prehepatic jaundice case study

• Open access
• Published: 26 October 2018

Jaundice revisited: recent advances in the diagnosis and treatment of inherited cholestatic liver diseases

• Huey-Ling Chen 1 , 2 , 3 ,
• Shang-Hsin Wu 4 ,
• Shu-Hao Hsu 5 ,
• Bang-Yu Liou 1 ,
• Hui-Ling Chen 3 &
• Mei-Hwei Chang 1 , 3  

Journal of Biomedical Science volume  25 , Article number:  75 ( 2018 ) Cite this article

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Jaundice is a common symptom of inherited or acquired liver diseases or a manifestation of diseases involving red blood cell metabolism. Recent progress has elucidated the molecular mechanisms of bile metabolism, hepatocellular transport, bile ductular development, intestinal bile salt reabsorption, and the regulation of bile acids homeostasis.

The major genetic diseases causing jaundice involve disturbances of bile flow. The insufficiency of bile salts in the intestines leads to fat malabsorption and fat-soluble vitamin deficiencies. Accumulation of excessive bile acids and aberrant metabolites results in hepatocellular injury and biliary cirrhosis. Progressive familial intrahepatic cholestasis (PFIC) is the prototype of genetic liver diseases manifesting jaundice in early childhood, progressive liver fibrosis/cirrhosis, and failure to thrive. The first three types of PFICs identified (PFIC1, PFIC2, and PFIC3) represent defects in FIC1 ( ATP8B1 ), BSEP ( ABCB11 ), or MDR3 ( ABCB4 ). In the last 5 years, new genetic disorders, such as TJP2, FXR, and MYO5B defects, have been demonstrated to cause a similar PFIC phenotype. Inborn errors of bile acid metabolism also cause progressive cholestatic liver injuries. Prompt differential diagnosis is important because oral primary bile acid replacement may effectively reverse liver failure and restore liver functions. DCDC2 is a newly identified genetic disorder causing neonatal sclerosing cholangitis. Other cholestatic genetic disorders may have extra-hepatic manifestations, such as developmental disorders causing ductal plate malformation (Alagille syndrome, polycystic liver/kidney diseases), mitochondrial hepatopathy, and endocrine or chromosomal disorders. The diagnosis of genetic liver diseases has evolved from direct sequencing of a single gene to panel-based next generation sequencing. Whole exome sequencing and whole genome sequencing have been actively investigated in research and clinical studies. Current treatment modalities include medical treatment (ursodeoxycholic acid, cholic acid or chenodeoxycholic acid), surgery (partial biliary diversion and liver transplantation), symptomatic treatment for pruritus, and nutritional therapy. New drug development based on gene-specific treatments, such as apical sodium-dependent bile acid transporter (ASBT) inhibitor, for BSEP defects are underway.

Short conclusion

Understanding the complex pathways of jaundice and cholestasis not only enhance insights into liver pathophysiology but also elucidate many causes of genetic liver diseases and promote the development of novel treatments.

Jaundice is a common symptom of inherited or acquired liver diseases of various causes. The underlying biochemical disturbance of jaundice is defined by direct or indirect hyperbilirubinemia. These two categories may represent different mechanisms causing jaundice. Indirect hyperbilirubinemia typically results from increased red blood cell turnover, increased bilirubin loading, or disturbances in hepatocellular update and bilirubin conjugation. Direct hyperbilirubinemia, typically defined as a direct/total bilirubin ratio of more than 15–20%, or a direct bilirubin level above 1.0 mg/dL, is collectively defined as cholestasis.

Recent progress in the past two decades has largely elucidated the molecular mechanisms underlying bile metabolism (including bilirubin, bile acids, cholesterol, phospholipid, and xenobiotics metabolism), hepatocellular transport (including uptake from sinusoidal blood and export to the canaliculus and bile ducts), bile ductular development, the intestinal reabsorption of bile salts, and the regulation of bile acids and cholesterol homeostasis. The understanding of these complex pathways not only provides insights into liver physiology but also elucidates many causes of genetic liver disease and facilitates the development of novel treatments. This review will focus mainly at hepatobiliary causes of jaundice and inherited cholestasis.

The composition and function of bile

The hepatobiliary system comprises the liver, bile duct and gall bladder. Bile is synthesized and secreted by polarized hepatocytes into bile-canaliculi, flows through bile ducts, stored in the gall bladder and is finally drained into the duodenum. The main physiological function of bile is to emulsify the lipid content of food, and this lipid emulsion facilitates lipid digestion and the absorption of lipid-soluble substances. Additionally, bile secretion is an important route to regulate cholesterol homeostasis, hemoglobin catabolism, and the elimination of drugs or drug metabolites [ 1 ].

Bile is a yellow-to-greenish amalgam of water, bile acids, ions, phospholipids (phosphatidylcholine), cholesterol, bilirubin, proteins (such as glutathione and peptides) and the other xenobiotics [ 1 ]. The yellow-to-greenish color of bile is caused by bilirubin and its derivative, which are also the origin of stool color. Bilirubin is the end catabolite of hemoglobin and other heme-containing proteins, such as myoglobin. The heme molecule is oxidized to biliverdin in hepatocytes and then reduced to unconjugated bilirubin. Unconjugated bilirubin is conjugated with one to two molecules of glucuronic acid via Uridine 5'-diphospho-glucuronosyltransferase 1A1 (UGT1A1). Bilirubin conjugation increases water solubility and reduces cytotoxicity of bilirubin. Hepatic and intestinal UGT1A1 are functionally reduced in neonatal stages, and hence, unconjugated hyperbilirubinemia is commonly found in human neonates [ 2 ]. Conjugated bilirubin, or direct bilirubin, is the major form of bilirubin in bile and is eliminated in stool. Jaundice, a yellowish pigmentation of the skin and sclera, is caused by the disrupted excretion of bilirubin and biliverdin. Interestingly, some studies involving neonates or adults have shown that hyperbilirubinemia is protective against diseases, including metabolic syndrome and asthma, [ 2 , 3 ] suggesting that bilirubin may play a role as an antioxidant [ 4 ].

Bile acids are colorless and are the most abundant organic components of bile. Bile acids, a group of detergent-like molecules, are synthesized from cholesterol and are typically associated with sodium or potassium ions in the form of bile salts. Bile salts mediate lipid emulsion and act as signaling molecules to regulate gene expression [ 5 , 6 , 7 ]. Phospholipids and cholesterol, the second and third most abundant organic components of bile, protect against injury of the biliary epithelium from bile acids [ 1 ].

Biosynthesis and enterohepatic circulation of bile acids

Bile acids can be synthesized from cholesterol via two pathways in hepatocytes to generate two primary bile acids, cholic acid (CA) and chenodeoxycholic acid (CDCA), through cytochrome P450 (CYP) enzymes, including CYP7A1, CYP8B1, and CYP27A1. Primary bile acids are conjugated with glycine or taurine (glyco- or tauro-conjugated CA and CDCA), with increased solubility and reduced cytotoxicity. In the intestines, gut-resident microbiota deconjugate bile salts to generate the secondary bile acids, deoxycholic acid (DCA) and lithocholic acid (LCA) [ 8 , 9 ]. In human livers, de novo synthesized bile salts are 500–600 mg daily [ 10 ]. More than 90% of bile acids are reabsorbed at the distal ileum and transported back to the liver through circulation systems for the next cycle, called the enterohepatic circulation. Bile salts cycle 6- to 10-times daily. The total amount of bile salt in the body is called bile acid pool, which is approximately 2–3 g. In contrast to bile acids, only trace amounts of conjugated bilirubin will enter the enterohepatic circulation. The blockage of enterohepatic circulation to enhance bile salt elimination has been applied in surgical and medical treatments for cholestasis (Fig.  1 ).

The enterohepatic circulation, homeostasis of bile acids and treatment targets for cholestasis. The grey arrows indicate the route of enterohepatic circulation of bile acids. Bile acids are synthesized from cholesterol in hepatocytes to generate the primary bile acids CA and CDCA. After conjugation with glycine or taurine, bile acids (BAs) are transported from hepatocytes into the bile canaliculi via BSEP. Intestinal microbiota converts primary bile acids into the secondary bile acids DCA and LCA. Most of BAs reabsorbed by the enterocytes through ASBT in the apical membrane and then delivered into the portal circulation system via BA efflux transporter OSTα/β in the basolateral membrane. BAs are re-absorbed into hepatocytes. Hepatocytes secrete these BAs along with the de novo synthesized bile acids enter the next cycle. Bile acids also play roles in signaling to regulate the homeostasis of bile acids. The nuclear receptor FXR is the bile acid receptor to regulate bile acid homeostasis at the synthesis and the elimination levels, acting in the hepatocytes and enterocytes. The figure also shows different therapeutic targets at hepatocellular transport or enterohepatic circulations. 1°BAs, primary bile acids; 2°BAs, secondary bile acids; 4-PB, 4-phenylbutyrate; ASBT, apical sodium dependent bile acid transporter; BAs, bile acids; BSEP, bile salt export pump; CA, cholic acid; CDCD, chenodeoxy cholic acid; DCA, deoxycholic acid; FGFR4, fibroblast growth factor receptor 4; FXR, farnesoid X receptor; G(T)CA, glyco- or tauro-cholic acid; G(T)CDCA, glyco- or tauro-chenodeoxy cholic acid; LCA, lithocholic acid; MRP3, multidrug resistance-associated protein 3; MRP4, multidrug resistance-associated protein 4; NTCP, sodium/taurocholate co-transporting polypeptide; OATP1B1/3, organic-anion-transporting polypeptide 1B1 and 1B3; OSTα/β, organic solute transporter-α/β; RXRα, retinoid X receptor α; SHP, small heterodimer partner; UDCA, ursodeoxycholic acid

In human fetuses after 22 and 26 weeks of gestation, taurine-conjugated di-hydroxyl bile acids can be detected in the gallbladder. After 28 weeks, small amounts of glycine conjugates are synthesized. In postnatal stages, the ratio of CA to CDCA declines from 2.5 to 1.2 [ 11 ]. Infant livers are under development, have a small bile acid pool, and have a limited capacity for bile excretion and reabsorption. Therefore, neonates and infants, particularly premature infants, are prone to cholestasis caused by various insults, such as ischemia, drugs, infection, or parenteral nutrition.

Hepatocellular transporters mediating bile flow (Fig.  2 )

Bile flow is generated by osmotic forces associated with the amount of bile salts secreted into bile canaliculi. Bile secretion from hepatocytes is mediated by a group of transport proteins, particularly ATP-binding cassette (ABC) containing proteins. The bile salt export pump (BSEP encoded by ABCB11 ) is the pivotal transporter mediating bile acid transport into bile canaliculi. BSEP is exclusively expressed in the apical/canalicular membrane of hepatocytes. After secreted into the small intestine, bile salts are absorbed into intestinal cells via the apical sodium-dependent bile acid transporter (ASBT encoded by SLC10A2 ) and then secreted into the circulation system through the basolateral heterodimeric transporter OSTα-OSTβ (encoded by OSTA and OSTB , respectively) [ 12 , 13 , 14 ].

Hepatocellular transporters, enzymes, and regulators involving in bile transport, metabolism, and secretion. A1AD, alpha-1 antitrypsin deficiency; A1AT, alpha-1 antitrypsin; ALG, Alagille syndrome; BAs, bile acids; BSEP, bile salt export pump; Canalicular, canalicular membrane; CF, cystic fibrosis; CFTR, cystic fibrosis transmembrane conductance regulator; DJ, Dubin-Johnson syndrome; FIC1, familial intrahepatic cholestasis 1; FXR, farnesoid X receptor; JAG1, jagged 1; MDR3, multidrug resistance protein 3; MRP2, multidrug resistance-associated protein 2; MRP3, multidrug resistance-associated protein 3; MRP4, multidrug resistance-associated protein 4; MYO5B, myosin VB; NTCP, sodium/taurocholate co-transporting polypeptide; OATP1B1, organic-anion-transporting polypeptide 1B1; OATP1B3, organic-anion-transporting polypeptide 1B3; OSTα/β, organic solute transporter-α/β; PC, phosphatidylcholine; PFIC, progressive familial intrahepatic cholestasis; PS, phosphatidylserine; Sinusoidal, sinusoidal membrane; SHP, small heterodimer partner; TJP2, tight junction protein 2

The basolateral/sinusoidal membrane of hepatocytes contains several bile acid transporters to absorb bile acids from sinusoidal blood, including Na + -taurocholate co-transporting polypeptide NTCP (encoded by SLC10A1 ), OATP1B1 and OATP1B3 (encoded by SLCO1B1 and SLCO1B3 , respectively) [ 12 , 15 ]. OATP1B1 and OATP1B3 also function in the uptake of bilirubin into hepatocytes [ 16 ]. Conjugated bilirubin and organic anions are transported via canalicular multidrug resistance-associated protein 2 MRP2 (encoded by ABCC2 ) and, to a lesser extent, via ABCG2 into bile. Under physiological or cholestatic conditions, conjugated bilirubin may be excreted via MRP3 (encoded by ABCC3 ) across sinusoidal membranes into blood, to a lesser extent, and reabsorbed by OATP1B1 and OATP1B3 [ 3 , 16 ].

Lipids are also important components of bile. The heterodimeric transporter ABCG5/8 mediates cholesterol across canalicular membranes. Phosphatidylcholine (PC) is flopped by the floppase multidrug resistance P-glycoprotein 3 (MDR3, encoded by ABCB4 ) to the outer lipid leaflet and then extracted by bile salts into bile to form micelles. The combination of cholesterol and sphingomyelin makes membranes highly detergent resistant [ 17 , 18 ]. The flippase FIC1( ATP8B1 ) is required to flip phosphatidylserine (PS) back from the outer lipid leaflet to the inner lipid leaflet of the canalicular membrane to stabilize the integrity of the canalicular membrane [ 19 ]. Additionally, FIC1 is required for the functional expression of MDR3 [ 20 ]. Thus, hepatocytes and biliary epithelium are protected from bile acid toxicity through the efflux of bile acids mediated by BSEP and the functions of MDR3 and FIC1.

Homeostasis of bile acid pools

The homeostasis of bile acids is tightly controlled by the de novo synthesis of bile acids and the expression of transporters that affect hepatocellular bile acid levels. The key regulating molecules are farnesoid X receptor (FXR, NR1H4 ) and membrane-bound Takeda G protein-coupled receptor (TGR5) [ 6 ]. FXR is a nuclear receptor that is highly expressed in hepatocytes and enterocytes in the distal small intestine and colon. TGR5 is expressed in enteroendocrine cells, gallbladder cells and cholangiocytes. FXR forms heterodimers with other nuclear receptors to mediate its transcriptional activity [ 21 , 22 , 23 , 24 ]. Upon binding with bile acids as its natural ligands, FXR downregulates the expression of bile acid synthesis enzymes (mainly CYP7A1) and the sinusoidal uptake transporter of NTCP but upregulates the expression of the bile acid efflux transporter BSEP to reduce intracellular bile acid concentrations [ 25 , 26 , 27 , 28 , 29 ]. When bile acids are accumulated in hepatocytes, activated hepatic FXR increases sinusoidal bile acid efflux via MRP4 and heterodimeric OSTα/β [ 30 , 31 ]. FXR also inhibits the expression of the ileal bile acid transporter ASBT to reduce the enterohepatic circulation of bile acids [ 32 , 33 ]. Activation of FXR induces enterocytes to release FGF19. Through enterohepatic circulation via the portal vein, FGF19 translocates to the liver and inhibits the expression of CYP7A1 in the hepatocytes [ 34 ]. Through FXR, bile is controlled via a negative feedback loop at the transcriptional level via transporters and bile acid synthesis systems.

• Cholestasis

Cholestasis is defined as disturbances in bile flow caused by diseases either in the hepatocytes, intrahepatic bile ducts or extrahepatic biliary system. Cholestatic liver disease is one of the most common forms of liver disorders resulting from inherited or acquired liver diseases. Inadequate bile flow of any causes results in accumulation of bile contents, including bilirubin, bile acids, and lipids in the liver, and consequently cause elevated levels of bilirubin and bile salts in the liver and blood, as well as dysregulated lipid metabolisms. Clinically, patients usually manifest jaundice as a result of hyperbilirubinemia. Other symptoms include clay stool, pruritus, or infrequently, bleeding episodes such as intracranial hemorrhage. Chronic cholestatic liver disease may progress to liver cirrhosis and liver failure and is the leading cause of pediatric liver transplantation. According to the anatomical location of its occurrence, cholestasis is divided into extrahepatic and intrahepatic cholestasis. Extrahepatic cholestasis is caused by structural abnormalities of the biliary tract including the obstruction of bile ducts and the gallbladder. Surgical treatments are typically applied to restore the physiological function. However, intrahepatic cholestasis is more complicated and typically requires sophisticated investigations. The common causes of extrahepatic and intrahepatic cholestasis are shown in Fig.  3 .

