Obstructive jaundice.

1. OBSTRUCTIVE JAUNDICE PATHOPHYSIOLOGY AND WORKUP DR.KIRAN KUMAR.G APOLLO BGS HOSPITALS

2. DEFINITION Failure of normal amount of bile to reach intestine due to mechanical obstruction of the extra hepatic biliary tree or within the porta hepatis

3. JAUNDICE Jaundice (derived from French word ‘ jaune ’ for yellow) or icterus (Latin word for Jaundice) Yellowing of sclera at 3 mg% Bilirubin has got high affinity for elastin and sclera has high elastin content Yellowing of skin and mucous membrane at 6 mg% D/D beta carotenemia,Quinacrine therapy malingering with picric acid They doesn’t stain mucous membrane and sclera Bilirubin level rise upto three weeks than stabilise

4. BILIRUBIN METABOLISM

5. PHYSIOLOGICAL FACTS Total bile flow- 600 ml/day(500-1000ml/day) Hepatocyte component is - 450 ml/day Can be bile salt dependent due to biliary glutathione and ductular bicarbonate secretion Cholangiocyte component- 150 ml/day It depends on secretin stimulation Total serum bilirubin is 0.3-1.2 mg/dl With conjugated bilirubin <15 % 1mg/dl of bilirubin = 17 mmol /l

6. PHYSIOLOGY OF OBSTRUCTION Normal secretory pressure of bile is 15-25 cm of water At 35 cm of water there is suppression of bile flow High pressure leads to cholangiovenous and cholangiolymphatic reflux of bile Dilatation of bile duct and intra hepatic biliary radicals(IHBR) IHBR dilatation may be absent if there is secondary hepatic fibrosis or cirrhosis

7. PATHOPHYSIOLOGY Increase in biliary pressure leads to Disruption of tight junctions between hepatocytes and bile duct cells with increased permeability Reflux of bile contents in liver sinusoids Neutrophil infiltration,increased fibrinogenesis and deposition of reticulin fiberes in portal triad Reticulin fibers gets converted in to type 1 collagen Laying down of collagen fibers leads to hepatic fibrosis obstruction of sinusoids and secondary biliary cirrhosis and portal hypertension Fibrosis can also lead to atrophy of obstructed liver

8. EFFECTS OF OBSTRUCTIVE JAUNDICE ON VARIOUS SYSTEMS

9. CHANGES IN LIVER BLOOD FLOW Acute obstruction increase in hepatic arterial blood flow No change in portal venous blood flow C hronic obstruction Decrease in total liver blood flow , dilatation of sinusoids and elevation of portal pressure

10. CARDIOVASCULAR EFFECTS Decreased cardiac contractability Reduced left ventricular pressure Impaired response to beta agonist drugs Decreased peripheral vascular resistance Bradycardia due to direct effect of bile salts on SA node. Net result Hypotensive patient Exaggerated hypotensive response to bleeding More prone to postoperative shock

11. RENAL FAILURE 10 % incidence with 70 % mortality Factors responsible are Decresed cardic function Increased levels of ANP resulting in hypovolemia Decreased effect of bile salts on kidney mediated by increased prostaglandin E2 Endotoxemia Resulting in Renal vasoconstriction Shunting of blood from cortex Activation of complement system peritubular and glomerular fibrin deposition leading to tubular and cortical necrosis

12. IMMUNE SYSTEM Defects in cellular immunity Impaired T cell proliferation Decreased neutophil chemotaxis Defective bacterial phagocytosis Depressed function of RE system ie Kupffer cells

13. WOUND HEALING Delayed wound healing High incidence of wound dehiscence Decresed activity of enzyme Propyl hydroxylase in the skin This helps in incorporation of proline in collagen Defective synthesis of collagen

14. COAGULATION FACTOR DEFECTS Prolongation of Prothrombin time Loss of calcium Endotoxin induced damage to factor XI ,XII ,platelets Low grade DIC with increased fibrin degradation products Thrombocytopenia from hyperspleenism Decreased absroption of fat solube vitamins A,D,E,K

15. ITCHING Retained bile salts Levels does not correlete well Itching disappears in terminal liver failure but bile salt level still increased Other theory Due to endogenous opiate peptides Inducing opiod receptor mediated scratching activity of central origin

