INTRODUCTION — The normal serum bilirubin concentration in children and adults is less than 1 mg/dL (17 micromol/liter), less than 5 percent of which is present in conjugated form. The measurement is usually made using diazo reagents and spectrophotometry. Conjugated bilirubin reacts rapidly ("directly") with the reagents. The measurement of unconjugated bilirubin requires the addition of an accelerator compound and is often referred to as the indirect bilirubin. (See "Clinical aspects of serum bilirubin determination".)
Jaundice is often used interchangeably with hyperbilirubinemia. However, a careful clinical examination cannot detect jaundice until the serum bilirubin is greater than 2 mg/dL (34 micromol/liter), twice the normal upper limit. The yellow discoloration is best seen in the periphery of the ocular conjunctivae and in the oral mucous membranes (under the tongue, hard palate). Icterus may be the first or only sign of liver disease; thus its evaluation is of critical importance.
For clinical purposes, the predominant type of bile pigments in the plasma can be used to classify hyperbilirubinemia into two major categories (table 1 and algorithm 1A-B).
●Plasma elevation of predominantly unconjugated bilirubin due to the overproduction of bilirubin, impaired bilirubin uptake by the liver, or abnormalities of bilirubin conjugation.
●Plasma elevation of both unconjugated and conjugated bilirubin due to hepatocellular diseases, impaired canalicular excretion, defective reuptake of conjugated bilirubin and biliary obstruction.
In some situations, both overproduction and reduced disposition contribute to the accumulation of bilirubin in plasma.
The frequency with which the different causes of jaundice occur varies markedly depending upon multiple factors such as age, geography, and socioeconomic class [1]. The causes of hyperbilirubinemia presenting in the neonatal period are quite different from those presenting later in life, and are discussed separately. (See "Etiology and pathogenesis of neonatal unconjugated hyperbilirubinemia" and "Causes of cholestasis in neonates and young infants".)
This topic will review the causes of jaundice. A schematic depiction of the hepatobiliary excretion pathway with disorders causing jaundice and their main site of interference with bilirubin metabolism and excretion is presented in the figure (figure 1). The diagnostic approach to the patient with jaundice is discussed separately. (See "Diagnostic approach to the adult with jaundice or asymptomatic hyperbilirubinemia".)
REFERENCE RANGES — Liver test reference ranges will vary from laboratory to laboratory. As an example, one hospital's normal reference ranges for adults are as follows [2]:
●Albumin: 3.3 to 5.0 g/dL (33 to 50 g/L)
●Alkaline phosphatase:
•Male: 45 to 115 international unit/L
•Female: 30 to 100 international unit/L
●Alanine aminotransferase:
•Male: 10 to 55 international unit/L
•Female: 7 to 30 international unit/L
●Aspartate aminotransferase:
•Male: 10 to 40 international unit/L
•Female: 9 to 32 international unit/L
●Bilirubin, total: 0.0 to 1.0 mg/dL (0 to 17 micromol/L)
●Bilirubin, direct: 0.0 to 0.4 mg/dL (0 to 7 micromol/L)
●Gamma-glutamyl transpeptidase:
•Male: 8 to 61 international unit/L
•Female: 5 to 36 international unit/L
●Prothrombin time: 11.0 to 13.7 seconds
DISORDERS ASSOCIATED WITH UNCONJUGATED HYPERBILIRUBINEMIA — Three basic pathophysiologic mechanisms, overproduction of bilirubin, reduced bilirubin uptake, and impaired bilirubin conjugation, are mainly responsible for unconjugated hyperbilirubinemia. The physiologic jaundice of the neonate represents a classic example which combines all of these mechanisms.
Overproduction of bilirubin — Bilirubin overproduction may result from excessive breakdown of heme derived from hemoglobin (figure 2). Extravascular or intravascular hemolysis, extravasation of blood in tissues, or dyserythropoiesis are causes of enhanced heme catabolism. (See "Gilbert syndrome and unconjugated hyperbilirubinemia due to bilirubin overproduction".)