Etiologies of intrahepatic and extrahepatic cholestasis of inherited or secondary causes. dis: disorders

Etiologies of inherited bilirubin metabolism disorders causing indirect hyperbilirubinemia

Disturbances in the bilirubin metabolisms result in accumulation of bilirubin in the liver and blood, and consequently cause hyperbilirubinemia detected by routine serum biochemistry test, or called jaundice clinically. Gilbert syndrome is a benign clinical condition usually present mild intermittent jaundice in children or adult. TA repeat polymorphism (UGT1A1*28) in the promoter of UGT1A1 gene is the most commonly affected region. Gilbert syndrome can be identified in the general population, and many are identified by blood test of a health exam [ 35 ].

Crigler-Najjar syndrome is also cause by mutations in the UGT1A1 gene. Type I is a rare autosomal recessive disorder with complete loss of enzymatic function that cause extremely high bilirubin levels (above 20 mg/dL) and may lead to encephalopathy due to kernicterus. Treatments include phototherapy, exchange transfusion, or liver transplantation. Crigler-Najjar syndrome Type II manifests medium levels of hyperbilirubinemia (around 5–20 mg/dL), with retention of some enzymatic activity. Phenobarbital can be used intermittently to reduce bilirubin levels below 10-15 mg/dL.

Genetic variations in the UGT1A1 gene, especially 211 G to A (G71R in exon 1) mutation, as well as variations in the glucose-6-phosphate dehydrogenase ( G6PD ) and OATP2 genes, also contribute to the occurrence of neonatal jaundice and breast-feeding jaundice [ 36 , 37 , 38 ]. Homozygous 211 G to A mutation has been reported to be associated with severe neonatal jaundice.

Etiologies of inherited cholestasis causing direct hyperbilirubinemia

Inherited cholestatic liver diseases may manifest early in life. The presenting age ranges from infancy to young adulthood. In the last 20 years, there has been tremendous progress in understanding the genetic background of cholestatic liver disease [ 39 , 40 , 41 , 42 , 43 ]. Table  1 lists the categories and genes involved in inherited genetic disorders. Up to now, more than 100 inherited diseases are identified to cause cholestatic liver diseases with the initial presentation of jaundice. Some disorders may be associated with congenital anomalies or with multiple organ involvement. We have previously investigated the genetic background of pediatric patients in Taiwan with BSEP, FIC1, MDR3 defects [ 44 , 45 , 46 , 47 ]. We have also reported adaptive changes of hepatocyte transporters associated with obstructive cholestasis in biliary atresia, an important extrahepatic cholestatic liver disease with common symptom of prolonged neonatal jaundice [ 48 , 49 ]. The distribution of disease types in Taiwanese infants with intrahepatic cholestatic liver diseases is shown in Fig.  4 .

Distributions of final diagnosis of intrahepatic cholestasis in infancy in 135 Taiwanese infants 2000–2012. (Adapted from Lu FT et al., J Pediatr Gastroenterol Nutr 2014;59: 695–701). ALG, Alagille syndrome; GGT, gamma-glutamyl transpeptidase; IEBAM, inborn error of bile acid metabolism; NH, neonatal hepatitis; NICCD, neonatal intrahepatic cholestasis caused by citrin deficiency; PFIC, progressive familial intrahepatic cholestasis

Progressive familial intrahepatic cholestasis (PFIC) is a clinical syndrome with features of chronic intrahepatic cholestasis that typically begin in infancy and progress to biliary cirrhosis and hepatic failure by the first or second decade of life [ 40 , 46 , 50 ]. The first three types of genetic defects identified are commonly referred to as PFIC1, PFIC2, and PFIC3. PFIC1 and PFIC2 are characterized by low serum γ-glutamyltransferase (GGT) levels. PFIC1 (Byler’s disease) patients have FIC1 gene mutations, and PFIC2 patients have mutated BSEP gene. PFIC3 is characterized by high serum GGT levels and is caused by genetic mutations in the MDR3 gene [ 51 , 52 ]. BSEP plays a pivotal role in bile physiology as it mediates canalicular bile salt export and is the main driving force of bile flow [ 53 ].

With the advances in genetic technologies in recent years, novel disease-causing genes for PFIC have been reported. FXR, the key regulator of bile acid metabolism, have been implicated in a novel form of infant cholestasis with liver failure in two European families [ 54 ]. We also identified a fatal case of infant cholestasis with liver failure occurring before 3 months of age [ 55 ]. Additionally, TJP2 and MYO5B have been found to cause PFIC. TJP2 is an important component of tight junctions, and a deficiency of TJP2 disrupts the tight-junction structure in the liver [ 56 ]. MYO5B is associated with low GGT infant cholestasis. MYO5B is an actin-based motor protein and an effector of Rab11a/b. MYO5B mutations result in the dysregulation of Rab proteins and further disrupt the trafficking of BSEP [ 57 , 58 ]. Doublecortin domain containing 2 (DCDC2), a tubulin-binding protein, is associated with renal-hepatic ciliopathy and neonatal sclerosing cholangitis [ 59 , 60 , 61 ]. The mitochondrial transcription factor TFAM is associated with mitochondrial DNA depletion syndrome [ 62 ]. Recently, a homozygous single nucleotide deletion in organic solute transporter-β (OSTβ/SLC51B) was demonstrated to cause congenital diarrhea and cholestasis [ 63 ].

Dubin-Johnson and Rotor syndrome are two inherited disorders manifesting direct hyperbilirubinemia but with normal or minimally elevated alanine transaminase (ALT) levels, clinically manifesting as jaundice. Dubin-Johnson syndrome is caused by disruption of MRP2 and characterized by grossly black livers and pigment deposition in hepatocytes. Neonatal cholestasis caused by Dubin-Johnson syndrome has been reported in Taiwan and Japan [ 64 , 65 ]. Our group has identified patients recovered from neonatal cholestasis had re-emergence of jaundice in young adulthood after long-term follow-up [ 64 ]. Rotor syndrome has recently been identified to be caused by genetic disruption of both SLCO1B1 and SLCO1B3 genes [ 66 , 67 ]. These two disorders are benign and do not require specific treatment.

Genetic cholestasis not only causes pediatric liver disease but may also be present in adult liver disease. Additionally, adult liver diseases may result from genetic liver diseases. In general, protein functional disturbances are less detrimental and are typically caused by missense genetic mutations or multifactorial disorders. Cholestasis in pregnancy has been associated with genetic variants/mutations in ABCB4 , ABCB11 , ATP8B1 , ABCC2 and TJP2 [ 68 ]. Adult benign recurrent intrahepatic cholestasis (BRIC) is also associated with PFIC-related genes and may have mutations that are less damaging [ 69 , 70 , 71 , 72 ]. Acquired forms of cholestasis, such as drug-induced liver disease, have also been associated with genetic variants [ 73 , 74 ].

Diseases related to ductal plate malformation are an important group of developmental disorders that lead to a paucity or malformation of intrahepatic or interlobular bile ducts. Alagille syndrome, first described by Alagille et al., is based on clinical diagnostic criteria including a characteristic face; a paucity of interlobular bile ducts in liver pathology; and cardiac, eye, and vertebral anomalies [ 75 ]. The JAG1 mutation accounts for > 90% of cases of Alagille syndrome, and mutations in NOTCH2 have been described in a minority of patients [ 76 ]. Other syndromic disorders and polycystic liver/kidney diseases may also present with infant cholestasis as the first symptom.

Cholestasis is a common manifestation of hepatic metabolic disorders, including carbohydrate, amino acid, and fat metabolism, as well as mitochondrial and endocrine anomalies. Most of these diseases are rare disorders, and the disease incidence largely depends on ethnic background. For example, neonatal cholestasis caused by citrin deficiency (NICCD) is an important cause of cholestasis in East Asian children [ 77 , 78 ]. We have previously identified facial features and biochemical characteristics for the phenotypic diagnosis of NICCD [ 79 , 80 ]. Alpha 1-antitrypsin (A1AT/SERPINA1) deficiency and cystic fibrosis are important causes in western countries but how lower incidences in Asian populations.

Inborn errors of bile acid metabolism constitute a group of important metabolic disorders causing infant cholestasis. Notably, oral primary bile acid supplementation is effective and can avoid patient deterioration and the need for liver transplantation upon timely treatment [ 81 , 82 ].

Neonatal hemochromatosis is an important cause of neonatal liver failure that manifests as early onset cholestasis. However, recent studies have elucidated this condition as a disorder of gestational alloimmune liver diseases instead of hereditary hemochromatosis [ 83 ]. Treatment involves exchange blood transfusion and intravenous immunoglobulin applied as early as when the neonate is born.

Other congenital anomalies, such as chromosomal anomalies, endocrine disorders, and developmental disorders may also cause cholestasis. Liver disease is typically a multi-organ manifestation of congenital anomalies.

Clinical history

A careful clinical history is important to investigate common secondary causes of jaundice and cholestasis, including hemolytic anemia, G6PD deficiency, hereditary spherocytosis and other red cell membrane disorders, prematurity, sepsis, drug-induced liver injury, parenteral nutrition-associated liver diseases, ischemia, and pregnancy. Ethnic background and parental consanguinity are clues for certain types of inherited liver disorders.

Phenotypic diagnosis

The traditional phenotypic diagnosis includes low GGT as a signature of PFIC1 (FIC1 defect) and PFIC2 (BSEP defect). GGT levels, Byler’s bile in electron microscopy, and duodenal biliary bile content can be used as clinical markers to indicate further genetic confirmation [ 84 , 85 ]. Syndromic cholestasis, including Alagille syndrome, can be diagnosed by phenotypic criteria [ 75 ]. Patients with NICCD have phenotypic features, and we have developed a clinical scoring system to aid in diagnosis [ 79 , 86 ]. Importantly, investigating the involvement of extrahepatic organs is important for differential diagnosis.

Biochemical diagnosis

For patients suspecting jaundice or cholestasis, routine liver biochemistry tests include total and direct bilirubin levels, aspartate transferase levels, ALT levels, GGT and alkaline phosphatase (ALP) levels. Low serum GGT level disproportionate to severity of cholestasis is a clinical clue for inherited cholestasis such as PFIC and inborn errors of bile acid synthesis. Some disorders with metabolic signatures can be diagnosed with biochemical analysis. Diseases, such as inborn error of bile acid metabolism (IEBAM), [ 87 ] and metabolic disorders, such as NICCD, [ 86 ] require analysis by mass spectrometry.

Genetic diagnosis

Genetic diagnosis is a definitive diagnosis for inherited genetic liver diseases, as many of these diseases lack adequate biomarkers. Genetic tests have largely evolved in the past two decades due to the tremendous progress of genetic analysis technologies. Conventional genetic diagnosis uses direct sequencing for selected genes based on the phenotype of the patient. High-throughput methods have subsequently been developed, such as a resequencing chip that detects 5 genes for genetic cholestasis ( SERPINA1 , JAG1 , ATP8B1 , ABCB11 , and ABCB4 ) in 2007 [ 88 ]. Denaturing high-performance liquid chromatography and high-resolution melting analysis have been used to detect single-gene variants in large numbers of patients [ 46 , 79 ]. Recent next generation sequencing (NGS) panels in liver diseases have incorporated a limited number of genes, particularly PFIC [ 65 , 89 ]. Expanded panel-based NGS involving more than 50 genes has been used in clinical patients with promising results [ 55 , 90 ]. Whole exome sequencing has been applied to identify novel disease-causing genes [ 57 , 63 ].

Nutritional support

Bile mediates the intestinal absorption of fat and fat-soluble vitamins. In cholestatic liver diseases, the defective absorption of fat and fat-soluble vitamins (vitamins A, D, E, and K) is commonly observed but clinically obscure. Fat malabsorption results in calorie insufficiency and failure to thrive, especially in early childhood. Patients are advised to use formulas containing medium-chain triglycerides or add oils containing medium-chain triglycerides to their food. Deficiency in fat-soluble vitamins may result in multiple organ dysfunctions, including rickets, coagulopathy, and defective neurological, immunological and visual functions. Without supplementation, symptoms of deficiency, such as coagulopathy, osteoporosis, fracture, growth failure and life-threatening hemorrhage, may occur in patients. In addition, deficiencies in fat-soluble vitamins may also cause inadequate anti-oxidation, which is frequently overlooked in clinical patients.

Medical treatment

Although jaundice is the common manifestation of the highly variable etiologies, treatment does not target only to jaundice improvement (to reduce serum bilirubin level), but to target the underlying disorders that may cause hepatobiliary injury and progressive fibrosis and cirrhosis, which is usually associated with elevated bile acid levels or abnormal metabolites. Additional treatment goals are to improve nutritional status, pruritus and life quality, to prevent or to treat cirrhosis related complications.

PFICs, Alagille syndrome, and inborn errors of bile acid synthesis are the most devastating disorders that cause cirrhosis and may need liver transplantation. Effective treatment options for PFICs and Alagille syndrome are limited. Several drugs are under investigation and clinical trial. Here we will discuss about the standard treatment and several newly developed therapeutic strategies for these disorders.

Ursodeoxycholic acid (UDCA) has widely been used to treat cholestatic liver disease and is effective to improve biochemical parameters and pruritus [ 91 ]. However, UDCA is not an ideal therapeutic option for PFIC2 patients with BSEP defects. In animal models, UDCA may aggravate liver injury due to the inability of BSEP to export UDCA from hepatocytes [ 92 ]. There is a need to develop new drugs targeting BSEP defects. Missense mutations in BSEP/ABCB11 impair protein translation or intracellular trafficking, which reduce canalicular expression of BSEP and eventually cause cholestasis. Recent studies have indicated that 4-phenylbutyrate (4-PB, Buphenyl), a clinically approved pharmacological chaperone, can be used to restore the canalicular expression of BSEP. By using MDCK II cells and SD rats, Hayashi et al. reported that 4-PB significantly relocalizes and enhances the cell surface expression of both wild-type and mutated rat Bsep [ 93 ]. Besides its effect on Bsep expression, 4-PB treatment significantly increased hepatic MRP2 and decreased serum bilirubin level in patient with ornithine transcarbamylase deficiency (OTCD) [ 94 ]. Moreover, Gonzales et al. applied 4-PBA to PFIC2 patients and successfully restored the hepatic secretion of bile acids and decreased total serum bilirubin via the re-localization of mutated BSEP to canalicular membranes [ 95 ]. In addition to 4-PB, steroids are a therapeutic option to enhance BSEP expression. Cell culture experiments have suggested that dexamethasone upregulates Bsep and Mrp2 at the mRNA level in rat primary hepatocytes [ 96 , 97 ], and treatment with glucocorticoids induces the expression of Bsep, Mrp2, and cytochrome P450 oxidase in rat livers [ 98 ]. Additional animal experiments and clinical tests have shown that steroid treatment improved bile homeostasis. For example, dogs receiving a high dosage of hydrocortisone (5 mg/kg) showed a significant increase in bile flow [ 99 ]. Engelmann et al. reported that steroids effectively ameliorated cholestatic itches and reduced the serum level of bile salts and bilirubin in two PFIC2 patients carrying missense mutations in BSEP [ 100 ].

Blocking enterohepatic circulation has been recently shown as a promising strategy to reduce the hepatic accumulation of bile acids in PFIC2 patients. After secretion from the gallbladder into the intestine, a majority of bile acid is absorbed by enterocytes via ASBT and recycled to liver via enterohepatic circulation. Two independent animal studies have shown that small molecule ASBT inhibitors, SC-425 and A4250, effectively reduced the enteric uptake of bile acid, decreased serum total bilirubin levels, and improved liver fibrosis and inflammation in Mdr2 knockout mice, an animal model of PFIC3 [ 101 ]. Moreover, on March 2018, A4250 successfully passed clinical phase II trials (ClinicalTrials.gov Identifier: NCT02630875).

The recently developed FXR agonist (Obeticholic acid) has been demonstrated to improve the ALP level in primary biliary cirrhosis [ 102 ], and has also been investigated for the treatment of nonalcoholic steatohepatitis (NASH) [ 103 , 104 , 105 ].

Certain types of the inborn errors of bile acid metabolism are treatable [ 81 ]. Oral cholic acid therapy is indicated for 3β-Hydroxy-Δ(5)-C27-steroid oxidoreductase (HSD3B7) deficiency, Δ (4)-3-oxosteroid 5β-reductase (SRD5B1, AKR1D1) deficiency, and Zellweger spectrum disorders [ 106 ]. CDCA has also been reported to be effective for oxysterol 7α-hydroxylase (CYP7B1) deficiency, cerebrotendinous xanthomatosis, and other forms of bile acid synthetic defects [ 107 ]. After treatment, patients may recover from liver dysfunction, free of jaundice, and avoid liver transplantation. Life-long therapy is indicated for the oral supplementation. Early diagnosis and treatment is important to improve outcome.