16. BIOCHEMICAL EFFECTS Bilirubin Rise by 25-43 micromol / litre /day Mechanism of hyperbilirubinemia Biliary venous & biliary regurgitation of conjugated bilirubin due to disruption of tight intracellular junction Trans hepatocytic regurgitation due to reversal of the secretory polarity of hepatocytes Rupture of dilated canaliculi in to sinusoids due to necrosis of hepatocytes

17. ALKALINE PHOSPHATSE Most sensitive indicator Factor responsible are Biliary component regurgitation Increase in hepatic synthesis

18. Why Bilirubin levels plateau Increased excretion of bile pigments by kidney by products other than bilirubin not giving DIAZO reaction With increasing levels of conjugated bilirubin A portion get covalently bounded to serum albumin This protein bound bilirubin -Delta bilirubin,is not measurable by routine technique

19. HISTORY AND CLINICAL EXAMINATION

20. The sensitivities of history, physical examination, and blood tests alone range from 70% to 95%, whereas the specificities are approximately 75%. The overall accuracy of clinical assessment of hepatic and posthepatic causes of jaundice ranges from 87% to 97%. 6.Lindberg G, BjÃjrkman A, Helmers C: A description of diagnostic strategies in jaundice. Scand J Gastroenterol 18:257, 1983 7. Lumeng L, Snodgrass PJ, Swonder JW: Final report of a blinded prospective study comparing current non-invasive approaches in the differential diagnosis of medical and surgical jaundice. Gastroenterology 78:1312, 1980 8. Martin W, Apostolakos PC, Roazen H: Clinical versus actuarial prediction in the differential diagnosis of jaundice. Am J Med Sci 240:571, 1960 9. Matzen P, Malchow-Möller A, Hilden J, et al: Differential diagnosis of jaundice: a pocket diagnostic chart. Liver 4:360, 1984 10. O'Connor K, Snodgrass PJ, Swonder JE, et al: A blinded prospective study comparing four current non-invasive approaches in the differential diagnosis of medical versus surgical jaundice. Gastroenterology 84:1498, 1983

21. HISTORY Previous dyspepsia, fat intolerance Jaundice- onset, course, itching Pain Pyrexia Weight loss Dark urine and clay coloured stools Travel to endemic area Contact with jaundice patient History of upper abdominal operation Drug intake ie ATT History of injection in preceding six months

22. CLINICAL EXAMINATION Age Anaemia - hemolysis , cancer , cirrhosis Gross weight loss-malignancy Hunched up position-chronic pancreatitis or ca pancreas Fetor, flapping tremors,personality changes-impending hepatic coma Skin changes- Bruising,purpuric spots,spider naevi,palmar erythema,white nails,loss of secondary sexual characters

23. ABDOMINAL EXAMINATION Dilated peri umbalical veins- cirrhosis & portal collateral circulation Ascitis -Cirrhosis or malignant disease Nodular liver Courvoisier’s Law -palpable non tender gall bladder in jaundice patient-malignant biliary obstruction Exceptions Double impaction of stones Impaction of pancreatic calculus at ampulla of vater Mirizzi syndrome

24. BIOCHEMICAL INVESTIGATIONS Routine investigations- Hb,TLC,DLC , Blood sugar, RFT ,Serum electrolytes Urinary bilirubin,Urobilinogen Serum Bilirubin -Total and Direct SGOT,SGPT,ALP.GGTP and 5- Nucleotidase PT and Serum Albumin

25. ALKALINE PHOSPHATSE(ALP) ALP levels are elevated in nearly 100 % of patients with extra hepatic obstruction except in some cases of intermittent obstruction. Values usually greater than 3 times the upper limit of reference range, and in most typical cases, they exceed 5 times the upper limit. An elevation less than 3 times the upper limit is evidence against complete extra hepatic obstruction.

