Approach to obstructive jaundice

A clinical approach to case of cholestatic jaundice.

1. Approach to obstructive jaundice

2. Jaundice, derived from the word jaune (in 1300 AD), is the yellowish discoloration of the skin, conjunctivae, and mucous membranes. The first description of jaundice is mentioned in EBERS PAPYRUS of Egypt dating to 3000 BC. The word obstructive jaundice was first used in 1935, by A. O. Whipple, an American surgeon.

3. BILE Bilirubin is the catabolic end product of heme metabolism. A healthy adult produces an average of 4 mg/kg of bilirubin each day. Most bilirubin (70% to 80%) results from catabolism of hemoglobin. The remaining 20% to 30% of bilirubin derived from breakdown of other heme-containing proteins (e.g., catalase, cytochrome oxidases) in hepatocytes.

4. Bilirubin metabolism heme oxygenase Fe, CO Biliverdin reductase Conversion of erythrocyte-derived hemoglobin to bilirubin occurs in macrophages in the spleen, bone marrow, and liver Free hemoglobin, haptoglobin-bound hemoglobin, are catabolized to bilirubin in hepatocytes .

5. Bilirubin(Unconjugated) BILIRUBIN IX-ALPHA-ZZ ALBUMIN TRANSPORTED TO LIVER NON COVALENT, TEMPORARY BOND Bilirubin(conjugated)

6. Zakim and boyer’s text book of hepatology

7. Rotor syndrome Dubin Johnson syndrome Gilbert Criggler Najar syndrome

8. CONJUGATED BILIRUBIN COLON UROBILINOGEN EXCRETED BY KIDNEYS 20% REABSORBED De-conjugation Excreted in feces

9. Backflow of conjugated bilirubin Water soluble Large free fraction Weak bond with Albumin Excreted by kidneys Glomerular filtration Unconjugated bilirubin never appears in the urine Cholestasis is defined as disturbances in bile flow caused by diseases either in the hepatocytes, intrahepatic bile ducts or extrahepatic biliary system.

10. INTRAHEPATIC CholestaSIS GRANULOMATOUS AMYLOIDOSIS MALIGNANCIES CYSTIC FIBROSIS(30%) GVHD PRIMARY BILIARY CHOLANGITIS BENIGN RECURRENT CHOLESTASIS PARANEOPLASTIC TPN INFILITRATIVE DISEASES DISEASES WITH CHOLANGIOCYTE INJURY DISEASES WITH MINIMAL HISTOLOGIC CHANGES

11. The most common Granulomatous disorders that produce jaundice are tuberculosis and sarcoidosis. In PBC, cholangiocyte is the target of immune mediated inflammation, predominantly seen in middle aged women. Erythromycin, septran , amoxicillin–clavulanic can cause cholangiocyte injury leading to cholestasis. JAUNDICE PUO SUSPECT GRANULOMATOUS DISEASE JAUNDICE ANOREXIA, WEIGHT LOSS SUSPECT NEOPLASTIC DISEASE

12. Jaundice may accompany cholestasis in the absence of hepatic infiltration or injury to hepatocytes or cholangiocytes . Mutations in the genes that encode transport proteins involved in bile formation and conditions that interfere with the function or expression of such proteins.

13. Extrahepatic causes Benign causes MALIGNANT CAUSES

14. BENJAMIN CLASSIFICATION OF cholestatic JAUNDICE

15. Ca Head of Pancreas Cholangiocarcinoma Ligated CBD TYPE 1- Complete obstruction Choledocholithiasis Choledochal cyst Duodenal diverticula Periampullary tumor Papillomas of the bile duct Intra biliary parasites TYPE 2- Intermittent obstruction

16. Strictures of the CBD Congenital/traumatic Sclerosing cholangitis Post radiotherapy Stenosed biliary- enteric anastomosis Cystic fibrosis Chronic pancreatitis TYPE 3- Chronic incomplete obstruction Trauma Sclerosing cholangitis Intrahepatic stones TYPE 4- Segmental obstruction