Many patients with cholestatic liver disease suffer from pruritus, except patients with inborn errors of bile acid synthesis. Alagille syndrome, PFIC1 and 2 commonly cause disturbing pruritus, which affects daily life quality. Antihistamines, rifampin, and cholestyramine have been used to partially improve the symptoms of this condition. UV-B phototherapy is an alternative therapy to treat pruritus.

Biliary diversion and nasogastric drainage

Palliative treatment with biliary diversion surgery by the disruption of enterohepatic circulation may relieve pruritus and improve liver biochemical profiles. Several strategies have been used, including external biliary diversion or ileal exclusion [ 108 , 109 , 110 ].

Liver transplantation

Liver transplantation is considered a curative treatment for various liver diseases [ 111 ]. However, for PFIC2 patients, the recurrence of the BSEP defect has been reported due to circulating BSEP antibodies [ 112 , 113 ]. Anti-CD20 antibody and plasmapheresis have been reported to treat recurrent BSEP deficiency [ 114 ]. The outcomes in BSEP defects of common European mutations, such as D482G, are better than those of other mutation types [ 85 ]. In addition, patients with multi-organ manifestations, such as diarrhea and pancreatic insufficiency in PFIC1, cannot be treated by liver transplantation.

Liver tumor surveillance

The disruption of bile acid transport not only causes PFIC but has also been associated with hepatocellular carcinoma and cholangiocarcinoma [ 115 , 116 ]. Patients with BSEP deficiency and tyrosinemia are of greater risk of developing hepatocellular carcinoma (HCC). It is mandatory that patients with PFIC be screened for liver tumors on a regular basis. Alpha-fetoprotein is not typically elevated. Some patients were found to have HCC in the explanted liver. Thirty-eight out of 175 pediatric HCC patients receiving liver transplantation were diagnosed with inherited liver diseases [ 117 ].

Hepatocyte transplantation and gene therapy

Liver transplantation is often an ultimate option for patients with severe cholestasis, but the rarity of organ sources is an important issue. Hepatocyte transplantation might be an alternative therapy to use efficiently donor tissue in a less invasive manner. Cell therapy has been investigated in animal models with various extents of hepatocyte repopulation, including models of PFIC3 ( Mdr2 knockout mice), PFIC2 ( Abcb11 knockout mice) and hereditary tyrosinemia [ 118 , 119 , 120 ]. In previous studies, we found that UDCA can provide a selective growth advantage to donor hepatocytes in Abcb11 knockout mice and enhance the repopulation of donor hepatocytes and partially correct the bile acid profile [ 92 ]. However, insufficient long-term substitution ratio of donor hepatocyte in the livers of recipients, and the lack of donor cell sources limits the wide application of UDCA to treat clinical patients. For the past two decades, more than 20 patients with inherited liver-based metabolic disorders have received hepatocyte transplantation. Most of these patients showed only partial and transient improvements in metabolic function for several months and finally underwent liver transplantation [ 121 , 122 , 123 ]. Among these individuals, two patients with PFIC2 showed no obvious benefits after hepatocyte transplantation, as the existing fibrosis impaired the engraftment of the transplanted hepatocytes [ 122 ]. Recently, glyceryl trinitrate have been shown to enhance the efficacy of the transplanted hepatocyte repopulation in Mdr2 knockout mice [ 124 ]. With additional treatment to boost donor cell repopulation, hepatocyte transplantation might be refined and benefit patients with cholestasis.

Few studies on experimental gene therapy for cholestatic liver diseases have been reported. The adenoviral transfer of the aquaporin-1 gene has been shown to improve bile flow in rats with estrogen-induced cholestasis, but the effect in inherited cholestatic disease has not been validated [ 125 ].

Conclusions

With the revolutionary development of genetic analysis technologies, we have largely elucidated the molecular mechanisms of jaundice, bile flow and bile metabolism and identified new causes of genetic liver diseases that cause cholestasis. The understanding of “bile biology” not only provides insights into the mechanisms of liver pathophysiology but also facilitates the diagnosis of genetic liver diseases and the development of novel treatments.

Abbreviations

4-phenylbutyrate

Alpha 1-antitrypsin

ATP-binding cassette

Alpha-fetoprotein

Apical sodium dependent bile acid transporter

Bile salt export pump

Cholic acid

Chenodeoxycholic acid

Cytochrome P450

Deoxycholic acid

Doublecortin domain containing 2

fibroblast growth factor receptor 4

farnesoid X receptor

Glyco- or tauro-cholic acid

Glyco- or tauro-chenodeoxy cholic acid

Gamma glutamyl transpeptidase

Hepatocellular carcinoma

Inborn error of bile acid metabolism

Lithocholic acid

Multidrug resistance protein 2/3

Multidrug resistance-associated protein 2/3/4

Nonalcoholic steatohepatitis

Neonatal hepatitis

Neonatal cholestasis caused by citrin deficiency

Sodium/taurocholate co-transporting polypeptide

Organic-anion-transporting polypeptide 1B1 and 1B3

Organic solute transporter-α/β

Phosphatidylcholine

• Progressive familial intrahepatic cholestasis

Phosphatidylserine

Retinoid X receptor α

Serpin family A member 1

Small heterodimer partner

Mitochondrial transcription factor A

Takeda G protein-coupled receptor 5 (G protein-coupled bile acid receptor 1 , GPBAR1)

Tight junction protein 2

Ursodeoxycholic acid

UDP-glucuronosyltransferase 1A1

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The authors’ work is supported by grants from Ministry of Science and Technology, Taiwan (MOST105–2314-B-002-132-MY3).

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Hepatitis Research Center, National Taiwan University Hospital, Changde St. No.1, Zhongzhen Dist., Taipei 100, Taiwan

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Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, No. 7 Chung Shan S. Rd, Taipei 100, Taiwan

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Chen, HL., Wu, SH., Hsu, SH. et al. Jaundice revisited: recent advances in the diagnosis and treatment of inherited cholestatic liver diseases. J Biomed Sci 25 , 75 (2018). https://doi.org/10.1186/s12929-018-0475-8

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25114 Jaundice

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The metabolism of bilirubin in humans is summarized in Figure 14.1 and can be divided into three sequential steps: 1 Production of unconjugated bilirubin. Red blood cells are broken down by macrophages (mainly in the spleen), which degrade haemoglobin into iron and unconjugated (water insoluble) bilirubin. The iron is stored inside transferrin proteins. Unconjugated bilirubin travels to the liver bound to albumin. In disease, unconjugated bilirubin can be produced by haemolysis of red cells intravascularly, rather than in the spleen. 2 Conjugation of bilirubin. Liver hepatocytes uptake unconjugated bilirubin and conjugate it to glucuronate, thus making water soluble, conjugated bilirubin. 3 Excretion of bilirubin. Once conjugated, bilirubin is secreted into the bile canaliculi. Conjugated bilirubin flows with bile down the bile ducts and into the duodenum. Inside the bowel, conjugated bilirubin is metabolized by bacteria into colourless products (urobilinogen, stercobilinogen). Some of these can be reabsorbed by the gut and excreted via the kidneys, but the vast majority are oxidized in the gut into coloured pigments (urobilin, stercobilin) which give faeces their brown colour. Consequently, if there is complete obstruction of the bile ducts there will be no flow of conjugated bilirubin into the gut, no conversion into urobilinogen, and therefore not even a trace of urobilinogen in the urine. The terminology is confusing because different people mean different things. If you are going to use this terminology, make sure that you and your colleagues agree on the definitions. Nonetheless, this is what people usually mean: • Prehepatic jaundice: this refers to jaundice caused by an excessive production of bilirubin. Remember that bilirubin is produced by the breakdown of haemoglobin in the blood vessels or the spleen, hence the term prehepatic. • Hepatic jaundice: for some people, this means any jaundice due to pathology in the liver (anatomically), such as points 3, 4, and 5 in Figure 14.1, and can thus include problems with hepatocytes (e.g. hepatitis) or with the bile canaliculi (e.g. primary sclerosing cholangitis, PSC).

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Introduction

Bilirubin metabolism and pathophysiology of jaundice, medical history, physical examination, laboratory analysis in assessment of jaundice, liver biopsy and transient elastography, unconjugated hyperbilirubinemia, mixed hyperbilirubinemia, conjugated hyperbilirubinemia, pseudojaundice, conflict of interest statement, funding sources, author contributions, jaundice as a diagnostic and therapeutic problem: a general practitioner’s approach.

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Aleksandra Pavlovic Markovic , Milica Stojkovic Lalosevic , Dragana Danilo Mijac , Tamara Milovanovic , Sanja Dragasevic , Aleksandra Sokic Milutinovic , Miodrag N. Krstic; Jaundice as a Diagnostic and Therapeutic Problem: A General Practitioner’s Approach. Dig Dis 10 May 2022; 40 (3): 362–369. https://doi.org/10.1159/000517301

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Background: Jaundice is a common clinical finding in clinical practice of hepatologists and general practitioners. It occurs when serum bilirubin levels exceed 3 mg/dL. Summary: In this review, we summarize the pathophysiological mechanism of jaundice, clinical approach to the patient with jaundice, and laboratory and imaging techniques. Clinical presentation of jaundice manifests through yellow skin and sclera coloration. Evaluation of every patient includes detailed medical history and examination. In the laboratory, evaluation of enzymes of hepatic inflammation as well as cholestatic enzymes with serum bilirubin must be included. Additional laboratory analysis and imaging modalities are needed in order to differentiate jaundice etiology. Moreover, imaging is available and needed in further evaluation, and treatment is dependent on the underlying cause. Key Messages: In this review, we will outline the pathophysiological mechanism of jaundice, clinical approach to the patient with jaundice, and diagnostic and treatment approach to these patients.

Jaundice is a clinical manifestation of elevated serum bilirubin. Accumulation of elevated serum bilirubin leads to yellow discoloration of the skin, sclera, and other mucous membranes known as jaundice or icterus. When serum bilirubin level exceeds 3 mg per dL, jaundice becomes clinically apparent. From general practitioners’ (GPs’) point of view, timely and adequate assessment of the patient with jaundice is of great importance [1]. A general approach to the patient with jaundice should include detailed medical history, careful clinical examination, and appropriate laboratory and imaging techniques (Fig.  1 ) [2]. Epidemiology data suggest that incidence of jaundice varies depending on the underlying cause, and it is more common in certain age groups. Namely, jaundice affects approximately 6 out of 10 otherwise healthy newborns, mainly due to immature hepatic conjugation and uptake [3]. Jaundice due to alcoholic liver disease, as well as nonalcoholic liver disease, is more common in men, while primary biliary cholangitis as an underlying cause of jaundice is dominantly seen in women [4]. In this review article, we aim to provide a systematic approach to the patient with jaundice, especially in terms of diagnosis and therapy.

Approach to the patient with jaundice. AST, aspartate aminotransferase; ALP, alkaline phosphatase; US, ultrasound.

Degradation of heme is responsible for bilirubin formation. The majority of hem derives from hemoglobin of erythrocytes, whereas small parts originate from ineffective erythropoiesis and degradation of other hem-containing proteins such as myoglobin, catalases, and cytochrome P450 isoenzymes [5]. Bilirubin formation is a 2-phase process, where in the first phase, heme transforms to biliverdin, and in the second phase through reductase, biliverdin is transformed to unconjugated bilirubin [6]. Unconjugated bilirubin is water insoluble and as such is transported with albumin to the liver, where conjugation occurs. The process of conjugation in the liver is intermediated by uridine diphosphate (UDP)-glucuronyltransferases. Conjugated bilirubin from liver cells is transferred to the biliary system and through bile it enters the intestines. Intestinal cells predominantly absorb conjugated bilirubin, which is later evacuated via urine as urobilinogen, while unabsorbed part is evacuated through stool as stercobilinogen. Elevation of unconjugated or conjugated bilirubin as a result of an alteration of bilirubin metabolism leads to jaundice [7]. Bearing in mind the pathophysiological mechanism of bilirubin, etiology of jaundice could be divided into prehepatic, hepatic, and posthepatic causes (Table  1 ).

Differential diagnosis of jaundice

Prehepatic jaundice occurs earlier than bilirubin enters the hepatocytes, and it is caused by increased bilirubin production or may be the result of interference of hepatocyte uptake by certain medications. A wide range of extrahepatic disorders may be the underlying cause of prehepatic jaundice such as hemolysis, ineffective erythropoiesis, blood transfusions, or hematoma absorption [8]. Hemolysis may be inborn or acquired, with a wide range of defect mechanisms such as atypical structure of hemoglobin, defects of erythrocyte membrane or enzymes, immune or mechanical deterioration of erythrocytes, or hypersplenism [9]. Additionally, hemolysis develops due to extravascular or intravascular degradation of erythrocytes. Drugs which may interfere with hepatocyte bilirubin uptake and further contribute to prehepatic jaundice are antivirals, antibiotics, and immunosuppressives [ 10 ].

Hepatic causes leading to hyperbilirubinemia are multiple. Several disorders of hepatocyte enzymatic activity have influence on conjugation processes, with the Gilbert syndrome as the most common in general population [ 11 ]. The affected gene in this benign condition is UGTA1 with a metabolic defect of decreased bilirubin conjugation. Interestingly, different mutations of the same gene UGTA1 lead to development of the very rare Crigler-Najjar syndrome, with severely decreased bilirubin conjugation in type II or even complete absence of conjugation in type I [ 12 ]. Dubin Johnson syndrome and Rotor syndrome are benign familiar metabolic defects, autosomally recessive inherited, characterized by impaired export of conjugated bilirubin [ 13 ]. Different liver diseases are accompanied by hyperbilirubinemia and jaundice with additional impairment of other liver function tests. Hepatocellular injury and cholestatic disorders are commonly seen in patients with various liver disorders. Conditions that manifest in acute or chronic hepatocellular dysfunction are viral hepatitis, autoimmune liver disease, metabolic liver diseases, toxic liver injury, or ischemic hepatitis. Additionally, intrahepatic cholestatic disorders include infiltrative diseases, primary biliary cholangitis, familial disorders, and certain drugs.

The etiopathogenesis of posthepatic jaundice is obstruction of biliary drainage. Posthepatic jaundice may be caused by bile duct obstruction due to choledocholithiasis, diseases of the bile duct including infectious, inflammatory, and malignant diseases, or compression outside the bile duct [ 14 ].

When approaching the patient with jaundice, detailed medical history is needed. Association with other symptoms can be extremely helpful in establishing the differential diagnosis of jaundice (Table  2 ). Namely, associated fever could indicate the presence of viral hepatitis but also could point to parasitic or bacterial infections [ 15 ]. Furthermore, if the patient is reporting symptoms such as loss of appetite, malaise, and muscle aches, clinical suspicion on viral hepatitis is on the rise. Additionally, thorough history of eventual risk factors for viral hepatitis is very useful in diagnosis establishment. Moreover, nausea and vomiting preceding jaundice may also suggest viral hepatitis or acute gallstone biliary obstruction, whereas prolongation of these symptoms may suggest chronic hepatitis or biliary obstruction. Also, if the chills are present alongside with fever, it could indicate possible biliary obstruction. Significant weight loss as well as loss of appetite could be a sign of underlying malignancy. Pruritus could be a manifestation of biliary obstruction or if the case of long lasting pruritus, primary biliary cholangitis [ 16 ]. In the medical history of jaundice patients, data regarding onset of the symptoms could also imply etiology of jaundice. Namely, abrupt onset may suggest hepatitis and infectious or drug-related disorder, while jaundice slowly appearing in weeks might indicate chronic hepatitis or some kind of obstruction of biliary drainage. Moreover, previous episodes of jaundice are characteristic for liver cirrhosis or familiar disorder of bilirubin metabolism. Data regarding the potential use of alcohol or drugs should be noted, as well as previous surgeries or other illnesses. Family history is needed in order to evaluate possible inborn and familial conditions.

Symptoms and signs associated with liver disease and biliary obstruction

In the majority of the patients with viral hepatitis, jaundice is painless, where in some cases, patients report dull pain in the right hemiabdomen, while pain in upper quadrants of the abdomen with irradiation to upper right parts of the thorax may suggest gallstone disease [ 17 ]. Heavy pain in the upper abdomen with irradiation to the back might be a sign of pancreatitis.

Physical examination of the patient with jaundice reveals yellow coloration of the skin and sclera and other tissues. If the patient is conscious, well oriented, and without any neurological disturbances, it may be assumed that cause of jaundice is probably not hepatocellular injury, and additional investigation may be oriented to obstruction. Further examination of the skin may show hematomas, which could solely be the underlying cause of jaundice or point to defects in the coagulation cascade. If the cause of the jaundice is chronic liver disorder, physical examination may be useful in detecting spider naevi, palmar erythema, Dupuytren contractures, hepatomegaly, splenomegaly, or ascites. Spider naevi are usually seen on the upper parts of the body, thorax, neck, arms, and face. Palmar erythema and Dupuytren contractures are usually seen on hands, where in Dupuytren, one or more fingers is permanently in a flexion. Physical examination is very important to determine the size of the liver, bearing in mind that it is dependable on the height and weight of the patient. Small liver, alongside with jaundice, may suggest liver failure due to various conditions, while enlarged liver may be seen in nonalcoholic liver disease, amyloidosis, and neoplasm. Furthermore, palpation of the abdomen may reveal enlarged tender gallbladder or tumors. Splenomegaly is commonly seen in patients with liver cirrhosis, due to portal hypertension, and also it may be seen in various hematological disorders, such as hemolytic disease. Ascites is a sign of decompensated cirrhosis or a portal vein occlusion. Sometimes in patients with primary biliary cholangitis, typical xanthomas or xanthelasmas may be seen on the skin and further contribute to diagnosis establishment. Detailed examination of all organ systems is necessary in every individual patient with jaundice.