Extravascular hemolysis — The reticuloendothelial cells of the spleen, bone marrow, and liver are responsible for the increased extravascular destruction of erythrocytes which occurs in most hemolytic disorders. These phagocytic mononuclear cells are rich in heme oxygenase and biliverdin reductase activities and rapidly degrade heme to bilirubin (figure 2). (See "Bilirubin metabolism".)
Extravasation — When blood is extravasated into tissues, or pleural or peritoneal cavities, erythrocytes are phagocytosed by tissue macrophages that degrade heme to biliverdin and subsequently bilirubin, resulting in the sequential green and yellow discoloration of the skin overlying a hematoma.
Intravascular hemolysis — With intravascular hemolysis, bilirubin is predominantly formed in the liver and the kidneys. Hemoglobin released in the circulation is bound to haptoglobin; this complex is internalized and degraded by hepatocytes. However, circulating haptoglobin may be depleted with massive hemolysis. In these cases, unbound hemoglobin is converted to methemoglobin, from which heme is transferred to hemopexin or to albumin forming methemalbumin. Heme-hemopexin and methemalbumin are internalized by hepatocytes, where heme is degraded to bilirubin.
A significant fraction of free methemoglobin is filtered by renal glomeruli after dissociation of the tetrameric globin to two dimers. Only the free (unbound) dimer is small enough to be filtered across the glomeruli. The heme moiety of filtered methemoglobin is largely degraded by tubular epithelial cells to bilirubin.
Dyserythropoiesis — Dyserythropoiesis is a term used in a variety of diseases including megaloblastic and sideroblastic anemias, severe iron deficiency anemia, erythropoietic porphyria, erythroleukemia, lead poisoning, and a rare disorder of unknown pathogenesis termed primary shunt hyperbilirubinemia [3,4]. In these disorders, the incorporation of hemoglobin into erythrocytes is defective, leading to the degradation of a large fraction of unincorporated hemoglobin heme.
Serum bilirubin concentration — In a stress situation, hemolysis, and therefore unconjugated bilirubin production, can increase up to 10-fold. The canalicular excretion of bilirubin is the rate-limiting step in bilirubin elimination since hepatic conjugating capacity normally exceeds maximum bilirubin production. These relationships account for two findings at a steady state of maximum bilirubin production in patients with normal hepatic function:
●The serum bilirubin concentration will not exceed 4 mg/dL (68 micromol/liter) in patients with normal liver function [5]; however, hemolysis can lead to severe hyperbilirubinemia in patients who have even mild hepatic disease.
●The proportion of conjugated bilirubin in plasma (approximately 3 to 5 percent of the total) remains normal [6].
There are two reasons why the bilirubin concentration increases during hemolysis in the presence of normal bilirubin glucuronidation. First, bilirubin is produced mainly outside the liver; as a result, it must enter the blood stream during transit to the liver. Second, a small amount of bilirubin taken up by the hepatocyte is transferred to plasma by diffusion or via ATP-consuming mechanisms. Because conjugated bilirubin is very efficiently cleared, the proportion of conjugated bilirubin in the plasma (around 5 percent) does not increase until canalicular excretion capacity is exceeded. At that point, a disproportionate amount of conjugated bilirubin accumulates.
Bilirubin overproduction with coexisting liver disease — Most liver diseases affect canalicular excretion, resulting in the accumulation of both conjugated and unconjugated bilirubin in hepatocytes. In cholestatic states, the canalicular ATP-dependent organic anion pump, MRP2 (also termed ABCC2), is down-regulated. This may lead to upregulation of other forms of MRP, such as MRP3 (also termed ABCC3), in the contiguous membranes of the hepatocyte, resulting in active transport of unconjugated and conjugated bilirubin into the plasma [7,8]. Thus, plasma bilirubin accumulating in conditions resulting from a combination of bilirubin overload and liver disease is always a mixture of unconjugated and conjugated bilirubin. In cases where there is an inherited deficiency of conjugation (eg, Gilbert syndrome), hemolysis causes almost pure unconjugated hyperbilirubinemia. The rate-limiting step in these patients is bilirubin glucuronidation, rather than canalicular excretion. (See "Gilbert syndrome and unconjugated hyperbilirubinemia due to bilirubin overproduction".)
