Gilbert's syndrome

From Wikipedia, the free encyclopedia

Gilbert's syndrome
Classification and external resources

Bilirubin

ICD-10

E80.4

ICD-9

277.4

OMIM

143500

DiseasesDB

5218

eMedicine

med/870

MeSH

D005878

Gilbert's syndrome (English pronunciation: /ilbr/ zheel-BAIR), often shortened to GS, also called GilbertMeulengracht syndrome, is the most commonhereditary cause of increased bilirubin and is found in up to 5% of the population (though some gastroenterologists maintain that it is closer to 10%). A major characteristic is jaundice, caused by elevated levels of unconjugated bilirubin in the bloodstream (hyperbilirubinemia). The cause of this hyperbilirubinemia is the reduced activity of the enzyme glucuronyltransferase, which conjugates bilirubin and some other lipophilic molecules. Conjugation renders the bilirubin water-soluble, after which it is excreted in bile into the duodenum.

Signs and symptoms

[edit]Jaundice Gilbert's syndrome produces an elevated level of unconjugated bilirubin in the bloodstream but normally has no serious consequences. Mild jaundice may appear under conditions of exertion, stress, fasting, and infections, but the condition is otherwise usually asymptomatic.[1][2] It has been reported that GS may contribute to an accelerated onset of neonatal jaundice, especially in the presence of increased hemolysis due to diseases like G6PD deficiency.[3][4] This situation can be especially dangerous if not quickly treated as the high bilirubin irreversible neurological disability in the form of kernicterus. [edit]Detoxification

of certain drugs

The enzymes that are defective in GS (UGT1A1) are also responsible for some of the liver's ability to detoxify certain drugs. For example, Gilbert's syndrome is associated with severe diarrhea andneutropenia in patients who are treated with irinotecan, which is metabolized by UGT1A1.[5] While paracetamol (acetaminophen or brand names Panadol, Tylenol) is not metabolized by UGT1A1,[6] it is metabolized by one of the other enzymes also deficient in some people with GS.[7][8] A subset of people with GS may have an increased risk of paracetamol toxicity.[8][9] [edit]Cardiovascular

effects

Several analyses have found a significantly decreased risk of coronary artery disease (CAD) in individuals with GS.[10][11] 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.[12] These researchers went on to perform a meta-analysis of data available up to 2002, and confirmed that the incidence of atherosclerotic disease (hardening of the arteries) in subjects with GS had a close and inverse relationship to the serum bilirubin.[10] This beneficial effect was attributed to bilirubin IX which is recognised as a potent antioxidant, rather than confounding factors such as high-density lipoprotein (HDL) levels.[12] This association was also seen in long-term data from the Framingham Heart Study.[13] Moderately elevated levels of bilirubin in people with GS and the (TA)7/(TA)7 genotype was associated with 1/3 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, non-mutated gene locus). A detailed summary of pre-2008 findings between cardiovascular disease and elevated serum bilirubin concentrations[11] also discussed the concept of intentional, artificial raising of bilirubin levels as a means of prevention of cardiovascular disease and other oxidative and inflammatory diseases.

[edit]Debated

signs and diffuse symptoms

Diffuse symptoms, whether connected or not to GS, have been reported in a subset of those affected: feeling tired all the time (fatigue), difficulty maintaining concentration, loss of appetite, abdominal pain, loss of weight and others,[14] but scientific studies found no clear pattern of adverse symptoms related to the elevated levels of unconjugated bilirubin in adults[15][16] (see below). There is consequently debate about whether GS should be classified as a disease.[15][17] [edit]Cause Gilbert's syndrome is a phenotypic effect, characterized by mild jaundice due to increased unconjugated bilirubin, that arises from several different genotypic variants of the gene for the enzymeresponsible for changing bilirubin to the conjugated form. Gilbert's syndrome is characterized by a 70%-80% reduction, rather than more severe loss of activity, in the glucuronidation activity of the enzyme, uridine-diphosphate-glucuronosyltransferase isoform 1A1 (UDPglucuronosyltransferase 1A1, or UGT1A1). The UGT1A1 gene is located on human chromosome 2.[18] There are considerably in excess of 100 variants of the UGT1A1 gene, designated as UGT1A1*n (where n is the general chronological order of discovery), either of the gene itself or of its promoter region. The UGT1A1 gene is associated with a TATA box promoter region ; this region most commonly contains the genetic sequence A(TA6)TAA; this variant accounts for about 50% of alleles in many populations. There are however several allelic polymorphic variants of this region, the most common adding another dinucleotide repeat TA to the promoter region, so that it is thus referred to as A(TA7)TAA, being also called UGT1A1*28; this common variant accounts for about 40% of alleles in some populations, but is seen less often, approximately 3% of alleles, in southeast and east Asian people and Pacific Islanders. In most populations, Gilbert's syndrome is most commonly associated with homozygous A(TA7)TAA alleles.
[19][20][21]

