection of elevated levels of unconjugated bilirubin in blood without any apparent reason. 

Bilurubin is an end product of human red blood cell breakdown. It has an orange-yellow color and is removed from the body only in the conjugated form. In the liver, toxic unconjugated bilirubin is changed into non-toxic conjugated form. In patients with Gilbert syndrome, there occurs an increased level of unconjugated bilirubin in the blood. Though, these levels fluctuate and rarely reach enough to produce the symptoms such as yellowing of the skin and eyes.

Pathogenesis of GS involves defects in the uptake of bilirubin by the liver which occurs due to low Glucuronyl transferase activity. In some patient's destruction of RBC's is also accelerated, though, it doesn't explain the hyperbilirubinemia. There is around 30% decrease in the activity of hepatic bilirubin UGT in patients with GS. However, it should be noted that the enzyme activity is not as low as that observed in cases of type 2 Crigler-Najjar syndrome. A drop is indicated by the presence of relatively increased concentration of monoconjugates of bilirubin in the bile.  The Liver, however, shows histology.

In the promoter region of the UGT-1TA gene, expansion of thymine-adenine (TA) repeat units occur. This gene provides the instruction for coding of uridine disphosphate-glucronosyltransferase-1A1 enzyme which is involved in the conversion of unconjugated bilirubin to conjugated form. The difference in the total number of TA repeats in the gene is found to be related to the activity of UGT1A1 enzyme.

In affected patients, hepatocytes fail to take up the unprocessed bilirubin leading to its accumulation in the blood plasma as unconjugated bilirubin (bound to albumin). The bilirubin-albumin product is insoluble in water. In normal individuals, unconjugated bilirubin is converted to conjugated form which is water soluble and is excreted into the bile in the liver. The bile produced is temporarily retained in the gall bladder and is then transferred to the duodenum (the upper part of the small intestine) via the common bile duct. Most of the bilirubin is excreted from the body through the feces. In asymptomatic individuals, UGT1A1 enzyme maintains one third of its activity to detoxify enough uncongugated bilirubin so that no symptoms develop. However under stressful conditions like fasting and dehydration patients may develop mild form of jaundice. Presence of bilirubin monoconjugates in high levels in the bile indicates reduced activity of transferase enzyme [5] [6] [7] [8].

Most patients of Gilbert syndrome are asymptomatic. However, certain conditions can lead to aggravation of the clinical jaundice and hence need to be avoided. These conditions are stress, dehydration, fasting [13], infection, extreme weather conditions, fatigue, menstruation [14], alcohol, etc. Unavoidable stressful events like surgical procedures and anesthesia [11] may sometimes lead to an episode of jaundice during or after operation and therefore adequate measures.

Gilbert`s syndrome (GS) is an inherited life long disease affecting the liver with mild or no symptoms. The affected individuals lack the liver enzyme, bilirubin uridine diphosphate glucuronosyltransferase (bilirubin-UGT) which is responsible for proper disposal of bilirubin. The only characteristic finding is unconjugated hyperbilirubinemia leading to jaundice, which presents as a yellowish discolouration of skin and eyes sclera. Jaundice may sometimes mistaken for other liver disorders or chronic hepatitis leading to incorrect diagnosis. The condition may go undetected until early adulthood and noticed accidentally during routine blood check up. The affected individuals often have high levels of bilirubin in the blood with no apparent symptoms. The condition generally does not require any medical interventions and the patient should be advised to avoid situations that trigger an episode of jaundice. The major physiological triggers to avoid include stress,dehydration, infections, excessive physical exertion and fasting. 

Gilbert syndrome (GS) is a condition characterized by increased bilirubin concentration in the blood. The toxic form of bilirubin called as unconjugated bilirubin is converted to non toxic conjugated bilirubin in the liver and is subsequently eliminated from the body via the gastrointestinal tract under normal conditions. In case of affected individuals, this does not happen as efficiently as in normal individuals. However, it should be noted that it is not a liver disorder and is therefore a harmless condition requiring no medical therapy in a majority of the cases. The condition has a very good prognosis. The life expectancy is normal and is not associated with any increased mortality. However, care should be taken while taking certain drugs such as irinotecan, an antitumor agent which are associated with an increased morbidity due to increased side effects in patients with Gilbert syndrome.