Serum bilirubin level is of particular significance when diagnosing Wilson disease in the setting of acute liver failure. In contrast to most liver diseases, serum alkaline phosphatase activity is low or normal in Wilson disease and, because of bilirubin overproduction due to hemolysis, the serum bilirubin level is high. A serum alkaline phosphatase (international unit/L)/bilirubin (mg/dl) ratio of <4 provides 94 percent sensitivity and 96 percent specificity for the diagnosis of Wilson disease in adult patients presenting with acute liver failure [9]. However, the sensitivity of this ratio may be reduced in children, probably because of a higher contribution of alkaline phosphatase from non-hepatic sources [10]. (See "Wilson disease: Clinical manifestations, diagnosis, and natural history", section on 'Acute hepatitis and acute liver failure'.)
Urobilinogen excretion — As bilirubin excretion in bile increases in states of bilirubin overproduction, more urobilinogen appears in the stool and urine. However, the amount of urobilinogen in stool and urine is not proportional to bilirubin excretion since conversion of bilirubin to urobilinogen is not quantitative [11].
Gallstones — Chronically increased biliary bilirubin excretion can lead to brown or black pigment stones consisting of precipitated monoconjugated and unconjugated bile pigments. Black pigment stones generally form in the gallbladder and may contain polymerized bile pigments. Brown stones form in the bile ducts, often in the presence of infection. They consist of calcium bilirubinate, mucin glycoproteins, and various other salts.
Impaired hepatic bilirubin uptake — Impaired delivery of bilirubin to the liver and disorders of internalization of bilirubin by the hepatocyte result in reduced hepatic bilirubin uptake (figure 3). Congestive heart failure or portosystemic shunts (spontaneously occurring collaterals in cirrhosis or surgical shunts) reduce hepatic blood flow and the delivery of bilirubin to hepatocytes, resulting in predominantly unconjugated hyperbilirubinemia. In some patients with cirrhosis, the direct contact of plasma with the hepatocytes may be compromised due to capillarization of the sinusoidal endothelial cells (loss of fenestrae), resulting in a further reduction in bilirubin uptake [12].
Other causes of abnormal bilirubin uptake include administration of several drugs (eg, rifamycin antibiotics, probenecid, flavaspidic acid, and bunamiodyl, a cholecystographic agent). The drug-induced defect usually resolves within 48 hours after discontinuation of the drug [13]. Impaired bilirubin uptake at the sinusoidal surface of hepatocytes has been reported in some cases of Gilbert syndrome (see "Gilbert syndrome and unconjugated hyperbilirubinemia due to bilirubin overproduction").
Impaired bilirubin conjugation — Reduced bilirubin conjugation as a result of a decreased or absent UDP-glucuronosyltransferase activity is found both in several acquired conditions and inherited diseases, such as Crigler-Najjar syndrome, type I and II and Gilbert syndrome. Bilirubin conjugating activity is also very low in the neonatal liver. (See "Gilbert syndrome and unconjugated hyperbilirubinemia due to bilirubin overproduction" and "Crigler-Najjar syndrome".)
UGT activity toward bilirubin is modulated by various hormones. Hyperthyroidism and ethinyl estradiol, but not other oral contraceptives, inhibit bilirubin glucuronidation [14]. In comparison, the combination of progestational and estrogenic steroids results in increased enzyme activity. Bilirubin glucuronidation can also be inhibited by certain antibiotics (eg, novobiocin or gentamicin at serum concentrations exceeding therapeutic levels) and antiretroviral drugs, particularly Atazanavir [15]. Reduced bilirubin glucuronidation by liver tissue has been reported in chronic persistent hepatitis, advanced cirrhosis, and Wilson's disease.