17. Effects of biliary obstruction

18. Intestines Obstruction to bile flow leads to absence of bile in intestine. This leads to Overgrowth of Gr negative bacteria Reduced expression of tight junctions Altered permeability Bacterial and endotoxin translocation Accumulation of bile acids in liver kupffer cells and macrophage functions  

19. Coagulation system Production of vit K dependent factors Disturbed extrinsic pathway of coagulation. Coagulation tests are not affected until plasma levels of the relevant factors fall below 30-40% of normal   SEPSIS Ca PANCREAS HCC THROMBOEMBOLISM Bleeding tendency

20. Coagulation system contd.. THROMBOCYTOPENIA PRODUCTION OF COAGULATION FACTORS   PORTAL VEIN STASIS THROMBOSIS

21. Renal system AKI

22. Hepatic effects Increased intraductal pressure Bacterial growth leading to cholangitis Liver cell apoptosis Regurgitation of conjugated bilirubin due to disruption of tight intracellular junction Long standing obstruction leads to secondary biliary cirrhosis

23. Dermatologic EFFECT ON WOUND HEALING Delayed wound healing and high incidence of wound dehiscence. This is due to decreased activity of enzyme propyl hydroxylase in the skin Normally, this enzyme helps in incorporation of proline into collagen Decreased activity leads defective synthesis of collagen

24. PRURITUS Elevated bile acids in skin- pruritogens Evidence against this- 1.Occaisonal subsidence of pruritus in spite of ongoing cholestasis 2.Not all patients of cholestasis have pruritus. Bile acids- hepatocyte injury – leakage of hepatocyte contents which are pruritogenic. Elevated endogenous mu agonist opioids via unknown mechanism in CLD. Lysophosphatidyl choline Lysophosphatidic acid autotaxin pruritus Bile acid sequestrants Opioid antagonists Rifampin

25. Clinical evaluation The main aims of clinical evaluation are 7. Postulate an investigation algorithm based on the clinical findings. Determining the obstructive nature of jaundice. The need for multiorgan system support. Impact of jaundice on other organ systems. If malignant then whether the disease is metastatic in nature. Whether the etiology is benign or malignant in nature. Identifying the cause for obstructive jaundice.

26. history Jaundice with pruritus, clay coloured stools (acholic stools) and high coloured urine is seen in the obstructive pattern of jaundice. Pain abdomen before the onset of jaundice --- choledocholithiasis or cholecystitis causing mirrizi syndrome Fever -- highly suggestive of cholangitis The onset of jaundice after any hepatobiliary surgery--- bile duct injury, bile leak. Any history of critical illness or shock that can cause cholestasis of sepsis. Any recent new medication use, especially antibiotics which can cause cholestasis Jaundice with nausea, vomiting, and prodrome phase -- viral hepatitis. History of travel, sexual contact, blood transfusion, major surgery, intravenous (IV) drug use can support this diagnosis

27. Family or personal history of any autoimmune disease can point toward PSC or PBC Severe pain and associated symptoms suggestive of pancreatitis can also cause transient obstructive jaundice. Painless progressive jaundice, Weight loss, bone pains, and abdominal distension due to ascites are suggestive of malignant etiology. History of abdominal masses is highly suggestive of malignancy. Jaundice in IBD should always raise suspicion of primary sclerosing cholangitis Patient giving history of recurrent episodes of malaise and pruritus in association with jaundice, starting from 2 nd decade of life- BRIC of a biliary stricture. History of inflammatory bowel disease presenting as jaundice is suggestive of primary sclerosing cholangitis.

28. Clinical evaluation Clinical evaluation has a positive predictive value of only about 75%. About 25% of patients with suspected obstruction actually have hepatocellular disease. General examination should be done to look for the presence of stigmata of chronic liver disease White nails Muehrcke nails Clubbing Palmer erythema Dupuytren contracture Carpel tunnel syndrome Loss axillary and pubic hairs Spider nevi Jaundice Glossy lip and tongue Gynecomastia Testicular atrophy Petechial rash Dry skin, paper money skin

29. Examination

30. Large, nodular liver suggests possible hepatic metastasis. Tender hepatomegaly can be seen in viral hepatitis, congestive heart failure, and alcoholic hepatitis. In choledocholithiasis and cholecystitis, right upper quadrant (RUQ) tenderness is appreciated. Palpable, enlarged, painless gallbladder can suggest malignant etiology . Splenomegaly can be seen due to massive hemolysis or portal HTN. Ascites can be observed in cirrhosis due to portal HTN.