26. AST and ALT Serum enzymes that provide evidence of hepato cellular damage.ALT found primarily in the liver, where as AST also found in heart ,kidney, skeletal muscle and brain AST is less specific for liver function. The levels of AST and ALT should be done simultaneously since ALT can confirm the hepatic origin of the less specific but more sensitive AST. In extra hepatic obstruction usually AST levels are not elevated(< 10 times the upper reference limit)

27. GAMMA –GLUTAMYL TRANSPEPTIDASE(GGTP) Correlates with ALP level Most sensitive indicator of biliary tract disease Better indicator of obstruction in children – levels are independent of age Helpful in the diagnosis of acute biliary tract obstruction in contrast to ALP because ALP requires synthesis of fresh ALP and hence lags behind the onset of obstruction

28. 5- NUCLEOTIDASE The principal value is to confirm the hepatic origin of an elevated ALP This is particularly helpful in children, pregnant women and patients who may have bone disease resulting in rise of ALP It is more useful than ALP/GGTP in detecting hepatic metastasis

29. OTHER LAB INVESTIGATIONS Prothrobin time Serum albumin Stool for occult blood Presence of occult blood in the stools of a patient with jaundice must raise the suspicion of malignancy.

30. Obstructive jaundice Medical jaundice Serum Bilirubun conjugated unconjugated +++ + + +++ Urobilinogen ↓ ↑ Urinary Bilirubin + Urinary Bile salts + Serum ALP ↑ No change Serum GGTP ↑ No change Serum 5-nucleotidase ↑ No change Transaminases Mildly raised Markedly raised

31. ETIOLOGY

32. TYPES OF BILIARY OBSTRUCTION Complete obstruction Intermittent obstruction Chronic incomplete obstruction Segmental obstruction

33. INTERMITTENT OBSTRUCTION Symptoms and typical biochemical changes Clinically jaundice may or may not be present Causes CBD stones Periampullary tumours Duodenal diverticulum Choledochal cyst Biliary parasites hemobilia

34. CHRONIC INCOMPLETE OBSTRUCTION With or without classical symptoms or biochemical changes Pathological changes in bile ducts or liver Causes Strictures of CBD Stenosis of biliary-enteric anastamosis Chronic pancreatitis Cystic fibrosis Sphincter of oddi stenosis

35. SEGMENTAL OBSTRUCTION one or more segment of intrahepatic biliary tract obstructed Causes Traumatic Intrahepatic stones Sclerosing cholangitis Cholangiocarcinoma

36. BILIARY OBSTRUCTION INTRINSIC Ductal calculi Primary - Develop de novo in bile ducts Secondary - Migrate from gall bladder Acute Cholangitis Biliary Strictures Idiopathic Iatrogenic Sclerosing Cholangitis Parasites Haemobilia Benign Biliary Tumours Cholangiocarcinoma Carcinoma of ampulla of vater and Periampullary tumours Intraductal secondary tumour seeding

37. BILIARY OBSTRUCTION EXTRINSIC Mirizzi syndrome Pancreatitis- acute and chronic Pancreatic pseudocyst Carcinoma of gall bladder Carcinoma of pancreas Cystic tumours of pancreas Metastatic carcinoma Hepatocellular carcinoma

38. BILIARY OBSTRUCTION CONGENITAL AND GENETIC DISORDERS Biliary atresia Choledocal cyst Caroli’s disease Progressive familial intra hepatic cholestasis Primary biliary cirrhosis Alpha 1 antitrypsin defeciency Tyrosinemia Neonatal hepatitis Wilson disease Others - dyskinesia of sphincter of odi

39. IMAGING GOALS To confirm the presence of an extrahepatic obstruction To determine the level of the obstruction, to identify the specific cause of the obstruction To provide complementary information relating to the underlying diagnosis (eg., Staging information in cases of malignancy).

40. Ultrasonography Ultrasound of the abdomen is an extremely useful and accurate method for identifying gallstones and pathologic changes in the gallbladder consistent with acute cholecystitis . Abdominal ultrasound, if performed by an experienced operator, should be part of the routine evaluation of patients suspected of having gallstone disease, given the high specificity (>98%) and sensitivity (>95%) of this test for the diagnosis of cholelithiasis [1] ( Table 54-1 ). In addition to identifying gallstones, ultrasound can also detail signs of cholecystitis such as thickening of the gallbladder wall, pericholecystic fluid, and impacted stone in the neck of the gallbladder. It is often the initial screening test for patients with suspected extrahepatic biliary obstruction ( Fig. 54-7 ). Dilation of the extrahepatic (>10 mm) or intrahepatic (>4 mm) bile ducts suggests biliary obstruction. Intraoperative ultrasound is now used frequently to further evaluate intrahepatic lesions, assess resectability , and determine involvement of vascular structures