DISORDERS ASSOCIATED WITH CONJUGATED HYPERBILIRUBINEMIA — A variety of acquired disorders with conjugated hyperbilirubinemia can be categorized according to their histopathology and pathophysiology: biliary obstruction (extrahepatic cholestasis), intrahepatic cholestasis, and hepatocellular injury. The differential diagnosis of extrahepatic and intrahepatic hyperbilirubinemia is summarized in the tables (table 2 and table 3).
Biliary obstruction — In biliary obstruction, both conjugated and unconjugated bilirubin accumulate in serum. Bilirubin may be transported back to the plasma via an MRP group of ATP-consuming pumps [8,16]. The serum concentrations of conjugated bilirubin and alkaline phosphatase can be used as markers for hepatobiliary obstruction. The diagnosis can usually be established with the help of noninvasive and invasive imaging techniques. (See "Diagnostic approach to the adult with jaundice or asymptomatic hyperbilirubinemia".)
Obstruction of biliary flow causes retention of conjugated bilirubin within the hepatocytes, where reversal of glucuronidation may take place. The unconjugated bilirubin formed by this process may diffuse or be transported back into the plasma.
Differential diagnosis of conjugated hyperbilirubinemia due to biliary obstruction is age dependent. In adults, it includes cholelithiasis, intrinsic and extrinsic tumors, primary sclerosing cholangitis (PSC), parasitic infections, lymphoma, AIDS cholangiopathy, acute and chronic pancreatitis, and strictures after invasive procedures [17]. In children, choledochal cysts and cholelithiasis are most common. Extrinsic compression from tumors or other anomalies are seen in all pediatric age groups as well as in adults. In neonates and young infants, important obstructive processes include biliary atresia and choledochal cysts. (See "Causes of cholestasis in neonates and young infants".)
●In the Mirizzi syndrome, a distended gallbladder caused by an impacted cystic duct stone may lead to compression of the extrahepatic bile ducts. (See "Mirizzi syndrome".)
●The intrahepatic and extrahepatic portions of the bile ducts can be affected in both PSC and cholangiocarcinoma. (See "Clinical manifestations and diagnosis of cholangiocarcinoma".)
●Different parasitic infections can be the cause of biliary obstruction. Adult Ascaris lumbricoides can migrate from the intestine up the bile ducts, thereby obstructing the extrahepatic bile ducts. Eggs of certain liver flukes (eg, Clonorchis sinensis, Fasciola hepatica) can obstruct the smaller bile ducts, resulting in intrahepatic cholestasis.
●AIDS cholangiopathy can be caused by Cryptosporidium sp, cytomegalovirus, or HIV itself [18]; imaging studies show similar findings to PSC [19] (see "AIDS cholangiopathy"). Only biopsies and bile cultures are able to give a definitive diagnosis.
Establishing the cause of jaundice in patients with AIDS is particularly complex because of its broad differential diagnosis. It includes viral hepatitis (hepatitis viruses, herpes simplex virus, Epstein-Barr virus), Mycobacterium tuberculosis and atypical mycobacteria (especially Mycobacterium avium intracellulare), fungal infections (Cryptococcus neoformans, Histoplasma capsulatum, Candida albicans, Coccidioides immitis), parasites (Pneumocystis carinii), tumor infiltration (lymphoma, Kaposi sarcoma), and drug-induced liver disease.
Intrahepatic causes — A number of intrahepatic disorders can lead to jaundice and an elevated serum alkaline phosphatase (in relation to serum aminotransferases). This presentation mimics that of biliary obstruction but the bile ducts are patent.
Viral hepatitis — Viral hepatitis can present as a predominantly cholestatic syndrome with marked pruritus. Unless the patient has risk factors for viral hepatitis, it is difficult to distinguish this clinically from other causes of cholestasis.