Laboratory investigations are necessary in order to establish the etiology of jaundice, and they must include bilirubin with its fractions, aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), γ-glutamyltransferase (GGT), proteins, albumins, prothrombin time, and complete blood count as well as haptoglobin and lactate dehydrogenase (LDH) (Table  3 ). LDH elevation is commonly seen in patients with hemolysis; however, this enzyme is nonspecific. Namely, there are several LDH isoenzymes, of which LDH-1 is found dominantly in the red blood cells and heart, LDH-2 is found in the reticuloendothelial system, LDH-3 is seen in the lungs, while LDH-4 is commonly found in the kidneys and pancreas, and LDH-5 is found in the liver and muscle cells [ 18 ]. Additionally, LDH is a nonspecific parameter of various malignancies. Haptoglobin is a protein, synthesized by the liver, which binds to free hemoglobin to later be deposited in the reticuloendothelial system. In the condition of intravascular hemolysis, hemoglobin in circulation will bind to haptoglobin, which will reflect in its low levels. Like ferritin, haptoglobin is an acute phase reactant; hence, it could be elevated in various inflammatory conditions. Patients with hemolysis, aside low haptoglobin and elevated LDH, will have also changes in CBC and bilirubin fractions.

Laboratory analysis in patients with jaundice

Bilirubin fractions are needed in order to distinguish conjugated from unconjugated bilirubin, where conjugated bilirubin usually refers to hepatobiliary disease. Elevation of unconjugated bilirubin is a characteristic for hemolysis; however, it also may be seen in Gilbert syndrome and impaired hepatic function. In cases of mixed hyperbilirubinemia, both fractions are elevated, and it can be seen in patients with familial conditions or hepatitis.

Elevated AST and ALT may suggest hepatocellular inflammation and necrosis, bearing in mind that they are predominately found in the liver, although they could be found in the muscles and heart and in smaller part in the red blood cells, kidneys, and pancreas [ 19 ]. ALT is principally found in the liver, so in comparison with AST, it is more specific in determining liver inflammation.

Elevated levels of ALP and γ-GGT may suggest cholestasis. ALP is mostly found in liver cells, but can also be found in the bones and in lesser amount in the intestines, kidneys, and white blood cells. When the serum values are elevated, usually patients present with cholestasis, biliary obstruction due to neoplasm, or infiltrative process. When elevation is mild to moderate, except liver disorders, cause of elevation may be bone infiltrations, malignancies, other processes or diseases of bones such as osteomyelitis, and systemic infections and hematological diseases. Low levels of ALP are commonly seen in patients with Wilson disease. γ-GGT synthesis is widespread through the different organs and organ systems. It is predominantly synthesized in the liver and has a role in the processes of detoxification. Besides the liver, small amount may be found in the kidneys, lymphocytes, and lungs. Elevated levels may suggest hepatobiliary disease and also a drug-induced liver injury among other conditions and diseases [ 20 ]. Previous findings have suggested that γ-GGT levels may also predict metabolic syndrome as well as cardiovascular risks bearing in mind that γ-GGT has a role in cholesterol metabolism [ 21 ]. In the assessment of patients with jaundice, low levels of albumins and prolonged prothrombin time could point to hepatic insufficiency. Additionally, thrombocytopenia in complete blood count may suggest advanced liver disease with portal hypertension and hypersplenism [ 22 ].

Liver biopsy in the majority of European countries is performed only in specialized centers, bearing in mind its costs, invasiveness, and possible complications [ 23 ]. In patients with hepatocellular inflammation, liver biopsy is the preferred method for histological severity of liver damage. When focal masses are seen in the liver, biopsy is ultrasound (US) guided. In patients with disturbed coagulation status, liver biopsy could be performed through the transjugular route. In the last decades, liver biopsy has been replaced with the noninvasive method for the assessment of liver fibrosis – transient elastography [ 24 ]. Transient elastography is based on share wave velocity measurement, which is later converted to liver stiffness and is expressed in kilopascals. It is easy to perform, cost-effective in comparison with liver biopsy, complications have not been noted, and results are immediate and simple for interpretation. Moreover, it can be used in monitoring the patients on antiviral and other therapies [ 25 ].

From GP point of view, in the majority of European countries, the approach to various imaging methods is applicable. Namely, >70% of GPs had open access to various imaging methods including endoscopy [1]. Imaging methods are needed in every patient with jaundice. Different imaging methods may be useful in order to establish the underlying etiology of jaundice adequately. Abdominal US is the most frequently used imaging technique and usually the first method in assessment of jaundice patients, especially in the context of suspected biliary obstruction. It is a noninvasive, portable, safe, and inexpensive method. The limitations of the method are operator dependency and performance difficulties in obese or flatulent patients. Color Doppler ultrasonography is available in addition to ultrasonography as well as contrast-enhanced sonography, in providing additional information about portal hypertension and small neoplasms. CT with contrast is an everyday used technique in assessment of patients with suspected hepatobiliary-pancreatic disease. This method is operator independent; however, it is expensive and with ionizing radiation. Magnetic resonance may be useful in detection of focal liver lesions and differentiation of benign focal changes from carcinomas [ 26 ]. Magnetic resonance cholangiopancreatography (MRCP) has a significant role in detection of bile duct changes [ 27 ]. MRCP is superior in comparison with CT and US in investigation of the biliary tract. Also, MR can be performed in the same act as MRCP, which provides additional information. Endoscopic ultrasonography can also detect lesions in the biliary system with similar sensitivity as MRCP with possibility of potential biopsy of the suspected lesion; however, as any upper endoscopy, it has a mortality risk. Endoscopy is necessary when underlying diagnosis of jaundice is cirrhosis, in order to assess the presence of complications including esophageal and gastric varices [ 28 ].

The underlying cause of unconjugated hyperbilirubinemia could be due to increased bilirubin production, altered bilirubin uptake, or altered bilirubin conjugation [ 29 ]. Increased bilirubin production is usually unrelated to liver disorders and is seen in different hematological conditions, such as hemolysis or hematomas, blood transfusions, or pulmonary infarctions. Hemolysis develops due to destruction of red blood cells because of intrinsic or extrinsic causes, when the bone marrow is incapable of further compensation of the red blood cell loss. The most common cause of unconjugated hyperbilirubinemia is hemolysis, where usually values of serum bilirubin do not surpass >5 mg/dL. Additionally, laboratory analysis in these patients aside unconjugated hyperbilirubinemia shows anemia, reticulocytosis, elevated serum LDH, and low haptoglobin levels. A list of conditions or diseases with increased bilirubin production is shown in Table  2 . Altered bilirubin uptake by the liver may be due to heart failure, different shunts, or drugs. Drug-induced hyperbilirubinemia is usually self-resolving after drug discontinuation. Gilbert syndrome and Crigler-Najjar syndrome are conditions of inherited defect in bilirubin conjugation. UDP-glucuronosyltransferase mutations that lead to reduced enzymatic activity are responsible for Gilbert syndrome. Namely, Gilbert syndrome manifests as occasional episodes precipitated by fasting, stress, menstrual cycle, or other illness. This benign condition is very common in general population with the prevalence up to 7% [ 30 ]. Except for jaundice, patients appear without any other symptoms. Usually, there is a male preponderance due to generally lower synthesis of bilirubin in women. Bearing that in mind, Gilbert syndrome is frequently diagnosed in puberty due to higher concentration of sex steroid hormones. Diagnosis is made after the fasting test or the phenobarbitone test. Treatment is unnecessary due to benign characteristics of this condition. Crigler-Najjar is an autosomal recessive inherited disorder due to mutations in the gene for UDP-glucuronosyltransferase which results in decreased or absent enzyme activity. It is an extremely rare disease affecting 1 per 1 million worldwide. Two types have been identified, type 1 autosomal recessive disorder related with kernicterus and type 2 with still undefined type of inheritance, which respond to treatment with phenobarbitone [ 12 ].

Two autosomally inherited syndromes Dubin Johnson syndrome and Rotor syndrome are benign familiar metabolic defects that are characterized by impaired export of conjugated bilirubin. Different molecular defects are responsible for development of these 2 syndromes. In Dubin Johnson syndrome, defect is on the MRP2 that leads to damage in the process of bilirubin secretion, whereas in Rotor syndrome, defect is on the transport proteins OATPB1 and OATPB3. In the mid of the twentieth century, such condition, Rotor syndrome, was firstly described. Rotor syndrome is an autosomal recessive benign condition characterized by conjugated hyperbilirubinemia with good prognosis and no need for treatment [ 30 ]. In the majority of adult patients with conjugated hyperbilirubinemia, there is either hepatocellular or cholestatic damage. Liver biopsy is not necessary in confirming these syndromes, bearing in mind that neither leads to progressive liver impairment.

Commonly, viral hepatitis may be the cause of conjugated hyperbilirubinemia with hepatocellular inflammation. That further emphasizes the need for additional serologic tests, imaging methods, and eventually even a liver biopsy in order to establish a definite diagnosis. In differential diagnosis of conjugated hyperbilirubinemia with hepatocellular inflammation, we must include autoimmune, metabolic, inherited, alcoholic, and drug-related liver injuries (Table  3 ). Intrahepatic cholestasis with conjugated hyperbilirubinemia may suggest primary biliary cholangitis, primary sclerosing cholangitis, veno-occlusive disease, and graft versus host disease. Additionally, infiltrative diseases such as granulomatous diseases or malignancy may be the cause of intrahepatic cholestasis [ 31 ]. Also, many drugs may affect bilirubin biliary secretion [ 32 ]. Extrahepatic obstruction remains still one of the frequent causes of cholestasis, and bearing that in mind, imaging modalities such as EUS, ERCP, and MRCP are extremely useful in diagnosis establishment [ 33 ]. Choledocholithiasis is one of the most common causes of jaundice worldwide. Jaundice occurs when bile stone blocks the common bile duct (CBD), and bilirubin excess enters the circulation. Occurrence of gallstone in general population goes up to 15% [ 34 ]. Factors involved in the gallstone formation in CBD include bile stasis, bacteria, imbalance in pH, and others. Typical symptoms of patients with CBD obstruction include light-colored stool, dark urine, and pain in the abdomen, and if the patient has fever and altered mental status, we may conclude that the patient has Charcot triad or Reynolds pentad. In much lesser percent, obstruction of the CBD may be precipitated by biliary strictures after cholecystectomy, or jaundice may be caused by some surgical procedures with formation of choledochojejunal anastomosis. Malignancies additionally may be the cause of obstructive icterus. A list of the causes that are related to extrahepatic obstruction is shown in Table  1 .

Patients may have skin discoloration similar to jaundice in various medical conditions such as Addison disease or due to skin tanning lotions or other skin-coloring agents. Pseudojaundice is commonly seen in individuals or infants consuming carotene-rich foods. Carotene is a molecule that gives yellow color to the skin. In order to distinguish pseudojaundice from jaundice, careful clinical examination is needed, since pseudojaundice does not affect the sclera. Furthermore, serum bilirubin levels in this condition are within the reference range. There have been cases of pseudojaundice due to side effects of certain drugs, such as rifabutin [ 35 ].

Treatment is fully dependent on the cause. In the management of clinical disorders across Europe, there are significant differences among countries [1]. Namely, treatment of pseudojaundice in cases of skin-coloring agents is not necessary. Treatment of prehepatic cause of jaundice is actually a treatment of the underlying disease. In the majority of previously described syndromes such as Gilbert syndrome, Rotor syndrome, and Dubin Johnson syndrome, treatment is not necessary. In cases of liver dysfunction, treatment of liver disease will affect bilirubin levels. Namely, in the cases of alcoholic hepatitis, treatment will firstly be directed to cessation of alcohol usage. In the cases of drug-induced hepatitis, treatment will firstly focus on withdrawal of the suspected drug. For viral hepatitis, nowadays, antivirals are the method of choice. In primary biliary cholangitis, treatment of choice remains UDCA. In patients with end-stage liver disease, liver transplantation is the only method of choice.

In patients with obstructive jaundice, endoscopic procedures as well as surgery remain the backbone of the therapy. Namely, the goal is to remove or relieve the obstruction, and ERCP is one of the preferred methods. This method relies on sphincterotomy, balloon dilatation, and stent placement. One of the life-threatening complications of this method is pancreatitis. In cases of malignant obstruction, surgery remains the method of choice.

In every patient with suspected jaundice, detailed clinical, laboratory, and imaging examinations are needed in order to establish the etiology and accordingly determine the adequate treatment. Detailed history and physical examination will at the very beginning give sufficient clinical suspicion and further direct laboratory and imaging modalities. Laboratory investigation will provide additional information if the jaundice is due to disorder of bilirubin metabolism, liver disease, or biliary obstruction. Imaging modalities will be especially significant in suspicion on hepatobiliary obstruction, so further treatment can adequately be performed.

The authors have no conflicts of interest to declare.

We declare that no funding has been received related to the manuscript.

Pavlovic Markovic A. and Stojkovic Lalosevic M. wrote the manuscript; Mijac D.D. and Dragasevic S. were included in the literature review and contributed to manuscript drafting; Sokic Milutinovic A., Pavlovic Markovic A., and Stojkovic Lalosevic M. contributed to study conception and design; Milovanovic T. and Krstic M. contributed to the review of the literature and final draft of the manuscript and were responsible for the revision of the manuscript for important intellectual content; all authors issued final approval for the version to be submitted.

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Last updated: October 25, 2022 Revisions: 26

• 1.1.1 Types of Jaundice
• 1.2 Bilirubinuria
• 2.1.1 Liver Screen
• 2.2 Imaging
• 3 Management
• 4 Key Points

Introduction

Jaundice refers to the yellow discolouration of the sclera and skin (Fig. 1) that is due to hyperbilirubinaemia , occurring at bilirubin levels roughly greater than 50 µmol/L.  

Figure 1 – Yellowing of the sclera

Pathophysiology

Jaundice results from high levels of bilirubin in the blood. Bilirubin is the normal breakdown product from the catabolism of haem , and thus is formed from the destruction of red blood cells.

Under normal circumstances, bilirubin undergoes conjugation within the liver , making it water-soluble. It is then excreted via the bile into the GI tract, the majority of which is egested in the faeces as urobilinogen and stercobilin (the metabolic breakdown product of urobilingoen). Around 10% of urobilinogen is reabsorbed into the bloodstream and excreted through the kidneys. Jaundice occurs when this pathway is disrupted .

Figure 2 – Bilirubin is produced as a byproduct of haem metabolism

Types of Jaundice

There are three main types of jaundice: pre-hepatic, hepatocellular, and post-hepatic.

Pre-Hepatic

In pre-hepatic jaundice, there is excessive red cell breakdown  which overwhelms the liver’s ability to conjugate bilirubin. This causes an unconjugated hyperbilirubinaemia.

Any bilirubin that manages to become conjugated will be excreted normally, yet it is the unconjugated bilirubin that remains in the blood stream to cause the jaundice.

Hepatocellular

In hepatocellular (or intrahepatic) jaundice, there is dysfunction of the hepatic cells . The liver loses the ability to conjugate bilirubin, but in cases where it also may become cirrhotic, it compresses the intra-hepatic portions of the biliary tree to cause a degree of obstruction.

This leads to both unconjugated and conjugated bilirubin in the blood, termed a ‘mixed picture’.

Post-Hepatic

Post-hepatic jaundice refers to obstruction of biliary drainage . The bilirubin that is not excreted will have been conjugated by the liver, hence the result is a conjugated hyperbilirubinaemia.

Table 1 – Potential Causes for Jaundice, divided into pre-hepatic, hepatocellular, and post-hepatic

Bilirubinuria

A good estimation of which type of jaundice is present (prior to any further investigation) can be made from observing the colour of the urine.

Conjugated bilirubin can be excreted via the urine (as it is water soluble), whereas unconjugated cannot. Consequently, dark (‘coca-cola’) urine manifests in conjugated or mixed hyperbilirubinaemias, whereas normal urine is seen in unconjugated disease.

Moreover, those with an obstructive picture will likely note pale stools, due to the reduced levels of stercobilin entering the GI tract, which normally colours the stool.

Investigations

In many cases, the likely underlying cause can be elicited from the history , with the investigations simply confirming suspicions. Hence, whilst a complete list of investigations is given below, these should be tailored to the clinical features of the patient.