41. . MAGNETIC RESONANCE CHOLANGIOPANCREATOGRAPHY (MRCP) Noninvasive test to visualize the hepato biliary tree No contrast Fluid found in the biliary tree is hyper intense on T2-weighted images. Surrounding structures do not enhance and can be suppressed during image analysis. Sensitive in detecting biliary and pancreatic duct stones, strictures, or dilatations within the biliary system. MRCP combined with conventional MR imaging of the abdomen can provide information about surrounding structures (eg, pseudocysts, masses). ERCP and MRCP similarly effective in detecting malignant hilar and perihilar obstruction MRCP is better able to determine the extent and type of tumor as compared to ERCP

42. Absolute contraindications cardiac pacemaker cerebral aneurysm clips ocular or cochlear implants Fluid stasis in the adjacent duodenum or ascitic fluid may produce image artifacts on MRCP, making it difficult to clearly visualize the biliary tree.

43. ENDOSCOPIC ULTRASOUND (EUS) Combines Endoscopy and US Higher-frequency ultrasonic waves compared to traditional US (3.5 mhz vs 20 mhz ) and allows diagnostic tissue sampling via EUS-guided fine-needle aspiration (EUS-FNA). EUS has been reported to have up to a 98% diagnostic accuracy in patients with obstructive jaundice The sensitivity of EUS for the identification of focal mass lesions in pancreas has been reported to be superior to that of CT scanning, both traditional and spiral, particularly for tumors smaller than 3 cm in diameter. Compared to MRCP for the diagnosis of biliary stricture, EUS has been reported to be more specific (100% vs 76%) and to have a much greater positive predictive value (100% vs 25%), although the two have equal sensitivity (67%). The positive yield of eus-fna for cytology in patients with malignant obstruction has been reported to be as high as 96%.

44. Investigations Metastasis poor Surgical risks No metastasis Good Surgical Risks Non operative procedures Operative Procedures Non resectable tumours Resectable tumours Biliary –enteric Bypass Surgically placed stents Percutanesly placed Stents Endoscopically placed stents Palliative resection Curative resection Malignant Obstructive jaundice

45. WORKUP AND MANAGEMENT OF POSTHEPATIC JAUNDICE   three possible clinical scenarios: DUCTAL OBSTRUCTION SUSPECTED CHOLANGITIS SUSPECTED CHOLEDOCHOLITHIASIS WITHOUT CHOLANGITIS SUSPECTED LESION OTHER THAN CHOLEDOCHOLITHIASIS

46. SUSPECTED CHOLANGITIS A clinical picture compatible with acute suppurative cholangitis ( charcot's triad or raynaud's pentad) the most likely diagnosis is choledocholithiasis . Appropriate resuscitation, correction of any coagulopathies if present, and administration of antibiotics ERCP is indicated for diagnosis and treatment If ERCP is unavailable or is not feasible (e.g., Because of previous roux-en-y reconstruction), transhepatic drainage or surgery may be necessary Mainstay of treatment of severe cholangitis is not just the administration of appropriate antibiotics but rather the establishment of adequate biliary drainage.

47. SUSPECTED CHOLEDOCHOLITHIASIS WITHOUT CHOLANGITIS Choledocholithiasis is the most common cause of biliary obstruction. Strongly suspected if the jaundice is episodic or painful or if usg has shown presence of gallstones or bile duct stones. Patients with suspected cbd stones should be referred for lap cholecystectomy with either preoperative ERCP, intra operative cholangiography Preoperative ERCP in this setting of jaundice is prefered Diagnostic yield is high Therapeutic-clearing the CBD of stones in 95% of cases. Many authors, however favor fully laparoscopic approach, in which CBD stone is detected in the OR by means of intraoperative cholangiography and laparoscopic biliary clearance is performed when choledocholithiasis is confirmed. The optimal approach in a particular setting should be dictated by local expertise.  