Alcoholic hepatitis — Cholestasis with fever and leukocytosis is often the distinctive sign of alcoholic hepatitis [20]. The diagnosis should be strongly considered in the jaundiced patient with ethanol dependency, especially if the ratio of serum AST to ALT exceeds 2.0 with the values being below 500 international unit/L. (See "Clinical manifestations and diagnosis of alcohol-associated fatty liver disease and cirrhosis".)
Nonalcoholic steatohepatitis — Nonalcoholic steatohepatitis has features similar to alcoholic hepatitis both in terms of histology and signs of cholestasis [21]. A variety of conditions such as diabetes mellitus, morbid obesity, certain stomach and small bowel operations, and drugs can cause this disorder. (See "Epidemiology, clinical features, and diagnosis of nonalcoholic fatty liver disease in adults".)
Primary biliary cholangitis — Primary biliary cholangitis typically presents with a cholestatic picture, though evidence of hepatocellular injury also exists. (See "Clinical manifestations, diagnosis, and prognosis of primary biliary cholangitis (primary biliary cirrhosis)".)
Drugs and toxins — Drug-induced cholestasis can occur in a dose-related fashion (eg, alkylated steroids such as methyltestosterone and ethinyl estradiol) or as an idiosyncratic or allergic reaction in a minority of subjects (eg, chlorpromazine). Drugs and toxins causing hepatocellular injury may eventually present as a predominantly cholestatic syndrome [22]. Therefore, it is imperative in every patient with cholestasis to scrupulously elucidate the current and past medication history including prescribed and over-the-counter drugs.
Certain plants used in "natural" medicines (eg, Jamaican bush tea) contain pyrrolizidine alkaloids which may cause veno-occlusive disease of the liver [23,24] (see "Hepatotoxicity due to herbal medications and dietary supplements"). The outbreak of jaundice that occurred in 84 individuals after accidental methylene dianiline ingestion in England in 1965 has been termed Epping jaundice [25].
Arsenic, which was used for the treatment of syphilis during the early years of the twentieth century, also can cause cholestasis. It has recently gained increased attention because of its contamination of ground water in various parts of the world including West Bengal, India [26], the southern United States, and Taiwan. In addition to the well-known skin lesions, arsenic-contaminated drinking water has been associated with hepatic fibrosis and portal hypertension, usually without the formation of cirrhotic nodules.
Sepsis and low perfusion states — Bacterial sepsis is very often accompanied by cholestasis. Multiple factors including hypotension, drugs, and bacterial endotoxins are responsible for the jaundice in these patients [27-29]. On the other hand, hyperbilirubinemia can promote bacterial sepsis by increasing intestinal wall permeability and altering mucosal immunity [30]. Signs of cholestasis can also be found in other low perfusion states of the liver (heart failure, hypotension) and hypoxemia that is not profound enough to produce hepatic necrosis.
Malignancy — Paraneoplastic syndromes associated with malignancy can induce a reversible form of cholestasis (Stauffer syndrome) [31]. It has most commonly been described in association with renal cell carcinoma, though it has also been reported in patients with malignant lymphoproliferative diseases, gynecologic malignancies, and prostate cancer [32,33]. (See "Clinical manifestations, evaluation, and staging of renal cell carcinoma".)
Liver infiltration — Infiltrative processes of the liver (eg, amyloidosis, lymphoma, sarcoidosis, tuberculosis) can precipitate intrahepatic cholestasis.
Inherited diseases — Elevated levels of conjugated bilirubin may occur in inherited diseases such as Dubin-Johnson syndrome, Rotor syndrome, progressive familial intrahepatic cholestasis (PFIC), benign recurrent intrahepatic cholestasis (BRIC), and low phospholipid-associated cholelithiasis (LPAC). BRIC is seen in adolescents and adults, while LPAC presents mainly in young adults. (See "Inherited disorders associated with conjugated hyperbilirubinemia".)
Disorders of fatty acid oxidation are characterized by episodes of metabolic decompensation, with hypoglycemia, liver dysfunction, and/or cardiomyopathy, triggered by fasting or intercurrent illness. These disorders may present at any age, from birth through adulthood. (See "Metabolic myopathies caused by disorders of lipid and purine metabolism", section on 'Defects of beta-oxidation enzymes'.)