Laboratory Tests

Any patient presenting with jaundice should have the following bloods taken:

• Liver function tests (LFTs), as summarised in Table 2
• Coagulation studies (PT can be used as a marker of liver synthesis function)
• FBC (anaemia, raised MCV, and thrombocytopenia all seen in liver disease) and U&Es
• Specialist blood tests , as summarised below as part of a liver screen

Table 2 – LFT serum markers. *as an estimate, if the AST:ALT ratio >2, this is likely alcoholic liver disease, whilst if AST:ALT is around 1, then likely viral hepatitis as the cause

Liver Screen

A liver screen can be performed for patients whereby there is no initial cause for liver dysfunction , tailored to whether acute or chronic liver failure

Table 3 – Acute and Chronic Liver Screens *Autoantibodies include anti-mitochondrial antibody (AMA), anti-smooth-muscle antibody (Anti-SMA), and anti-nuclear antibody (ANA), used to identify a variety of autoimmune liver conditions, such as primary sclerosing cholangitis (PSC)

The imaging used will depend on the presumed aetiology. An  u ltrasound abdomen is usually first line, identifying any obstructive pathology present or gross liver pathology (albeit often user dependent).

Magnetic Resonance Cholangiopancreatography (MRCP) is used to visual the biliary tree, typically performed if the jaundice is obstructive , but US abdomen was inconclusive or limited, or as further work-up for surgical intervention.

A liver biopsy can be performed when the diagnosis has not been made despite the above investigations.

The definitive treatment of jaundice will be dependent on the underlying cause . Obstructive causes may require removal of a gallstone through Endoscopic Retrograde CholangioPancreatography (ERCP) or stenting of the common bile duct.

Symptomatic treatment is often needed for the itching caused by hyperbilirubinaemia. An obstructive cause may warrant cholestyramine (acting to increase biliary drainage), whilst other causes may respond to simple anti-histamines.

Identify and manage any complications where possible. Monitor for  coagulopathy , treating promptly (either vitamin K or fresh frozen plasma (FFP) is needed) if any evidence of bleeding or rapid coagulopathy, and treat hypoglycaemia orally if possible (otherwise 5% dextrose is needed).

Where patients become confused from decompensating chronic liver disease (‘hepatic encephalopathy’), laxatives (lactulose or senna) +/- neomycin or rifaximin may be used, in attempt to reduce the number of ammonia-producing bacteria in the bowel.

Figure 3 – Images from a laparoscopic cholecystectomy

• Jaundice refers to the yellow discolouration of the sclera and skin that is due to hyperbilirubinaemia
• Causes can be broken down into pre-hepatic, hepatocellular, and post-hepatic
• Most cases will warrant initial blood tests and ultrasound imaging, however this should be tailored to the clinical presentation
• Definitive treatment of jaundice will be dependent on the underlying cause
• Ensure to monitor for complications, such as coagulopathy, encephalopathy, or infective sequelae

This leads to both unconjugated and conjugated bilirubin in the blood, termed a ‘mixed picture'.

[start-clinical]

[end-clinical]

Table 3 - Acute and Chronic Liver Screens *Autoantibodies include anti-mitochondrial antibody (AMA), anti-smooth-muscle antibody (Anti-SMA), and anti-nuclear antibody (ANA), used to identify a variety of autoimmune liver conditions, such as primary sclerosing cholangitis (PSC)

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Jaundice: What's the Diagnosis?

Disclosures.

Retired GP and former Royal College of General Practitioners/British Liver Trust Champion for Liver Disease

Dr Jez Thompson Uses Case Studies to Explore Possible Causes of Jaundice and How They Should Be Diagnosed and Managed in Primary Care

Jaundice, derived from the French word for yellow, jaune , can be a patient’s presenting symptom or a clinical sign identified by a clinician. It describes a yellow or sometimes greenish-yellow pigmentation of the skin, conjunctiva, and mucous membranes that is caused by raised plasma bilirubin. 1 Jaundice usually becomes clinically apparent when a patient’s serum bilirubin concentration reaches 40–50 micromol/l. 2

Jaundice can present at any age. It can be caused by a wide range of disorders that includes benign conditions, those that can result in permanent and irreversible liver damage, and those that are rapidly life threatening. 1 Jaundice is the result of dysfunction in the bilirubin metabolism pathway, and its causes can be categorised as pre-hepatic (for example, excessive breakdown of red blood cells), intra-hepatic (for example, disease-related perturbation of liver function or intrahepatic anatomy), or post-hepatic (for example, obstruction of the bile ducts). 1,2

Some of the common causes of jaundice in adults are summarised in Box 1. 3

In the neonatal period, more than half of healthy full-term babies develop jaundice as part of normal physiological processes 4,5 and, in 2–15% of births, jaundice persists beyond 14 days. 6 Outside the neonatal period, the incidence of jaundice has not been established; however, one prospective study looking at clinically overt jaundice (a serum bilirubin level in excess of 120 micromol/l) in Wales found an annual incidence of 56 cases per 100,000 people, approximating to one patient presenting with visible jaundice each year for a typical UK GP. 7  

The challenge for the clinician is to establish the cause of jaundice and, as part of this, decide whether jaundice represents a benign and self-limiting condition or a serious underlying illness. Through the following case studies, this article aims to explore some common and important conditions that can present with jaundice, provide suggestions for first-line investigations and management in primary care, and offer guidance on when to consider specialist referral or admission.

A previously well man in his early 20s presents with a 1-week history of progressive fatigue, nausea, anorexia, low-grade fever, and flu-like symptoms followed by a 1-day history of yellowing of his eyes and skin. He has experienced no abdominal pain or itching, but admits to paler stools than usual and dark urine over the preceding 24 hours. 

The patient has reported no previous episodes of jaundice, and has no relevant medical history. Abdominal and general examinations are normal, apart from the presence of jaundice and a mild fever of 37.9°C. The patient is fully alert, and shows no signs of serious systemic illness. There are no red flags for a serious underlying condition.

The patient’s clinical presentation is suggestive of acute hepatitis. Differential diagnoses for hepatitis A are shown in Box 2. 8

Further history taking with this patient established that, 3 weeks previously, he returned from a 2-week holiday in a nonmalarial area in the Far East, where he got a tattoo. The patient drinks within recommended limits and, apart from smoking cannabis as a teenager, has not used illicit drugs and is a ‘never injector’. He has not taken any medications or remedies recently and has been abstinent from sex for the preceding 3 months, including while on holiday. He works in an office.

The patient underwent blood tests and, because there were no clinical features to suggest severe illness, was managed without specialist referral while waiting for the results. When the results returned, full blood count and urea and electrolytes were normal. Liver function tests (LFTs) showed a markedly raised alanine aminotransferase (ALT; 1012 IU/l) level and a significantly raised serum bilirubin concentration (82 micromol/l). Alkaline phosphatase (ALP) was only mildly raised, at around 1.5 times the upper end of the reference range. Prothrombin time and albumin level were normal. These results are consistent with a diagnosis of hepatitis with normal liver synthetic function. 9

Because of the patient’s history of recent foreign travel and tattooing, serology testing was arranged for hepatitis A, B, and C, and HIV. Initial hepatitis B and C and HIV serology test results were negative, but hepatitis A serology tests yielded positive results for both hepatitis A virus immunoglobulin (Ig) M and IgG. A likely clinical diagnosis of acute hepatitis A infection was made and, in the absence of complications or signs of severe illness, it was decided that the patient should be managed in primary care. 

There is no specific treatment for hepatitis A, as it is generally a self-limiting condition; unless hospital admission is needed, treatment focuses on supportive symptomatic care. 10 The patient was advised that he would likely feel more tired than normal, perhaps for several months, and that he should rest and stay hydrated. He was directed to take simple analgesia as required, and to avoid fatty foods and eat small, regular meals and snacks to help reduce nausea. He was also advised to avoid drinking alcohol while acutely unwell, to stay off work while he was infectious (typically 7 days after the onset of jaundice, or 7 days after the onset of symptoms if there is no history of jaundice), and to use hygiene measures to reduce the risk of transmission to partners and contacts (see Box 3). 10

The patient was ‘safety netted’ for worsening of any symptoms, and weekly telephone follow up was arranged while he was symptomatic. Repeat liver tests were booked at 4 weeks and, because of the ‘seroconversion window’ (the time after exposure during which an antibody response cannot be detected by routine testing methods), arrangements were made to recheck serology for hepatitis B at 6 months, hepatitis C at 3 months, and HIV at 3 months after his tattoo. 11,12

The patient was made aware that his GP would seek specialist advice if LFTs became significantly worse (ALT levels greater than 2000 IU/l, bilirubin greater than 300 micromol/l, significantly abnormal prothrombin time), or if there were any other signs of deterioration of liver function.

Clinical Outcome

Follow-up calls showed that the patient made a fairly quick return to a symptom-free condition, and he went back to work after 2 weeks’ sick leave. 

ALT levels were normal after 4 weeks and liver monitoring was stopped, and other viral serology tests were normal when retested.

A mother brings her 3-week-old baby to the GP. His delivery was uncomplicated, and he took to breastfeeding well, gaining weight normally for the first 2 weeks. He became mildly jaundiced at 1 week old, but the mother was reassured by her health visitor that this was most likely physiological, and that it should resolve by the time the baby was 2 weeks old. However, by the time of presentation, the jaundice has deepened rather than lightened, and the baby has become irritable and lost some weight. 

When asked, the mother said that she noticed that his stools have been pale for the last few days, which is confirmed using a stool colour chart, but that she is unsure about any change in urine colour. Apart from jaundice, there are no specific findings on clinical examination and no enlarged liver or spleen, although the baby seems abnormally irritable and looks unwell.

Although jaundice in neonates is common and normal, especially in breast-fed babies, both early jaundice (within the first week of life) and prolonged jaundice (jaundice persisting beyond the first 14 days) may be indicators of an underlying medical condition. 5 In a child with prolonged jaundice, the clinician must always consider biliary atresia as a possible cause, and early diagnosis of this condition is crucial. 13 If it is diagnosed promptly and the baby has surgical treatment early, the response to surgery and outlook are greatly improved; 13 if surgery is delayed beyond 90 days after birth and the condition is untreated, it will typically progress to biliary cirrhosis with portal hypertension, end-stage liver disease, and death within the first 2 years of life. 14 In this case, pale stool colour is another red flag for biliary cirrhosis, as would be persistent yellow or dark urine. 15 A stool colour chart can be downloaded from childliverdisease.org/yellow-alert .

Because of his irritability and the fact that he appeared unwell, the baby was admitted to hospital for urgent investigations, which included measurement of conjugated and unconjugated bilirubin and abdominal ultrasound. 

The child’s conjugated bilirubin level was 29 micromol/l, ultrasound was consistent with biliary atresia and, after further investigation, he underwent an operative cholangiogram under general anaesthesia to establish the diagnosis. Biliary sclerosis was confirmed, and the cholangiogram was followed immediately by a Kasai procedure under the same anaesthetic to replace damaged bile ducts with a loop of the child’s intestine and restore bile drainage. 13,16

For more information on the care of babies with prolonged jaundice, see Box 4. 5

The child managed the surgery well and will be followed up long term in the hepatology clinic, as development of liver complications and cirrhosis at a later date remains a risk even when the Kasai procedure is performed early. 17

A GP processing the day’s pathology results spots a mildly raised bilirubin level of 28 micromol/l in the otherwise normal LFT panel of a 63-year-old man. Reviewing his notes, there had been two previous borderline or mildly elevated bilirubin readings with no other LFT abnormalities, and the tests had been filed as ‘satisfactory’ with no action taken. The patient has no history of liver disease, is a nondrinker, has no risk factors for viral hepatitis, and is taking a statin but no other medication.

The most likely cause of an isolated elevated bilirubin concentration (which may be visible or invisible to the naked eye) with otherwise normal LFT results is Gilbert’s syndrome. 9,18 This is an inherited disorder in which reduced activity of the enzyme glucuronyl transferase causes impaired bilirubin conjugation. 9 The condition affects 2–10% of the Caucasian population, and in most cases is inherited as an autosomal recessive condition (but may be dominant in some cases). 18 As Gilbert’s syndrome is not associated with liver disease or ill health, and may actually be associated with a survival benefit, those diagnosed with it can be fully reassured. 9,19

A full blood count was performed to exclude haemolytic anaemia, and LFTs repeated with measurement of conjugated and unconjugated bilirubin. 

The full blood count was normal, and the hyperbilirubinaemia was confirmed to be unconjugated. Gilbert’s syndrome was diagnosed, the patient was informed and reassured, and he was able to continue living life as normal with no further follow up.

A 72-year-old otherwise well woman presents with a 2-day history of upper abdominal pain, jaundice, vomiting, and fever. Before the presenting illness, she had been fit, well, and active for her age, and there are no red flags for malignant disease. She does, however, report a history of occasional grumbling ‘indigestion’ pain over the preceding 10 years.

Examination shows visible jaundice, marked right upper-quadrant tenderness, but no palpable liver or abdominal masses. She is pyrexial, with a temperature of 38.2°C, and looks dehydrated. The patient is admitted to hospital as an ‘acute abdomen’ with jaundice. 

Initial blood tests show a raised total white blood cell count (12.4 × 10 9 /l), with an excess of neutrophils, elevated C-reactive protein (8.3 mg/dl), raised total bilirubin (79 micromol/l), raised ALP (893 IU/l), and raised ALT (178 IU/l). 

Jaundice with predominantly raised ALP and only moderately raised ALT suggests a cholestatic or post-hepatic picture, in which the biliary tree external to the liver is blocked. 9 In adults, common causes of cholestatic jaundice comprise biliary obstruction by stones, strictures, and malignancy. Other causes include: 9

• primary biliary cholangitis
• primary sclerosing cholangitis
• hepatic congestion
• drug-induced liver injury.

In this case, presentation was acute, and urgent admission was indicated. In less acute presentations, liver screening blood tests and ultrasound may be appropriate initial investigations in primary care, but urgent referral is indicated whenever there is any suspicion of hepatic or biliary malignancy. 9

For this woman, urgent abdominal ultrasound demonstrated an atrophic gallbladder with stones, together with a large gallstone impacted in the common bile duct. The common and intrahepatic bile ducts were dilated. The hospital team proceeded to endoscopic retrograde cholangiopancreatography, and the stones were successfully removed. 

The patient made an excellent postoperative recovery, and was soon back home.

There is a wide range of potential causes to consider in both infants and adults who present with jaundice. This article considers just a few of the potential diagnoses. 

For the jaundiced patient, careful and detailed history taking and examination should always be performed to elicit any red-flag symptoms and identify risk factors for liver disease, including alcohol misuse. Some cases of jaundice can be managed safely in primary care. However, emergency admission should be considered if the patient is systemically unwell in conjunction with jaundice, and any patient with marked derangement of liver blood tests, evidence of liver synthetic failure such as reduced albumin or prolonged prothrombin time, or clinical symptoms suspicious of malignancy or other serious underlying condition should be urgently referred. 9 Nonurgent referral may be appropriate if there is diagnostic uncertainty. 9

In neonates, a referral for urgent medical review should be made for babies with suspected or obvious jaundice in the first 24 hours of life to exclude pathological causes of jaundice. 5 Babies with prolonged jaundice should be investigated in accordance with NICE guidance, and all babies with a conjugated bilirubin level greater than 25 micromol/l should be referred urgently to secondary care to assess for severe underlying liver disease. 5

A useful summary of further investigation pathways following abnormal LFTs in adults is shown in Figure 1. 9

Figure 1: British Society of Gastroenterology Response to Abnormal Liver Blood Tests Algorithm

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Continuing Education Activity

Jaundice, also known as hyperbilirubinemia, is defined as a yellow discoloration of the body tissue resulting from the accumulation of excess bilirubin. Deposition of bilirubin happens only when there is an excess of bilirubin, and this indicates increased production or impaired excretion. The normal serum levels of bilirubin are less than 1 milligram per deciliter (mg/dL). However, the clinical presentation of jaundice with peripheral yellowing of the eye sclera, also called scleral icterus, is best appreciated when serum bilirubin levels exceed 3 mg/dl. With further increase in serum bilirubin levels, the skin will progressively discolor ranging from lemon yellow to apple green, especially if the process is long-standing; the green color is due to biliverdin. This activity reviews the evaluation and differential diagnosis of jaundice and highlights the role of an interprofessional team in evaluating and improving care for patients with this condition.

Objectives:

• Describe the etiology and pathophysiology of jaundice.
• Outline the approach to performing a history and physical examination for patients with jaundice.
• Summarize the treatment and management options available for patients with jaundice.
• Explain the interprofessional team strategies for improving care coordination to advance the management of jaundice and improve outcomes.