48. SUSPECTED LESION OTHER THAN CHOLEDOCHOLITHIASIS No gallstones are seen Clinical presentation is less acute (e.g., constant abdominal or back pain) Associated constitutional symptoms (e.g., weight loss, fatigue, and long-standing anorexia) Possible causes of may be classified into three categories depending on the location of the obstructing lesion the upper third of the biliary tree the middle third the lower (distal) third  

49. Upper-third obstruction Polycystic liver disease   Caroli diseas HCC Oriental cholangiohepatitis Hemobilia ( e.g.,afterbiliarymanipulation ) Iatrogenic bile duct injury Cholangiocarcinoma ( Klatskin'stumor )   Sclerosing cholangitis Papillomas of the bile duct Mid-third obstruction Cholangiocarcinoma Sclerosing cholangitis Papillomas of the bile duct Gallbladder cancer Choledochal cyst Intrabiliary parasites Mirizzi syndrome Extrinsic nodal compression (e.g., lymphoma) Iatrogenic bile duct injury Cystic fibrosis Benign idiopathic bile duct stricture Lower-third obstruction Cholangiocarcinoma Sclerosing cholangitis Papillomas of the bile duct Pancreatic tumors Ampullary tumors Chronic pancreatitis Sphincter of Oddi dysfunction Papillary stenosis Duodenal diverticula Penetrating duodenal ulcer Retroduodenal adenopathy (e.g., lymphoma, carcinoid ETIOLOGY

50. DIAGNOSIS AND ASSESSMENT OF RESECTABILITY Involvement of the SUPERIOR MESENTERIC VEIN, THE PORTAL VEIN, THE SUPERIOR MESENTERIC ARTERY , and the PORTA HEPATIS and on whether there is evidence of significant LOCAL ADENOPATHY or EXTRAPANCREATIC EXTENSION OF TUMOR indicates UNRESECTABILITY The majority of lesions will be clearly unresectable , either because of tumor extension or because of the presence of hepatic or peritoneal metastases

51. NON OPERATIVE MANAGEMENT DRAINAGE PROCEDURES      

52. In the majority of patients with malignant obstructions, treatment is palliative rather than curative. Cholangiography and decompression of obstructed biliary system In the absence of preexisting or concomitant hepatocellular dysfunction, drainage of one half of the liver is generally sufficient for resolution of jaundice

53. Routine preoperative drainage of an obstructed biliary system does not benefit patients who will soon undergo resection . 90,91 There is evidence suggesting that in patients with either pancreatic 92,93 or hepatic malignancies, routine preoperative direct cholangiography with decompression is associated with a higher incidence of postoperative complications when tumor resection is ultimately carried out. 90. Pitt HA, Gomes AS, Lois JF: Does preoperative percutaneous biliary drainage reduce operative risk or increase hospital cost? Ann Surg 201:545, 1985 91. McPherson GA, Benjamin IS, Hodgson HJ, et al: Preoperative percutaneous transhepatic biliary drainage: results of a controlled trial. Br J Surg 71:371, 1984 92. Povoski SP, Karpeh MS Jr , Conlon KC, et al: Preoperative biliary drainage: impact on intraoperative bile cultures and infectious morbidity and mortality after pancreaticoduodenectomy . J Gastrointest Surg 3:496, 1999 93. Sohn TA, Yeo CJ, Cameron JL, et al: Do preoperative biliary stents increase postpancreaticoduodenectomy complications? J Gastrointest Surg 4:258, 2000

54. OPERATIVE MANAGEMENT AT SPECIFIC SITES BYPASS AND RESECTION

55. UPPER-THIRD OBSTRUCTION PALLIATION. Because the left hepatic duct has a long extrahepatic segment and is more accessible, the preferred bypass -is a left hepaticojejunostomy Laparoscopic bypass techniques that make use of segment 3 have been developed, but their performance has yet to be formally assessed

56. RESECTION FOR CURE The hilar plate is taken down to lengthen the hepatic duct segment available for subsequent anastomosis . A formal hepatectomy or segmentectomy is required to ensure an adequate proximal margin of resection If the resection is carried out proximal to the hepatic duct bifurcation, several cholangiojejunostomies have to be done to anastomose individual hepatic biliary branches. The results of aggressive hilar tumor resections that included as much liver tissue as was necessary to obtain a negative margin appear to justify this approach. In cases of left hepatic involvement, resection of the caudate lobe is indicated as well.