Inherited diseases that cause conjugated hyperbilirubinemia that present during the neonatal period include Alagille syndrome, cystic fibrosis, and disorders of carbohydrate, lipid, or bile acid metabolism. (See "Causes of cholestasis in neonates and young infants".)
Parenteral nutrition — Steatosis, lipidosis, and cholestasis are frequently encountered in patients receiving parenteral nutrition. This complication usually requires at least two to three weeks of therapy for the development of cholestasis [34]. The underlying illness, preexisting liver disease, hepatotoxic drugs, and the parenteral nutrition itself all may contribute to the cholestasis.
Parenteral nutrition promotes bacterial overgrowth in the small intestine, which in turn favors conditions well known to induce cholestasis such as translocation of intestinal endotoxins into the portal system [35], bacterial sepsis [36], and the formation of secondary bile acids (eg, lithocholic acid) (see "Management of the short bowel syndrome in adults"). Other contributing factors to cholestasis include biliary sludge, which occurs in all patients after six weeks of TPN, and hepatotoxic factors such as tryptophan degradation products and aluminum contaminants.
Infants are particularly prone to TPN cholestasis, particularly those born prematurely. Contributing factors and potential treatment approaches are discussed separately. (See "Causes of cholestasis in neonates and young infants", section on 'Intestinal failure (parenteral nutrition)-associated liver disease'.)
Postoperative patient — Jaundice occurs regularly in postoperative patients and is usually multifactorial in origin. Serum unconjugated bilirubin levels may increase because of blood transfusions, hematoma resorption, and hemolysis after heart surgery. Other contributing factors include sepsis, TPN, the administration of hepatotoxic drugs during surgery (such as halothane) [37], postoperative hypoxia, hypotension, or a newly acquired viral hepatitis [38]. Concomitant renal failure will exaggerate the hyperbilirubinemia. (See "Approach to the patient with postoperative jaundice".)
Surgery also can exacerbate a preexisting hemolytic disease or unmask an underlying genetic disorder (eg, Gilbert syndrome or glucose-6-phosphate dehydrogenase deficiency).
Following organ transplantation — Intrahepatic cholestasis is common in transplant recipients (especially bone marrow and liver). These patients are generally very sick, often require TPN, and receive multiple potentially hepatotoxic drugs including immunosuppressive agents, which increase the susceptibility to infection.
In addition to the skin and intestinal epithelium, other target sites of graft-versus-host disease in bone marrow transplants include the small interlobular bile ducts. The resulting inflammation and destruction lead to cholestasis. Intensive pretransplantation radiation and chemotherapy predisposes to the development of veno-occlusive disease of the liver, with cholestasis and liver failure.
Signs of cholestasis after orthotopic liver transplantation may reflect preservation injury of the donor organ, an operative complication (bile leak, stricture) [39], and chronic allograft rejection ("vanishing bile duct syndrome"). In addition, cholestasis is occasionally the sole indicator of acute transplant rejection.
Sickle cell disease — Jaundice in patients with sickle cell disease can result from an interaction of several factors. The average serum bilirubin concentration in these patients is higher than normal because of the combination of chronic hemolysis and a mild hepatic dysfunction. Both unconjugated and conjugated bilirubin accumulate in the plasma. Viral hepatitis, particularly hepatitis C virus, also may contribute in selected patients. (See "Hepatic manifestations of sickle cell disease".)
Hepatic crisis, which is usually associated with enlargement and tenderness of the liver, is thought to result from sequestration of sickled erythrocytes. In severe cases, acute attacks of intrahepatic cholestasis can occur, leading to very high levels of serum bilirubin and bile salts [40]. This condition must be differentiated from acute biliary obstruction. Bilirubin microliths, sludge, calcium bilirubinate stones, and black stones consisting of polymers of bilirubin are almost universal in patients with sickle cell disease [41]. However, biliary obstruction from these stones is not common.