Introduction

Jaundice, also known as hyperbilirubinemia, [1] is a yellow discoloration of the body tissue resulting from the accumulation of an excess of bilirubin. Deposition of bilirubin happens only when there is an excess of bilirubin, a sign of increased production or impaired excretion. The normal serum levels of bilirubin are less than 1mg/dl; however, the clinical presentation of jaundice as scleral icterus (peripheral yellowing of the eye sclera), is best appreciated only when the levels reach more than 3 mg/dl. Sclerae have a high affinity for bilirubin due to their high elastin content. [2] With further increase in serum bilirubin levels, the skin will progressively discolor ranging from lemon yellow to apple green, especially if the process is long-standing; the green color is due to biliverdin. [3]

Bilirubin has two components: unconjugated(indirect) and conjugated(direct), and hence elevation of any of these can result in jaundice. Icterus acts as an essential clinical indicator for liver disease, apart from various other insults. [4]

Yellowing of skin sparing the sclerae is indicative of carotenoderma which occurs in healthy individuals who consume excessive carotene-rich foods. [5]

CONJUGATED HYPERBILIRUBINEMIA [6]

  Defect of canalicular organic anion transport  [7]

• Dubin-Johnson syndrome

Defect of sinusoidal reuptake of conjugated bilirubin

• Rotor syndrome

Decreased intrahepatic excretion of bilirubin [8]

• Hepatocellular disease - Viral hepatitis A, B, D; alcoholic hepatitis; cirrhosis, nonalcoholic steatohepatitis, EBV, CMV, HSV, Wilson, autoimmune 
• Cholestatic liver disease-Primary biliary cholangitis, primary sclerosing cholangitis
• Infiltrative diseases (e.g., amyloidosis, lymphoma, sarcoidosis, tuberculosis)
• Sepsis and hypoperfusion states
• Total parenteral nutrition
• Drugs & Toxins - oral contraceptives, rifampin, probenecid, steroids, chlorpromazine, herbal medications (e.g., Jamaican bush tea, kava kava), arsenic
• Hepatic crisis in sickle cell disease

Extrahepatic cholestasis (biliary obstruction) [9]

• Choledocholithiasis
• Tumors (e.g., cholangiocarcinoma, head of pancreas cancer)
• Extrahepatic biliary atresia
• Acute and chronic pancreatitis
• Strictures 
• Parasitic infections (e.g., Ascaris lumbricoides, liver flukes)

  UNCONJUGATED HYPERBILIRUBINEMIA 

  Excess production of bilirubin

• Hemolytic anemias, extravasation of blood in tissues, dyserythropoiesis

Reduced hepatic uptake of bilirubin

• Gilbert syndrome  [10]

Impaired conjugation [11]

• Crigler–Najjar syndrome type 1 and 2
• Hyperthyroid

Epidemiology

The prevalence of jaundice differs among patient populations; newborns and elderly more commonly present with the disease. [12]

The causes of jaundice also vary with age, as mentioned above. Around 20 percent of term babies are found with jaundice in the first week of life, primarily due to immature hepatic conjugation process. [13] Congenital disorders, overproduction from hemolysis, defective bilirubin uptake, and defects in conjugation are also responsible for jaundice in infancy or childhood. Hepatitis A was found to be the most afflicting cause of jaundice among children. [14] [15] Bile duct stones, drug-induced liver disease, and malignant biliary obstruction occur in the elderly population.

Men have an increased prevalence of alcoholic and non-alcoholic cirrhosis, chronic hepatitis B, malignancy of pancreas, or sclerosing cholangitis. [16] In contrast, women demonstrate higher rates of gallbladder stones, primary biliary cirrhosis, and gallbladder cancer. [17]

Kernicterus or Bilirubin-induced neurologic dysfunction (BIND), a complication of severe jaundice is a very rare cause of death in neonates with a death rate of 0.28 deaths per one million live births. [18]

Pathophysiology

The pathophysiology of jaundice is best explained by dividing the metabolism of bilirubin into three phases: prehepatic, hepatic, and post-hepatic. [19] [4]

• Production - Bilirubin is the end product of heme, which is released by senescent or defective RBCs. In the reticuloendothelial cells of spleen, liver and bone marrow, heme released from the RBC undergoes a series of reactions to form the final product bilirubin:

 Heme-->Biliverdin-->Bilirubin (insoluble due to tight hydrogen bonding)

• Hepatocellular uptake - The bilirubin released from the reticuloendothelial system is in an unconjugated form (i.e., non-soluble) and gets transported to the hepatocytes bound to albumin which accomplishes solubility in blood. The albumin-bilirubin bond is broken, and the bilirubin alone is then taken into the hepatocytes through a carrier-membrane transport and bound to proteins in the cytosol to decrease the efflux of bilirubin back into the plasma.
• Conjugation of bilirubin - This unconjugated bilirubin then proceeds to the endoplasmic reticulum, where it undergoes conjugation to glucuronic acid resulting in the formation of conjugated bilirubin, which is soluble in the bile. This is rendered by the action of UDP-glucuronosyl transferase. 

POSTHEPATIC

• Bile secretion from hepatocytes - Conjugated bilirubin is now released into the bile canaliculi into the bile ducts, stored in the gallbladder, reaching the small bowel through the ampulla of Vater and finally enters the colon.
• Intestinal metabolism and Renal transport - The intestinal mucosa does not reabsorb conjugated bilirubin due to its hydrophilicity and large molecular size. The colonic bacteria deconjugate and metabolize bilirubin into urobilinogen’s, 80% of which gets excreted into the feces and stercobilin and the remaining (10 to 20%) undergoes enterohepatic circulation. Some of these urobilin’s are excreted through the kidneys imparting the yellow pigment of urine.

Dysfunction in prehepatic phase results in elevated serum levels of unconjugated bilirubin while insult in post hepatic phase marks elevated conjugated bilirubin. Hepatic phase impairment can elevate both unconjugated and conjugated bilirubin.

Increased urinary excretion of urobilinogen can be due to increased production of bilirubin, increased reabsorption of urobilinogen from the colon, or decreased hepatic clearance of urobilinogen.

Histopathology

There are four different patterns of intrahepatic cholestasis, namely [20] :

• Cytoplasmic cholestasis: fine yellow pigment (bile) filling the cytoplasm of hepatic cells.
• Canalicular cholestasis : Bile found in the canaliculi.
• Ductular cholestasis: Accumulation of bile in the periportal bile ductules of Hering. Ductular cholestasis is associated with severe obstruction and sepsis.
• Ductal cholestasis: Demonstrates the presence of bile casts in portal bile ducts.

The histopathological changes of excess bile appear to result from the detergent effect of retained bile acids.

Toxicokinetics

As mentioned earlier, the serum level of bilirubin is a balance between production and hepatic excretion. After reaching the colon, the bacteria metabolize it into urobilinogen. A vast majority of urobilinogen is converted in stercobilin and excreted in feces. About 10 to 20% of urobilin gets reabsorbed by the action of beta-glucuronidase in the brush border of the gut and facilitates enterohepatic circulation and re-excreted by the liver; less than 3mg/dl escapes the hepatic uptakes and filters into the urine. [4]

Owing to its lipid soluble nature, bilirubin may cross the blood-brain barrier and thus enter the brain. Its clearance from the brain is ensured by the presence of an enzyme on the inner mitochondrial membrane, which aids in the oxidation of bilirubin, thus protecting against its neurotoxic effects. The mechanism of toxicity is yet obscure, but bilirubin has a higher affinity to settle in glia and neurons.

However, in newborns, since the blood-brain barrier is yet to develop, pathological increase in serum levels of bilirubin can result in death in the neonatal period or survival with disastrous neurological sequalae called kernicterus. Also, newborns are at increased risk due to lack of colonic bacteria resulting in deconjugation and enterohepatic reabsorption by b-glucuronidase enzymes resulting in hyperbilirubinemia. [21]

History and Physical

Patients usually present with varying symptoms apart from yellowish discoloration of skin along with pruritus, thus providing clues to narrow down the etiology or can also be asymptomatic. A thorough questioning regarding the use of drugs, alcohol or other toxic substances, risk factors for hepatitis (travel, unsafe sexual practices), HIV status, personal or family history of any inherited disorders or hemolytic disorders is vital. Other important points include the duration of jaundice; and the presence of any coexisting signs and symptoms, like a joint ache, rash, myalgia, changes in urine and stool. [22] A history of arthralgias and myalgias before yellowing indicates hepatitis, either due to drugs or viral infections.

Further, fever, chills, severe right-upper-quadrant-abdominal pain as seen in cholangitis and anorexia, malaise as seen in hepatitis and significant weight loss suggesting malignancy obstructing the bile ducts provide additional information for diagnosis. Additionally, a patient with a history of ulcerative colitis may present with hyperbilirubinemia due to PSC.

Physical examination begins by evaluation of body habitus and nutritional status. Temporal and proximal muscle wasting suggests malignancy or cirrhosis. [23] It is worth reviewing the well-known stigmata of chronic liver disease, which includes spider nevi, palmar erythema, gynecomastia, caput medusae, Dupuytren contractures, parotid gland enlargement, and testicular atrophy. Palpable lymph nodes can also direct the clinician towards malignancy (left supraclavicular & periumbilical). Increased volume status of the patient evidenced by jugular venous distension can be a sign of right-sided heart failure, suggesting hepatic congestion.

The abdominal examination should provide information on the presence of hepatosplenomegaly, or ascites. Jaundice with ascites indicates either cirrhosis or malignancy with peritoneal spread.

Right upper quadrant tenderness with palpable gallbladder (Courvoisier sign) suggests obstruction of the cystic duct due to malignancy. [24]

(After obtaining a thorough history and performing physicals, the most important laboratory test to be done is liver function tests. [25] [26]

Liver function tests - to check serum levels of aspartate transaminase (AST), alanine transaminase (ALT), alkaline phosphatase (ALP), gamma-glutamyltransferase, serum albumin, protein, and bilirubin

AST, ALT and ALP levels - if the liver transaminase levels increase but ALP levels are low, then the insult is hepatic in origin.

• AST/ALT ratio is more than 2 to 1 in alcoholic liver disease.
• AST and ALT values are in 1000s; then the hepatocellular disease is likely due to toxins like acetaminophen or ischemia or viral.
• If ALP levels are five times elevated than normal and liver transaminases are normal or less than two times normal, then the most likely cause is biliary obstruction. The high serum ALP levels due to a biliary injury can be differentiated from bone disorders by ordering a GGT serum profile, increased levels confirm hepatic origin.
• If AST, ALT and ALP levels are normal- then the jaundice is not due to liver or bile duct injury. The cause must probably be pre-hepatic: inherited disorders of liver conjugation or blood disorders or defect in hepatic excretion (Rotor, Dubin-Johnson). 

Serum Bilirubin -  whether there is a rise in unconjugated or conjugated bilirubin

 In addition to the liver panel, all jaundiced patients should have additional tests such as albumin and prothrombin time – which are indicative of chronic and acute liver function, respectively. The inability of prothrombin time to correct with parenteral administration of vitamin K suggests severe hepatocellular dysfunction.

 The results of the bilirubin, enzymes, and liver function tests will direct the diagnosis towards a hepatocellular or cholestatic cause and offer some idea of the duration and severity of the disease.

 Further evaluation can be conducted based on the initial assessment.

Hepatocellular workup: viral serologies, autoimmune antibodies, serum ceruloplasmin, ferritin.

Cholestatic workup: Additional tests include abdominal ultrasound, CT, magnetic resonance cholangiopancreatography (MRCP), endoscopic retrograde cholangiopancreatography (ERCP), percutaneous transhepatic cholangiography (PTC), endoscopic ultrasound (EUS).

Treatment / Management

Treatment of choice for jaundice is the correction of the underlying hepatobiliary or hematological disease, when possible.

Pruritis associated with cholestasis can be managed based on the severity. For mild pruritis, warm baths or oatmeal baths can be relieving. Antihistamines can also help with pruritis. [27]  Patients with moderate to severe pruritis respond to bile acid sequestrants such as cholestyramine or colestipol. Other less effective therapies include rifampin, naltrexone, sertraline, or phenobarbital. If medical treatments fail, liver transplantation may be the only effective therapy for pruritis. [28]

Jaundice is an indication for hepatic decompensation and may be an indication for liver transplant evaluation depending on the severity of the hepatic injury.

Differential Diagnosis

The differential for yellowish discoloration of the skin is narrow. Healthy individuals with high consumption of vegetables and fruits that contain carotene, such as carrots can present with carotenoderma which classically spares the sclerae. [5]

Quinacrine leads to yellowish discoloration of the skin in up to one-third of patients treated with it. [29]

Prognosis of jaundice depends on the etiology.

Etiologies of jaundice with excellent prognosis include jaundice from resorption of hematomas, physiologic jaundice of newborn, breastfeeding, breast milk jaundice, Gilbert syndrome, choledocholithiasis.

As a general rule, malignant biliary obstructions and cirrhosis with jaundice predict a poorer prognosis. [30]

Complications

Indirect (insoluble) bilirubin is harmful to cells and cellular structures. Due to the physiologic mechanisms that protect against elevated bilirubin, the toxic effects are limited to neonates due to the poorly developed blood-brain barrier. High levels of bilirubin are neurotoxic and can lead to permanent neurologic injury (kernicterus) (Bilirubin-induced neurologic dysfunction). [21]

Consultations

Specific challenging patients may require specialty consultations for further workup and management. Gastroenterology specialists most frequently consult on undiagnosed cases of jaundice. [31]

Deterrence and Patient Education

Most cases of jaundice can be effectively prevented by following a few simple recommendations which include: [32]

• Avoid herbal medications without consulting with a physician, most herbal supplements are toxic to the liver and can cause irreversible liver damage leading to jaundice
• Avoid smoking, consumption of alcohol, and intravenous drugs
• Avoid exceeding the recommended dose on prescribed medications
• Visit your doctor if you notice yellowish discoloration of body tissue
• Encourage safe sex practices
• Always get the recommended vaccines before traveling to a foreign country

Pearls and Other Issues

The best initial step in the evaluation of jaundice is history and physical examination. The next step is to classify jaundice by etiology and type-Hepatocellular, cholestatic or mixed.

The basic mechanisms of jaundice include elevated production, decreased uptake, and faulty conjugation.

Treatment focuses on the cause.

Enhancing Healthcare Team Outcomes

The biggest challenges in improving patient health outcome include a healthcare delivery system that focuses more on treating as opposed to preventing disease. Most cases of jaundice are preventable by vaccinations, safe sex practices, health education, risk factor modification.

The responsibility of the healthcare team in the incidence and management of jaundice is well known. Physicians, nurses, and pharmacists working together can significantly improve team outcomes. Encouragement from health care professionals to promote breastfeeding is vital in the management of neonatal jaundice.

With the wide range of etiologies for jaundice, the entire interprofessional team must collaborate to ensure optimal patient outcomes. Clinicians, including NPs and PAs, will be involved in the diagnosis and selection of therapy based on etiology. Nursing will work on patient compliance, and depending on the etiology, counseling the patient on lifestyle and other changes, and inform the treating clinicians about potential risks, non-compliance, and adverse reactions to therapy. Pharmacists are responsible for reporting back to the rest of the team on medication interactions following a medication review, and verifying dosing and duration; any concerns need to be brought to the attention of nursing and/or the prescriber. Only through this type of interprofessional collaboration can the healthcare team ensure the treatment matches the diagnosis and is executed in the best possible manner to bring about successful outcomes. [Level 5]

Review Questions

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Scleral Icterus/Jaundice Contributed by Steve Bhimji, MS, MD, PhD

Normal Urine Color Versus Jaundice/Tea Colored Urine Contributed by Steve Bhimji, MS, MD, PhD

Jaundice in a male Image courtesy S Bhimji MD

Disclosure: Abel Joseph declares no relevant financial relationships with ineligible companies.

Disclosure: Hrishikesh Samant declares no relevant financial relationships with ineligible companies.

This book is distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) ( http://creativecommons.org/licenses/by-nc-nd/4.0/ ), which permits others to distribute the work, provided that the article is not altered or used commercially. You are not required to obtain permission to distribute this article, provided that you credit the author and journal.

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Jaundice (Case 25)

Published on 24/06/2015 by admin

Filed under Internal Medicine

Last modified 24/06/2015

This article have been viewed 10285 times

Austin Hwang MD and Giancarlo Mercogliano MD, MBA, AGA

Case: A 60-year-old man presents with jaundice, 20-pound weight loss, intermittent nausea, and decreased appetite over the last month. He has a history of hypertension, hyperlipidemia, and diabetes. There is no past surgical history. He takes hydrochlorothiazide, simvastatin, and metformin. His BP, cholesterol, and diabetes are under good control. He has drunk three beers each day and smoked half a pack of cigarettes per day for the last 40 years. He has no abdominal pain, but he has noticed that his stools have become lighter in color and his urine has become tea-colored. He presents in the outpatient office accompanied by his wife and three of his children, who have urged him to seek medical attention.