In 94% of GS cases, two other glucoronyltransferase enzymes, UGT1A6(rendered 50% inactive)

and UGT1A7 (rendered 83% ineffective), are also affected. However, Gilbert's syndrome can arise without TATA box promoter polymorphic mutations; 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,[22] which may be associated with significantly higher bilirubin levels.[22] 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.

[edit]Diagnosis People with GS predominantly have elevated unconjugated bilirubin, while conjugated bilirubin is usually within the normal range and is less than 20% of the total. Levels of bilirubin in GS patients is reported to be from 20 M to 90 M (1.2 to 5.3 mg/dL)[20] compared to the normal amount of < 20 M. GS patients will have a ratio of unconjugated/conjugated (indirect/direct) bilirubin that is commensurately higher than those without GS. The level of total bilirubin is often further increased if the blood sample is taken after fasting for two days,
[23]

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;[24] the bilirubin will decrease substantially. There are also tests that detect DNA mutations of UGT1A1 by polymerase chain reaction or DNA fragment sequencing. [edit]Differential

diagnosis

While this 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: Hemolysis can be excluded by a full blood count, haptoglobin, lactate dehydrogenase levels and

the absence of reticulocytosis (elevated reticulocytes in the blood would usually be observed in haemolytic anaemia). Viral hepatitis can be excluded by negative blood samples for antigens specific to the different

hepatitis viruses. Cholestasis can be excluded by the absence of lactate dehydrogenase, low levels of conjugated

bilirubin and ultrasound scan of the bile ducts. More severe types of glucoronyl transferase disorders like Crigler-Najjar syndrome (types I and II).

These are much more severe, with 0-10% UGT1A1 activity, with sufferers at risk of brain damage in infancy (type I) and teenage years (type II). DubinJohnson syndrome and Rotor syndrome, which are rarer autosomal recessive disorders that

are characterized by an increase of conjugated bilirubin. In GS, unless another disease of the liver is also present, the liver-

enzymes ALAT, ASAT and albumin are within normal ranges. [edit]History Gilbert's syndrome was first described by French gastroenterologist Augustin Nicolas Gilbert and coworkers in 1901.[25][26] In German literature, it is commonly associated with Jens Einar Meulengracht.[27]

Alternative, less common names for this disorder include: Familial benign unconjugated hyperbilirubinaemia Constitutional liver dysfunction Familial non-hemolytic non-obstructive jaundice Icterus intermittens juvenilis Low-grade chronic hyperbilirubinemia Unconjugated benign bilirubinemia

[edit]Notable

cases

Napoleon I of France[28] Arthur Kornberg, Nobel laureate in Physiology or Medicine, 1959[29] Nicky Wire, Manic Street Preachers bassist.[30] Noel Fielding (The Mighty Boosh)[31] James Padden (Irish Classical Pianist)

alexandre dolgopolov (tennis player) [edit]See

also

Crigler-Najjar syndrome Dubin-Johnson syndrome Rotor syndrome

Primary sclerosing cholangitis

From Wikipedia, the free encyclopedia

Primary sclerosing cholangitis

Classification and external resources

Cholangiogram of primary sclerosing cholangitis.

ICD-10

K83.0

ICD-9

576.1

DiseasesDB

10643

MedlinePlus

000285

eMedicine

med/3556

MeSH

D015209

Primary sclerosing cholangitis (PSC) is a chronic liver disease caused by progressive inflammation and scarring of the bile ducts of the liver. The inflammation impedes the flow of bile to the gut, which can ultimately lead to liver cirrhosis, liver failure and liver cancer. The underlying cause of the inflammation is believed to be autoimmunity.[1] The definitive treatment is liver transplantation.