Finally, cirrhosis can be caused by chronic vascular lesions [42] or iron overload after multiple blood transfusions (secondary hemochromatosis).
Intrahepatic cholestasis of pregnancy — Pruritus, usually occurring in the third trimester of pregnancy but sometimes earlier, typically heralds cholestasis which may evolve into frank jaundice [43] and may be associated with an increased frequency of stillbirths and prematurity [44]. All the pathologic changes disappear following delivery. (See "Intrahepatic cholestasis of pregnancy".)
Intrahepatic cholestasis of pregnancy is thought to be inherited, although the mode of inheritance is not well defined [45]. Interestingly, this disorder has been reported to be associated with heterozygosity for missense or non-sense mutations of the ABCB4 gene that, in homozygous state, causes familial intrahepatic cholestasis type III [46]. A possible relationship to one type of benign recurrent intrahepatic cholestasis has been postulated. It is of crucial importance to distinguish this entity from other potentially lethal liver disorders in pregnancy such as acute fatty liver and the HELLP syndrome. (See "Acute fatty liver of pregnancy".)
End-stage liver disease — The hallmarks of end-stage liver disease and cirrhosis, regardless of its etiology, include jaundice with an elevation of both conjugated and unconjugated bilirubin as well as portal hypertension and decreased hepatic synthetic function.
Hepatocellular injury — A partial overview of disorders causing hepatocellular jaundice is presented in the table (table 4). These conditions cannot always be separated clearly from the cholestatic syndromes because of the variability in presentation of these diseases. There are, however, characteristic differences between the two mechanisms of hepatic disease. Hepatocellular injury is typically characterized by the release of intracellular proteins and small molecules into the plasma. Thus, in contrast to cholestatic syndromes, the elevations in serum conjugated and unconjugated bilirubin and bile salts are accompanied by elevations in the serum concentrations of hepatocellular enzymes, such as aspartate aminotransferase (AST) and alanine aminotransferase (ALT).
With chronic hepatocellular injury, the biochemical profile changes over time as the liver injury progresses to cirrhosis and liver failure. The elevation of liver enzymes, a marker of active liver injury, becomes less prominent or even disappears. The primary manifestations at this time result from impaired hepatic protein synthesis (eg, hypoalbuminemia and a prolonged prothrombin time) and impaired excretory function, leading to jaundice.
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Here are the patient education articles that are relevant to this topic. We encourage you to print or email these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Basics topic (see "Patient education: Jaundice in adults (The Basics)" and "Patient education: Gilbert syndrome (The Basics)")
SUMMARY AND RECOMMENDATIONS
●Classification of hyperbilirubinemia – For clinical purposes, the predominant type of bile pigments in the plasma can be used to classify hyperbilirubinemia into two major categories: conjugated and unconjugated (table 1 and algorithm 1A-B). The diagnostic approach to the patient with jaundice is discussed separately. (See "Diagnostic approach to the adult with jaundice or asymptomatic hyperbilirubinemia".)
●Mechanisms for unconjugated hyperbilirubinemia – Three basic pathophysiologic mechanisms, overproduction of bilirubin, reduced bilirubin uptake, and impaired bilirubin conjugation, are mainly responsible for unconjugated hyperbilirubinemia. Bilirubin overproduction may result from excessive breakdown of heme derived from hemoglobin. Extravascular or intravascular hemolysis, extravasation of blood in tissues, or dyserythropoiesis are causes of enhanced heme catabolism. (See 'Disorders associated with unconjugated hyperbilirubinemia' above.)
●Causes of conjugated hyperbilirubinemia – A variety of acquired disorders with conjugated hyperbilirubinemia can be categorized according to their histopathology and pathophysiology: biliary obstruction (extrahepatic cholestasis), intrahepatic cholestasis, and hepatocellular injury. The differential diagnosis of extrahepatic and intrahepatic hyperbilirubinemia is summarized in the tables (table 2 and table 3). (See 'Disorders associated with conjugated hyperbilirubinemia' above.)