Differential Diagnosis

Speaking Intelligently

When asked to see an older patient with jaundice, we worry about cancer. A helpful start in patients with this clinical presentation is to decide whether the cause is hepatocellular or obstructive. These two categories serve as a useful framework to think about elevated serum bilirubin levels. Treatment of hepatocellular causes is generally supportive, while treatment of obstructive causes is with endoscopy or surgery. History taking allows me to create a diagnostic hypothesis. Laboratory values and imaging help me to corroborate this hypothesis. Liver function tests (LFTs) are crucial. Ultrasonography evaluates the hepatic parenchyma and biliary ducts.

PATIENT CARE

Clinical thinking.

• Use the framework mentioned above to focus history taking and to come up with a working differential diagnosis.

• Use LFTs and imaging (ultrasound, CT, MRI) to help corroborate your hypothesis.

• Pattern recognition of LFTs aids in diagnosis. Please see below .

• History of associated pain or lack of pain is important.

• If an elderly patient presents with painless jaundice , think malignancy. This presentation will be associated with weight loss, fatigue, and poor appetite.

• If abdominal pain is present, the differential diagnosis is broad. Choledocholithiasis causes intermittent RUQ abdominal pain followed by more constant pain. Acute hepatitis can cause distension of the liver capsule and subsequent vague RUQ pain. Chronic abdominal pain that is dull in nature can be related to invasion of pancreatic cancer into adjacent tissues.

• Past medical history is important: History of gallstones (choledocholithiasis), colon cancer (liver metastases), or chronic pancreatitis (bile duct strictures).

• Take a good social history , including the following: travel, food ingestions, multiple sexual partners, alcohol use, cigarette use, injection drug use, tattoos, herbal medications, and new medications.

• Family history: Between 5% and 10% of patients with pancreatic cancer have a family history of pancreatic cancer.

Physical Examination

• Jaundice appears as yellowing of the skin, yellowing under the tongue, or scleral icterus (yellowing of the sclerae). This usually occurs with total serum bilirubin levels greater than 3.5 mg/dL.

• Fractionate the bilirubin: If indirect bilirubin is predominant, hemolysis and Gilbert syndrome (hereditary condition caused by the decreased ability of glucuronyltransferase to conjugate bilirubin) are the top two diagnoses. If direct bilirubin is predominant, the differential includes intrahepatic dysfunction vs. biliary duct obstruction.

• In the presence of fever , think cholangitis.

• Asterixis (flapping of hands with arms extended; “stopping traffic”) and encephalopathy are signs of hepatocellular dysfunction.

• Signs of chronic liver disease: spider angiomas, palmar erythema, caput medusae, and gynecomastia and testicular atrophy in men.

• Abdominal exam: Inspect the abdomen for ascites (think malignancy or cirrhosis); listen for bowel sounds; assess hepatic size and palpate for hepatosplenomegaly and tenderness in RUQ (choledocholithiasis or acute hepatitis).

Tests for Consideration

Table 32-1 Typical Laboratory Values *

* For clarity, we have chosen typical values that are representative of each condition. Those fields that are empty are either too variable to quantify or not useful as diagnostic guides.

CBD, common bile duct.

IMAGING CONSIDERATIONS

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• Published: 21 February 2024

Factors associated with neonatal jaundice among neonates admitted at referral hospitals in northeast Ethiopia: a facility-based unmatched case-control study

• Tsedale Ayalew 1 ,
• Asressie Molla 2 ,
• Bereket Kefale 3 ,
• Tilahun Dessie Alene 4 ,
• Gebremeskel Kibret Abebe 5 ,
• Habtamu Setegn Ngusie 6 &
• Alemu Birara Zemariam 7  

BMC Pregnancy and Childbirth volume  24 , Article number:  150 ( 2024 ) Cite this article

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Neonatal jaundice is a significant contributor to illness and death in newborns, leading to frequent admissions to neonatal intensive care units. To better understand this issue, a study was conducted to identify the factors contributing to neonatal jaundice among newborns admitted to Dessie and Woldia comprehensive specialized hospitals in northeast Ethiopia.

The study took place from April 1 to May 30, 2022, using unmatched case-control design. A total of 320 neonates paired with their mothers were involved, including 64 cases and 256 controls. Data were collected through a structured interviewer-administered questionnaire and a review of medical records. The collected data were analyzed using SPSS Version 23, and a multivariate logistic regression model was employed to understand the relationship between independent factors and the occurrence of neonatal jaundice. Statistical significance was determined at a threshold of P  value less than 0.05.

The study findings revealed that maternal age over 35 years, residing in urban areas [adjusted odds ratio (AOR) = 2.4, 95% confidence interval (CI): 1.23, 4.82], male gender (AOR = 4.3, 95% CI: 1.90, 9.74), prematurity (AOR = 3.9, 95% CI: 1.88, 8.09), and ABO incompatibility (AOR = 2.6, 95% CI: 1.16, 5.96) were significant determinants of neonatal jaundice. Conversely, the study indicated that cesarean birth was associated with a 76% lower likelihood of infant jaundice compared to vaginal delivery (AOR = 0.24, 95% CI: 0.08, 0.72).

To prevent, diagnose, and treat neonatal jaundice effectively, efforts should primarily focus on managing ABO incompatibility and early detection of prematurity. Additionally, special attention should be given to neonates born through vaginal delivery, those with mothers over 35 years old, and those residing in urban areas, as they are at higher risk of developing newborn jaundice. Close monitoring of high-risk mother-infant pairs during the antenatal and postnatal periods, along with early intervention, is crucial for reducing the severity of neonatal jaundice in this study setting.

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Introduction

Jaundice refers to the yellowish discoloration of the skin, sclerae, and mucous membranes caused by the accumulation of bilirubin in the tissues [ 1 , 2 ]. In older children and adults, a total blood bilirubin level exceeding 1.5 mg/dL is considered hyperbilirubinemia [ 3 ]. However, during the postpartum phase of transition, infants experience physiological jaundice, where their blood bilirubin levels surpass 1.5 mg/dL due to normal transitional processes [ 4 , 5 ]. Jaundice becomes detectable clinically when the total blood bilirubin level reaches 5 mg/dL [ 3 , 6 ].

If the timing, duration, or pattern of jaundice significantly differs from physiological jaundice, or if the infant shows additional indications of susceptibility to neurotoxicity, the jaundice and its underlying hyperbilirubinemia are considered pathological. The progression of jaundice, measured in milligrams per deciliter (mg/dL), typically starts with the face (5 mg/dL), followed by the mid-abdomen (15 mg/dL), and the soles of the feet (20 mg/dL) [ 7 , 8 ].

Severe hyperbilirubinemia affects approximately 1.1 million infants worldwide each year, with the majority residing in sub-Saharan Africa and South Asia [ 9 ]. Neonatal jaundice ranks as the seventh and eighth leading causes of death in South Asia and sub-Saharan Africa, respectively [ 10 ]. In Africa, neonatal jaundice is a significant contributor to neonatal admissions [ 11 ]. and Ethiopia is among the top ten countries globally in terms of infant deaths from jaundice [ 11 ].

Several risk factors for neonatal jaundice have been identified, including prematurity [ 12 ], maternal age [ 13 , 14 ], low birth weight [ 15 ], glucose-6-phosphate dehydrogenase deficiency (G6PD) [ 16 ], genetics [ 17 ], sex [ 18 ], drugs, race [ 19 ], altitude, polycythemia [ 15 ], maternal diabetes [ 20 ], blood extravasation cutaneous bruising [ 21 ],, oxytocin induction [ 13 , 16 ], delayed bowel movement, family history of physiological jaundice [ 18 ], breast milk, weight loss [ 21 ], blood-group incompatibilities [ 22 ], and other hemolytic diseases [ 23 ].

Various interventions have been implemented to reduce the morbidity and mortality associated with neonatal jaundice. These interventions include genetic screening to identify enzymatic deficiencies, educating mothers to recognize the early signs of jaundice and seek timely healthcare services, and conducting blood group screening during antenatal care (ANC) with the provision of Anti D for mothers who have Rh negative status during pregnancy and postpartum [ 24 ]. Furthermore, guideline development and implementation have been among the strategies employed to enhance perinatal and neonatal health outcomes [ 25 ]. To combat this neonatal complication, the Ethiopian government has taken steps to ensure the accessibility of phototherapy treatment in hospitals. Currently, the government of Ethiopia has set a target to reduce the neonatal mortality rate from 28 per 1000 live births to 11 per 1000 live births by 2035, as indicated in the Ministry of Health report [ 26 ].

Limited research has been conducted to identify the factors contributing to neonatal jaundice in Ethiopia. One study conducted in Mekelle City, located in northern Ethiopia, reported a prevalence of 37.3% for newborn jaundice [ 27 ]. Another case-control study conducted in northern Ethiopia examined intervention strategies for addressing neonatal jaundice [ 15 ]. Previous studies assessing the determinants of newborn jaundice [ 21 , 28 , 29 ], often did not utilize statistical regression models to identify predictors. Moreover, there were conflicting findings regarding predictors such as mode of delivery and their association with neonatal jaundice. Therefore, this study aims to address the aforementioned gaps and determine the causes of neonatal jaundice.

Study area and period

The study was conducted at Woldia and Dessie Referral Hospitals from April 1 to May 30, 2022. Woldia and Dessie are the capital cities of the North and South parts of Wollo, respectively. Dessie is located approximately 401 km north of Addis Ababa, the central city of Ethiopia, while Woldia is situated about 521 km away. Dessie Referral Hospital serves a catchment population of over 5 million people, including areas in South Wollo, Amhara, Tigray, Afar, and Oromia Regions. The hospital has a large staff of more than 500 individuals working in various departments, including administrative personnel. Specifically, the pediatrics department at Dessie Referral Hospital is staffed with 5 pediatricians, 20 general practitioners, and over 40 nurses. The department is equipped with four rooms, 20 beds, and three phototherapy machines.

On the other hand, Woldia Referral Hospital is a public healthcare facility that provides services to approximately 3 million people. The hospital has a staff of over 400 individuals in different departments, including administrative personnel. Currently, two pediatricians are working at Woldia Referral Hospital. The hospital’s Neonatal Intensive Care Unit (NICU) has 15 beds and four phototherapy machines.

Study design and population

We carried out a facility-based unmatched case-control study among cases and controls admitted in NICU at Dessie and Woldia referral hospitals. For cases, our source population was jaundiced neonates who came to the NICU of Dessie and Woldia referral hospitals and their mothers. On the other hand, the source population for controls was all neonates seeking care but without jaundice who came to the NICU of Dessie and Woldia comprehensive specialized hospitals to seek any clinical care and their mothers. For instance, a neonate who came to the hospital for asphyxia, sepsis, birth trauma, surgical problems, and so on was considered the reason for the admittance of the control group.

The study population for cases was all neonates who had jaundiced and were admitted to the NICU of Dessie and Woldia referral hospitals within the study period and their mothers. For controls, the study population was all neonates seeking care, but without jaundice admitted to the NICU ward at Dessie and Woldia referral hospitals within the study period and their mothers. The exclusion criteria for the case were neonates with jaundice who were critically ill, whose mothers were not around, and who had critically ill mothers. In line with this, neonates without jaundice whose mothers were not around and who had critically ill mothers were excluded from the control group.

Sample size determination and sampling procedure

We calculated the sample size using Epi Info version 7 by using predictors, which were identified in previous studies of similar settings to that of our study area or resource-limited settings due to the scarcity of research for identified factors in Ethiopia [ 30 ], and finally, the largest was taken. The sample size was calculated for each determinant factor using the following formula:

Where n = number of cases, r = ratio of controls to cases, ZB = power, Za/2 = level of statistical significance, P  = average proportion exposed, and P  1- P  2 = difference in proportions.

A 95% level of certainty, a power of 80%, and a ratio of case-to-control 1:4 were considered. After calculating for each factor, we took the largest sample size, which was calculated using prolonged labor [ 30 ], the percent of the case exposed was 43%, and the percent of control exposed was 24%. Accordingly, the final sample size became 320 (case = 64, control = 256). A total of 320 neonates paired with their mothers were approached in the study.

The two hospitals are among the public hospitals in the area that give NICU service to a larger catchment population and treat neonates having jaundice. We included all neonates who presented to NICU wards with or without neonatal jaundice and their mothers in the study. All neonates who met the inclusion criteria for the study were included in the cases using sequential sampling until we obtained the required sample size. For each case identified during data collection, four controls were included because we used a case-to-control ratio of 1:4. We also used systematic sampling to select controls from neonates who came to NICU to seek any care but didn’t have jaundice, such as asphyxia, sepsis, birth trauma, surgical problems, and so on. We calculated the sampling interval (k) using the estimation of the total neonates to be seen in the study period from previous experience.

On average, there were ten admissions per day at Dessie Referral Hospital and eight admissions daily at Woldia Referral Hospital. Therefore, the total admissions estimated in the study period became 1,008. Then we calculated the sampling interval by dividing it by the sample size (1008/256). We got K = 4. We used the lottery method to select the first neonate and included every 4th neonate who presented to the hospitals at the time of the data collection period. Cases were neonates diagnosed as having jaundice by the pediatrician or general practitioner using a physical examination. Controls were neonates diagnosed as not having jaundice by the pediatrician or general practitioner using the physical examination.

The outcome variable was neonatal jaundice. The explanatory variables were maternal socio-demographic variables, maternal obstetric, and clinical variables (including parity, complications during pregnancy, blood group incompatibility, and previous history), labor and delivery-related variables (including prolonged labor, mode of delivery, induction of labor, oxytocin use for labor augmentation) and neonatal variables (including sex of the infant, prematurity, birth weight, birth asphyxia, hypothermia, sepsis, breastfeeding, cephalohematoma, polycythemia).

Operational definition

• Neonatal jaundice

It can be operationally defined as the condition characterized by the yellowing of the newborn’s skin and the whites of the eyes, resulting from the accumulation of bilirubin in the bloodstream. Diagnosis is typically made by a medical professional through a physical examination, specifically observing the presence of yellow discoloration. Laboratory investigation is performed to confirm the diagnosis, typically involving the measurement of total serum bilirubin levels. A commonly used threshold for diagnosing neonatal jaundice is a total serum bilirubin level of 5 mg/dL (85 μmol/L) or higher, although specific thresholds may vary depending on the infant’s age, gestational age, and other factors [ 31 , 32 , 33 ].

Neonatal sepsis

Neonatal sepsis was identified using a set of established clinical features known as the Integrated Management of Neonatal and Childhood Illness (IMNCI) criteria. These criteria encompass a range of indicators that healthcare providers use to evaluate newborns for sepsis. Specifically, the presence of two or more of the following signs is considered: a persistent fever (≥ 37.5 °C) or prolonged hypothermia (≤ 35.5 °C) lasting for over an hour, rapid breathing (≥ 60 breaths per minute), severe chest indrawing, grunting, insufficient feeding, minimal movement unless stimulated, a bulging fontanelle, convulsions, lethargy, or unconsciousness. Additionally, at least two hematological criteria are taken into account, including the total leukocyte count (less than < 4000 or greater than > 12,000 cells/mm3), absolute neutrophil count (less than < 1500 cells/mm3 or greater than > 7500 cells/mm3), platelet count (less than < 150 or greater than > 450 cells/mm3), and random blood sugar (less than < 40 mg/dl or greater than > 125 mg/dl). By evaluating these clinical and hematological factors, healthcare professionals can make a diagnosis of neonatal sepsis [ 34 , 35 , 36 ].

Polycythemia

It is defined as a condition characterized by an elevated hematocrit level or hemoglobin level in a peripheral venous blood sample. Specifically, polycythemia is diagnosed when the hematocrit level is equal to or greater than 65% or when the hemoglobin level is equal to or greater than 22 g/dL. These thresholds serve as indicators of increased red blood cell mass in the bloodstream. It is important to note that the diagnosis of polycythemia should consider other clinical factors, such as symptoms and medical history, to confirm the presence of the condition and rule out other potential causes [ 15 , 37 , 38 ].

Premature rupture of membranes (PROM)

It is an amniotic sac ruptured before the onset of labor. Preterm premature rupture of membranes (PPROM) is the term used when PROM occurs before 37 weeks of pregnancy [ 39 ].

Preeclampsia

It is a pregnancy-specific hypertensive disorder characterized by the onset of high blood pressure after 20 weeks of gestation in a previously normotensive woman. It is typically accompanied by proteinuria (excess protein in urine), end-organ dysfunction (such as renal, hepatic, neurological, or hematological abnormalities), and/or placental dysfunction (including fetal growth restriction or abnormal umbilical artery Doppler velocimetry) [ 40 ].

High blood pressure

It is often known as hypertension, and it is a frequent illness where the blood’s long-term strain against your artery walls is so great that it may eventually result in health issues like heart disease [ 41 ]. Hypertension in pregnancy is characterized as two separate occurrences of blood pressure > 140/90 mm Hg [ 42 ].

Antepartum hemorrhage (APH)

It refers to the occurrence of bleeding from or into the vaginal tract that begins at or before the 24th week of pregnancy and continues until the delivery of the baby. This condition involves the presence of vaginal bleeding during the period leading up to childbirth. The bleeding can be either evident or concealed and detectable only through medical tests or imaging. It is crucial to seek medical attention and evaluation for APH, as it can have various underlying causes and may pose risks to the health and well-being of both the mother and the developing fetus [ 43 ].