57. MIDDLE-THIRD OBSTRUCTION Palliation . Surgical bypass of middle-third lesions is technically simpler Hepaticojejunostomy is done distal to the hepatic duct bifurcation, Exposure of the hilar plate or the intrahepatic ducts is unnecessary. Resection for cure. Tumors in this part usually quite amenable to resection along with the lymphatic chains in the porta hepatis . Mirizzi syndrome -extrinsic obstruction of the CBD, either by causing inflammation of the gallbladder wall or via direct impingement. Treatment of this syndrome - Hepaticojejunostomy

58. Lower-third obstruction Palliation The preferred bypass technique for lower-third lesions is a Roux-en-Y choledochojejunostomy . Cholecystojejunostomy carries a higher risk of complications and subsequent development of jaundice Resection for cure . Resection of a lower-third lesion usually involves a pancreaticoduodenectomy though transduodenal ampullary resection may be an acceptable alternative for a small adenoma of the ampulla For optimal results, pancreaticoduodenectomy is best performed in specialized centers. postoperative adjuvant therapy may improve the prognosis after resection of a pancreatic adenocarcinoma

59. PALLIATION IN PATIENTS WITH ADVANCED MALIGNANT DISEASE When a patient has advanced malignant disease, drainage of the biliary system for palliation is not routinely indicated, because the risk of complications related to the procedure may outweigh the potential benefit The best treatment for a patient with asymptomatic obstructive jaundice and liver metastases may be supportive care alone.   Biliary decompression is indicated if cholangitis or severe pruritus interferes with quality of life. Stent placed with ercp to be the palliative modality of choice for advanced disease, Upper-third lesions may be managed most easily through the initial placement of an internal/external catheter at the time of ptc .  

60. Metal expandable stents remain patent longer than large conventional plastic stents RCTs suggest that surgical biliary bypass should be reserved for patients who are expected to survive for 6 months or longer because bypass is associated with more prolonged palliation at the cost of greater initial morbidity.   The role of prophylactic gastric drainage at the time of operative biliary drainage remains controversial, 101,102 RCTs demonstrated a reduced incidence of subsequent clinical gastric outlet obstruction when this measure was employed. When a pancreatic malignancy is present, intraoperative celiac ganglion injection should be performed for either prophylactic or therapeutic pain

61. POSTOPERATIVE JAUNDICE The development of jaundice in the postoperative setting is approximately 1% of all surgical patients after operation. 120 When jaundice occurs after a hepatobiliary procedure, Attributable to specific biliary causes, Retained cbd stones, Postoperative biliary leakage (through reabsorption of bile leaking into the peritoneum) injury to the cbd Development of biliary strictures

62. JAUNDICE WITHIN 48 HOURS OF THE OPERATION Breakdown of rbc –due to multiple blood transfusions , The resorption of a large hematoma, Transfusion reaction. Known underlying hemolytic anemia and may be precipitated specific drugs ( e.G. , Sulfa drugs in a patient who has G6PD deficiency). Gilbert syndrome may first manifest itself early in the postoperative period. Intraoperative hypotension or hypoxemia or the early development of heart failure can lead to hyperbilirubinemia within 5 to 10 days after operation. The hyperbilirubinemia may be associated with other end-organ damage ( e.G. , Acute tubular necrosis). Impairment of renal function causes a decrease in bilirubin excretion and can be responsible for a mild hyperbilirubinemia .

63. Jaundice developing 7 to 10 days after operation In association with a medication-induced hepatitis attributable to an anesthetic agent. Incidence of 1/10,000 after an initial exposure. Administration of antibiotics or other medications used in the perioperative setting Jaundice associated with intrahepatic cholestasis is often a manifestation of a sepsis, particularly in patients with mods Jaundice may occur in as many as 30% of patients receiving total parenteral nutrition ( tpn ). It may be due to steatosis , particularly with formulas containing large amounts of carbohydrates. Decreased export of bilirubin from the hepatocytes may lead to cholestasis Acalculous cholecystitis or even ductal obstruction may develop as a result of sludge in the gallbladder and the cbd .

64. Unsuspected hepatic or post-hepatic causes ( e.G. , Occult cirrhosis, choledocholithiasis , or cholecystitis ) A rare cause of postoperative jaundice is the development of thyrotoxicosis . A diagnosis of exclusion- is so-called benign postoperative cholestasis , a primarily cholestatic , self-limited process with no clearly demonstrable cause that typically arises within 2 to 10 days after operation. Mechanism-combination of an increased pigment load, impaired liver function, and decreased renal bilirubin excretion caused by varying degrees of tubular necrosis. The predominantly conjugated hyperbilirubinemia may reach 40 mg/dl and remain elevated for as long as 3 weeks.

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