The bilirubin level keeps fluctuating and when rises beyond a particular level manifest in the form of jaundice. Yellowing of skin and eyes are the major symptoms. The condition usually goes unnoticed during childhood and is accidentally diagnosed later in adolescence. The condition is usually aggravated during stressful periods of life like illness, during menstrual cycle, fasting, dehydration, fever, surgeries involving anesthesia and fasting, repeated illness or vigorous exercise [15]. Extended periods of fasting induce jaundice due to the presence of fatty acids that hinder the normal bilirubin excretory mechanism. In some cases jaundice is accompanied by mild abdominal pain and fatigue. These discomforts along with jaundice usually disappear spontaneously without any medical intervention. 

1. Strassburg CP. Hyperbilirubinemia syndromes (Gilbert-Meulengracht, Crigler-Najjar, Dubin-Johnson, and Rotor syndrome). Best Pract Res Clin Gastroenterol. 2010;24(5):555-571.
2. Chapman RW, Collier JD, Hayes PC. Liver and biliary tract disease. In: Boon NA, Colledge NR, Walker BR, editors. Davidson's Principles and Practice of Medicine. 20th ed. Philadelphia, USA: Churchill Livingstone Elsevier. 2008; 925–926.
3. Bosma PJ, Chowdhury JR, Bakker C, Gantla S, de Boer A, Oostra BA, Lindhout D,  Tytgat GN, Jansen PL, Oude Elferink RP, Chowdhury NR. The genetic basis of the reduced expression of bilirubin UDP-glucuronosyltransferase 1 in Gilbert's syndrome. N Engl J Med. 1995;333(18):1171-1175.
4. Fretzayas A, Moustaki M, Liapi O, Karpathios T. Gilbert syndrome. Eur J Pediatr. 2012.171(1):11- 15.
5. MacDonald MG, Mullett MD, Seshia MK. 6th ed. Avery's Neonataology: pathophysiology and management of the newborn. Lippincott, Williams and Wilkins;Philadelphia: 2005. 
6. Ostanek B, Furlan D, Mavec T, Lukac-Bajalo J. UGT1A1(TA)n promoter polymorphism--a new case of a (TA)8 allele in Caucasians. Blood Cells Mol Dis. 2007;38(2):78-82.
7. Papez MJ, Civalier CJ, Thorne LB, Gulley ML. UGT1A1 promoter genotype is not strongly associated with severity of coronary artery disease. Diagn Mol Pathol. 2009;18(4):226-31.
8. Tapan S, Dogru T, Tasci I, Ercin CN, Ozgurtas T, Erbil MK. Soluble CD40 ligand and soluble P-selectin levels in Gilbert's syndrome: a link to protection against atherosclerosis?. Clin Biochem. 2009;42(9):791-795.
9. Kaneko J, Sugawara Y, Maruo Y, Sato H, Tamura S, Imamura H, Kokudo N, Makuuchi M. Liver transplantation using donors with Gilbert syndrome. Transplantation. 2006; 82(2):282-285.
10. Yilmaz M, Unal B, Isik B, Ozgor D, Piskin T, Ersan V, Gonultas F Yilmaz S. Can an extended right lobe be harvested from a donor with Gilbert's syndrome for living-donor liver transplantation? Case report. Transplant Proc. 2012; 44(6):1640-1643.
11. Taylor S. Gilbert's syndrome as a cause of postoperative jaundice.
    Anaesthesia. 1984 Dec;39(12):1222-4.
12. Bakhotmah MA, Gasem AA, Bairotee B. Asymptomatic unconjugated hyperbilirubinemia (Gilbert syndrome) among Saudis in Jeddah. Ann Saudi Med. 1995; 15(4):422-423.
13. Thomsen HF, Hardt F, Juhl E. Diagnosis of Gilbert's syndrome. Reliability of the caloric restriction and phenobarbital stimulation tests. Scand J Gastroenterol. 1981;16(5):699-703.
14. Radu P, Atsmon J. Gilbert's syndrome--clinical and pharmacological implications. Isr Med Assoc J. 2001;3(8):593-598.
15. Lopardo G, Bissio E, Espinola L, Gallego P, Stambullian M, Gadano A. Short communication: fasting increases serum concentrations of bilirubin in patients receiving atazanavir: results from a pilot study. AIDS Res Hum Retroviruses. 2013;29(3):456-460.