Contents
[hide]

1 Signs and symptoms 2 Diagnosis 3 Etiology 4 Pathophysiol ogy 5 Epidemiolog y 6 Related diseases 7 Therapy 8 Prognosis 9 See also 10 References 11 External links

[edit]Signs

and symptoms

Chronic fatigue (a non-specific symptom often present in liver disease) Severe jaundice with intense itching Malabsorption (especially of fat) and steatorrhea (pale stools) due to biliary Signs of cirrhosis Hepatomegaly Portal hypertension Ascending cholangitis, or infection of the bile duct. Dark urine due to excess conjugated bilirubin, which is water soluble, being excreted

obstruction, leading to decreased levels of the fat-soluble vitamins, A, D, Eand K.

by the kidneys

[edit]Diagnosis

The diagnosis is by imaging of the bile duct, usually in the setting of endoscopic retrograde cholangiopancreatography (ERCP, endoscopy of the bile duct and pancreas), which shows "beading" (both strictures and dilation) of the intrahepatic and extrahepatic bile ducts. Another option is magnetic resonance cholangiopancreatography (MRCP), where magnetic resonance imaging is used to visualise the biliary tract. Most patients with PSC have evidence of autoantibodies. Approximately 80% of patients have perinuclear anti-neutrophil cytoplasmic antibodies, also called p-ANCA; however, this finding is not specific for PSC. Antinuclear antibodies and anti-smooth muscle antibody are found in 20%-50% of PSC patients and, likewise, are not specific for the disease.[1] Other tests often done are a full blood count, liver enzymes, bilirubin levels (usually grossly elevated), renal function, electrolytes. Fecal fat determination is occasionally ordered when the symptoms of malabsorption are prominent. The differential diagnosis can include primary biliary cirrhosis, drug induced cholestasis, cholangiocarcinoma, and HIV-associated cholangiopathy.
[edit]Etiology

The cause of PSC is unknown, although it is thought to be an autoimmune disorder. There is an increased prevalence of HLA alleles A1, B8, and DR3 in primary sclerosing cholangitis.[1]
[edit]Pathophysiology

Inflammation damages bile ducts both inside and outside of the liver. The resulting scarring of the bile ducts blocks the flow of bile, causing cholestasis. Bile stasis and back-pressure induces proliferation of epithelial cells and focal destruction of the liver parenchyma, forming bile lakes. Chronic biliary obstruction causes portal tract fibrosis and ultimately biliary cirrhosis and liver failure.[2] Bile assists in the enteric breakdown and absorption of fat; the absence of bile leads to fat malabsorption and deficiencies of fat-soluble vitamins (A, D, E, K).
[edit]Epidemiology

There is a 2:1 male-to-female predilection of primary sclerosing cholangitis.[2] The disease normally starts from age 20 to 30, though may begin in childhood. PSC progresses slowly, so the diseasecan be active for a long time before it is noticed or diagnosed. There is

relatively little data on the prevalence and incidence of primary sclerosing cholangitis, with studies in different countries showing annual incidence of 0.0681.3 per 100,000 people and prevalence 0.228.5 per 100,000; given that PSC is closely linked with ulcerative colitis, it is likely that the risk is higher in populations where UC is more common.[3]
[edit]Related

diseases

Primary sclerosing cholangitis is associated with cholangiocarcinoma, a cancer of the biliary tree, and the lifetime risk for PSC sufferers is 10-15%. Screening for cholangiocarcinoma in patients with primary sclerosing cholangitis is encouraged, but there is no general consensus on the modality and interval of choice. Colon cancer is also associated with PSC. PSC has a significant association with ulcerative colitis, an inflammatory bowel disease primarily affecting the large intestine. As many as 5% of patients with ulcerative colitis may progress to develop primary sclerosing cholangitis [4] and approximately 70% of people with primary sclerosing cholangitis have ulcerative colitis.[2]
[edit]Therapy

Standard treatment includes ursodiol, a bile acid naturally produced by the liver, which has been shown to lower elevated liver enzyme numbers in people with PSC, but has not improved liver- or overall survival.[5] Treatment also includes medication to relieve itching (antipruritics), bile acid sequestrants (cholestyramine), antibiotics to treat infections, and vitamin supplements, as people with PSC are often deficient in vitamin A, vitamin D, vitamin E and vitamin K. In some cases, ERCP, which may involve stenting of the common bile duct, may be necessary in order to open major blockages (dominant strictures). Liver transplantation is the only proven long-term treatment of PSC. Indications for transplantation include recurrent bacterial cholangitis, jaundice refractory to medical and endoscopic treatment, decompensated cirrhosis and complications of portal hypertension. In one series, 1, 2, and 5 year survival following liver transplantation for PSC was 90%, 86% and 85% respectively.[1]
[edit]Prognosis

A German study in 2007 estimated the average survival time from time of diagnosis to be approximately 25 years, and the median time until either death or liver transplantation to be approximately 10 years.[6]

[edit]