Intrauterine growth restriction (IUGR)

When a fetus (a baby in the womb) does not grow as expected, this condition is known as intrauterine growth restriction (IUGR) [ 44 ].

Hypothermia

When your body loses heat more quickly than it can produce it, a medical emergency known as hypothermia occurs, resulting in a dangerously low body temperature. A neonate of a newborn was considered hypothermic if the axillary temperature was below 36.5 °C [ 45 , 46 , 47 ].

ABO incompatibility

When a mother’s blood type is O, and her child has an A, B, or AB blood type, this condition is known as ABO incompatibility [ 48 ]. In this investigation, the presence of at least two of the following conditions was required for ABO incompatibility: (1) different degrees of anemia, (2) red blood cells with nuclei in circulation, (3) spherocytosis, or (4) polychromasia on a peripheral blood smear [ 49 ].

Critically ill neonates

In this study, critically ill neonates are defined as newborn infants who present with severe clinical manifestations or laboratory abnormalities related to jaundice, requiring immediate medical attention and intensive medical interventions [ 50 , 51 ].

Data collection instruments and quality control

The data for this study was collected by a team of four BSc nurses through interviews with the mothers of the neonates and by reviewing the corresponding medical records. To gather the required information, a structured questionnaire and checklist were used. These tools were developed by the principal investigator and included predictors identified in previous studies on this topic [ 30 ].

The study encompassed various aspects, including socio-demographic characteristics, obstetric characteristics of the mother, and neonatal characteristics. Two medical doctors were assigned as supervisors to oversee the research. To maintain consistency, the questionnaire was initially translated from English to Amharic for data collection purposes and then back-translated to English. This process underwent a pre-test where 5% of the total sample size was tested at Boru-Meda Hospital. Based on the feedback received during the pre-testing phase, relevant changes and modifications were made to the questionnaire. Data collectors underwent a one-day training session covering the entire data collection process. Throughout the data collection period, the supervisors diligently reviewed the completed questionnaires to ensure the accuracy, completeness, and clarity of the data.

Data analysis

We entered the collected data into EpiData version 4.6 and then exported it to SPSS 23 for analysis. Descriptive analysis such as frequencies, cross tab, and mean were done. A binary logistic regression model was then used in a bivariate study to determine the relationship between each determinant and the outcome variable. The multivariable analysis model then includes variables from the bivariate analysis with a P -value of less than or equal to 0.25. The assumptions of logistic regression were fulfilled, the constant for variables in the equation was significant ( P  < 0.05), model prediction of variables improved from 80 to 84.7%, and we checked the model fitness using the Hosmer Lemeshow test and it was not significant ( P  = 0.716). In the multivariable binary logistic regression, a P -value of less than 0.05 was utilized as a cut point to assess the level of statistical significance. The adjusted odds ratio (AOR) and 95% confidence interval (CI) were estimated to see the strength of the relationship.

Socio-demographic characteristics

About 320 (case = 64, control = 256) mother and neonate pairs participated in the study, making the response rate 100%. The age of mothers included in this study ranged from 18 to 40 years. The mean age of mothers in the cases and controls were 27.3 (SD ± 3.86) and 26.7 (SD ± 5.39) years, respectively. Of the respondents, 63(98.4%) cases and 246(96.1%) controls were married. Of the cases involved in the study, 43(67.2%) were from urban areas. Among neonates included in the study, 24(37.5%) cases and 163(63.7%) controls were admitted on their first day of birth. Regarding the sex of the neonates, 53(82.8%) cases and 152(59.4%) controls were males (See Table  1 ).

Obstetric and clinical characteristics of the mother

Among mothers included in the study, 43(67.2%) cases and 136(53.1%) controls were multi-parous. Eight (12.5%) mothers participated in the study as cases had a previous history of a child with neonatal jaundice. All cases and 254(99.2%) controls had ANC follow-up during pregnancy. Among participant mothers, 33(51.6%) cases and 76(29.7%) controls had a complication during pregnancy. The commonest complication was PROM, 20(60.6%) from cases and 26(34.2%) from controls. All participants gave birth at a health facility. All cases and 242 (94.5%) controls had labor lasting less than 24 h. Regarding mode of delivery, 9(14.1%) of cases and 23(9%) of controls gave birth via instrumental delivery. The most common blood group and Rh of mothers were O-positive with a total of 113 respondents, which include 31(48.4%) cases and 82(32%) controls (See Table  2 ).

Neonatal characteristics

Among neonates included in the study, 33(51.6%) cases and 72(28.1%) controls had low birth weights (< 2500 g). Concerning gestational age, 30(46.9%) of cases and 57(22.3%) of controls were preterm neonates (gestational age < 37 weeks). From neonates who had birth trauma, cephalohematoma was the most common one, with 10(76.9%) cases and 10(47.6%) controls. The majority of the neonates had hypothermia, and from those with hypothermia, 50(78.1%) were cases, and 221(86.3%) were among the control.

Among neonates who had jaundice, the range of their serum total bilirubin level was 16.4 to 40.6 mg/dl, and the mean bilirubin level was 21.47 mg/dl (+ 4.67). The majority, 42(65.6%) of cases range a bilirubin level of 16.4–19.9. About 19 (29.7%) had a bilirubin level between 20 and 24.9. On the left, 3 (4.7%) of the cases had a bilirubin level above 25. Among those who had jaundice, 38 (59.4%) cases were pathological neonatal jaundice, and the left 26 (40.6%) were found to be physiological jaundiced. Additionally, only 10 (15.6%) infants were treated with double exchange transfusion. The left 54 (84.4%) were treated with phototherapy due to the serum bilirubin level reaching the phototherapy range based on the butane curve [ 32 , 52 ].

Among 256 controls, 64(25.0%) were admitted with asphyxia and sepsis, 147 (57.4%) neonates were admitted with sepsis, 13(5.1%) were admitted with birth trauma like cephalohematoma, subgaleal hemorrhage, and other. Additionally, 10 (3.9%) were admitted with anemia, and 22 (8.6%) were admitted with surgical problems. The common blood group was A with Rh positive found among a total of 104 respondents, which included 15(23.4%) cases and 89(34.8%) controls (See Table  3 ).

Determinant factors of neonatal jaundice

During multivariable analysis among the independent variables, residence, sex of the neonate, mother’s age, mode of delivery, gestational age, and presence of ABO incompatibility between the neonate and mother were found to be independent predictors of neonatal jaundice.

Hence, the probability of having a neonate with jaundice is 8.8 times higher for mothers older than 35 years of age compared to those younger than 25 years [AOR = 8.8, 95%CI: (1.99, 38.78)]. Respondents who lived in urban areas were 2.4 times more likely to have neonatal jaundice than those from rural areas [AOR = 2.4, 95%CI: (1.23, 4.82)]. Additionally, male neonates were found to have a 4.3 times higher likelihood of having neonatal jaundice than female neonates [AOR = 4.3, 95%CI: (1.90, 9.74)].

This study showed that cesarean delivery was 76% protective of neonatal jaundice compared with vaginal delivery [AOR = 0.24, 95%CI: (0.08, 0.72)]. Whereas premature neonates (Gestational age less than 37 weeks) had a 3.9 times higher probability of having jaundice than those with gestational age greater than or equal to 37 weeks [AOR = 3.9, 95%CI: (1.88, 8.09)]. Finally, neonates who had ABO incompatibility had 2.6 times more likely to have jaundice than those who had no ABO incompatibility [AOR = 2.6, 95%CI: (1.16, 5.96)] (See Table  4 ).

This facility-based, unmatched case-control study was conducted to identify the causes of newborn jaundice. The study’s findings provided valuable insights, revealing that mothers aged 35 years and older had a significantly higher likelihood of giving birth to neonates with jaundice when compared to mothers younger than 25 years. This finding is supported by previous studies conducted in Sweden and Tehran [ 13 , 14 ]. One potential explanation for this finding is that older mothers, who are 35 years and older, have a higher likelihood of experiencing medical conditions like gestational diabetes and hypertensive disorders. These conditions can affect how the liver functions and how bilirubin is metabolized in the body, leading to an increased risk of neonatal jaundice [ 53 , 54 , 55 ]. Additionally, older mothers also have a higher incidence of genetic factors associated with neonatal jaundice, such as genetic disorders and variations in genes related to bilirubin metabolism [ 55 , 56 , 57 ]. These combined factors contribute to the heightened probability of neonatal jaundice in neonates born to mothers aged 35 years and older. Therefore, it is important to screen women over 35 years of age before conception and provide enhanced follow-up care during pregnancy, labor, and delivery.

The study also revealed that, after adjusting for other factors, respondents residing in urban areas were twice as likely to develop neonatal jaundice compared to those from rural areas. This difference could be explained by the fact that mothers in urban areas tend to bring their babies to healthcare facilities at an earlier stage when they notice any changes, resulting in a higher diagnosis rate in urban areas compared to rural areas. Conversely, rural mothers often follow traditional practices and stay at home in darker room setups during the postpartum period, which may prevent them from noticing the signs of jaundice. As a result, there may be a higher reporting of jaundice cases in urban areas, leading to a significant effect. Additionally, rural mothers may face challenges in accessing healthcare facilities due to distance, leading them to rely on traditional home remedies instead of seeking medical care. A study conducted in Northern Ethiopia revealed a significant disparity in knowledge levels between urban and rural mothers, bolstering our justification that urban mothers possess a greater understanding of the importance of seeking medical care for their neonates upon observing symptoms related to jaundice. The findings underscore the notion that urban mothers are more informed and equipped to recognize the signs of jaundice in their infants, prompting them to take proactive measures such as seeking medical attention promptly [ 58 ].

Based on the implication of this finding, future researchers are encouraged to investigate the underlying factors that contribute to the difference in neonatal jaundice prevalence between urban and rural areas. They should also explore the influence of cultural practices and conduct comparative studies to understand variations across regions. The sex of the neonate was identified as an important predictor of newborn jaundice. The study found that male neonates were more likely to develop jaundice than females. This finding is consistent with studies conducted in the Amhara region [ 59 ], Mekele [ 27 ], Malaysia [ 60 ], Nepal [ 19 ], Iran [ 18 ], and Sweden [ 13 ]. This can be attributed to the fact that some causes of neonatal jaundice are genetically linked to the X chromosome, making male babies more susceptible.

Additionally, the prevalence of glucose-6-phosphate dehydrogenase (G6PD) deficiency, which can contribute to jaundice, may be higher in males. However, further research is needed as population-based studies are scarce on G6PD deficiency, and routine G6PD screening is not commonly practiced in healthcare facilities. Moreover, males generally have higher levels of bilirubin, which can result in pathologic jaundice [ 7 ].

It is important to closely observe male neonates during the early neonatal period to enable early diagnosis and intervention for neonatal jaundice. However, it is worth noting that this finding contradicts a report from Iran [ 16 ], which could be due to differences in the study area and socio-demographic distribution. The higher representation of males in our study may also contribute to this discrepancy.

The mode of delivery was identified as another factor significantly associated with neonatal jaundice. The study revealed that cesarean delivery was found to be protective against neonatal jaundice by 76% compared to vaginal delivery. This finding is consistent with a study conducted in Iran, where vaginally delivered infants had a higher likelihood of developing newborn jaundice compared to those delivered via cesarean delivery [ 18 ]. The reason behind this association could be the possibility of birth trauma during vaginal delivery, which exposes the newborn to physical strain and increases the likelihood of bleeding and hemolysis, leading to neonatal jaundice.

Improving the follow-up of labor through the use of a partograph could potentially reduce the occurrence of neonatal jaundice. However, these findings do not align with a study conducted in Malaysia, which found a higher risk of newborn jaundice following cesarean births [ 60 ]. These variations in results could be attributed to differences in sample sizes or other unaccounted-for obstetric practices.

The study also demonstrated that premature neonates were almost four times more susceptible to jaundice compared to full-term neonates. This finding is consistent with studies conducted in India [ 61 ], America [ 62 ], Rwanda [ 63 ], and India [ 62 ]. Premature newborns have immature livers, which play a vital role in bilirubin metabolism. Their immature livers may not be able to effectively process and excrete bilirubin, resulting in its accumulation and neonatal jaundice [ 7 ]. Therefore, interventions aimed at reducing preventable causes of prematurity could be an effective approach to reducing neonatal jaundice.

Another determinant factor identified was ABO incompatibility. Neonates with ABO incompatibility were more likely to develop neonatal jaundice compared to those without. This finding is supported by a study conducted in India [ 62 ]. ABO incompatibility can lead to immune-mediated hemolysis of the newborn’s blood due to maternal antigens, which is one of the causes of infant jaundice [ 8 ]. Therefore, it is important to investigate the neonatal blood group before discharge, especially for neonates born to mothers with an O-blood group, to identify ABO incompatibility and provide appropriate advice to the mother regarding the probability of jaundice and the need to seek healthcare for the neonate.

Limitations of the study

The first limitation of this study was it might lead to bias since it was a facility-level study. Secondly, males were highly represented in the study, which might reduce its generalizability. The study also shares the limitation of a case-control study.

Governments, non-governmental organizations, health officers, and policymakers should stress mainly the management of ABO incompatibility and early detection of prematurity to prevent, diagnose, and treat neonatal jaundice. Additionally, neonates who were born with vaginal delivery and whose mothers were > 35 years old as well as those who lived in cities had a higher chance of developing newborn jaundice. Following mother-infant pairs at increased risk for neonatal jaundice, both at the time of antenatal and postnatal periods and intervening earlier is likely a key factor in decreasing severe neonatal jaundice in this study setting.

To advance the field, future researchers should address the limitations of this study by mitigating gender-related biases and enhancing our understanding of the factors linked to neonatal jaundice. Moreover, it is advisable to explore alternative study designs, as doing so can bolster the evidence, minimize biases, and provide better control over confounding variables. Additionally, it is recommended to investigate the underlying factors that contribute to the disparity in neonatal jaundice prevalence between urban and rural areas. Furthermore, researchers should delve into the influence of cultural practices and conduct comparative studies to gain insights into variations across different regions. By pursuing these avenues, we can foster a more comprehensive understanding of neonatal jaundice and its associated factors.

Data availability

The data sets generated and/ or analyzed in the current study are not available publicly due to the consent we took from the study participants in order not to share this data with others but are available from the corresponding author upon a reasonable request.

Abbreviations

Adjusted Odds Ratio

Antepartum Hemorrhage

Confidence Interval

Crude Odds Ratio

Diabetes Mellitus

Integrated Management of Neonatal and Childhood Illness

Intra Uterine Growth Restriction

Neonatal Intensive Care Unit

Premature Rupture of Membrane

Statistical Package for Social Science

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Acknowledgements

We would like to thank the Wollo University College of Medicine and Health Science Ethical Review Board for the approval of ethical clearance, all administrative and clinical staff of Dessie and Woldia referral hospitals for their cooperation, and the data collectors, and supervisors included in this study.

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Department of Emergency and Critical Care Nursing, School of Nursing, College of Medicine and Health Sciences, Woldia University, Woldia, Ethiopia

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Contributions

The design, data collecting, supervision, investigation, data analysis, interpretation, and writing up of the manuscript were done by the efforts of TA, HSN, and TDA. The proposal’s development, validation, manuscript revision, figure preparation, analysis, data visualization, and interpretation have all been done by AM, BK, GKA, ABZ, and TA. Finally, the final paper was evaluated and approved by all authors (TA, TDA, AM, BK, GKA, HSN, and ABZ).

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Correspondence to Habtamu Setegn Ngusie .

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We obtained ethical clearance from the ethical review board of the College of Medicine and Health Science, Wollo University with the ethical reference number: CMHS1156/07/12. Verbal informed consent was obtained from each mother/caregiver or legal guardians of the child after they were informed of the objective and benefits of the study. Due to the time to survey and the illiteracy level, it was deemed non-viable to obtain written consent from each participant’s mother or caregiver or legal guardians, and the ethical review board of the College of Medicine and Health Science, Wollo University approved this procedure. To keep the confidentiality of information provided by the study subjects, the data collection procedure was anonymous. Likewise, this study was conducted by the standard Declaration of Helsinki.

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Ayalew, T., Molla, A., Kefale, B. et al. Factors associated with neonatal jaundice among neonates admitted at referral hospitals in northeast Ethiopia: a facility-based unmatched case-control study. BMC Pregnancy Childbirth 24 , 150 (2024). https://doi.org/10.1186/s12884-024-06352-y

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Received : 25 July 2023

Accepted : 15 February 2024

Published : 21 February 2024

DOI : https://doi.org/10.1186/s12884-024-06352-y

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• Bilirubin level
• Hyperbilirubinemia
• Prematurity
• Northeast Ethiopia

BMC Pregnancy and Childbirth

ISSN: 1471-2393

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