31. Curvoiser’s law- a palpable non-tender gallbladder in the presence of jaundice is unlikely to be due to gallstones. It usually indicates a neoplastic stricture obstructing the distal common bile duct. Exceptions- 1.Double impaction: stones, simultaneously occluding the cystic duct and the distal common bile duct (CBD). The stone in the CBD causes obstructive jaundice and a synchronous stone in the cystic duct leads to mucocele or empyema of gall bladder. 2. Pancreatic calculus obstructing the ampulla of vater 3. Oriental cholangiohepatitis (ductal stones formed secondary to liver fluke infestation)

32. Investigations Determining the severity of illness Urgency of intervention Level of care required

33. Increasing PT/INR: hepatocellular dysfunction. PT/INR can also be deranged in cholestasis d ue to the malabsorption of vit. K. Coagulopathy in obstructive jaundice is rapidly corrected by parenteral administration of vit k. Obstructive pattern Hemolytic pattern Serum Bilirubin  conjugated  unconjugated +++ + + +++ Urobilinogen ↓ ↑ Urinary Bilirubin + Serum ALP ↑ No change Serum GGTP ↑ No change Serum 5- nucleotidase ↑ No change Transaminases Mildly raised Markedly raised Complete blood count- to look for anemia(malignancies), Leucocytosis (cholangitis). Liver function tests

34. LIVER FUNCTION TESTS – CHOLESTATIC PATTERN ALP- Hydrolyze the phosphate esters in alkaline environment, found in Liver, Placenta, bone, intestine. Liver ALP – Canalicular membrane of hepatocytes and apical membrane of cholangiocytes . Elevation of 5′-nucleotidase levels is used in parallel as specific marker to confirm a suspected hepatic origin of ALP. Elevations of ALP and Bil out of proportion to AST and ALT - Cholestasis bile duct obstruction Duct cell injury liver infiltration Architectural disarray, damaged liver lobule Raised ALP

35. History, clinical examination, basic routine investigations Ultrasonography of abdomen

36. USG ABDOMEN It is the preliminary investigation of choice 1. Helps in identifying the cause of obstruction 2. Level of obstruction and degree of back pressure changes. 3. Status of the liver and abdominal metastases in suspected malignant obstruction. 4. Splenic enlargement. 5. Presence of ascites. Limitations of USG- Excess bowel gas, obesity hampers the window. Does not clearly identify distal CBD pathology Except mass lesion in the head of the pancreas, USG usually does not identify the type of obstruction

37. Algorithm for imaging Biliary dilatation on USG absent present CECT/MRCP/ERCP likelihood of biliary obstruction high medium low Evaluate for intrinsic liver disease EUS/MRCP ERCP

38. Jaundiced patients with biochemical evidence of cholestasis in whom imaging studies do not suggest biliary obstruction should be evaluated for underlying liver disease. Depending on the disorder suspected, laboratory studies include Viral serologies – HBV HCV HEV,EBV,CMV AMA (for PBC) ANA,ANCA – PSC One protocol suggests that if all the tests are negative and still ALP is 2 times the normal for minimum of 6 months, liver biopsy is done.  

39. COMPUTERIZED TOMOGRAPHY SENSITIVITY 63-96% SPECIFICITY 93-100%

40. 82-100% sensitivity and 94-98% specificity MRCP

41. It shows the abrupt termination of the dilated pancreatic and bile ducts at the level of the pancreatic head, the classic sign of the presence of a carcinoma of the head of the pancreas.

42. ERCP 89%-98% sensitivity & 89%-100% specificity. ERCP is the procedure of choice in choledocholithiasis and in suspected ampullary or duodenal lesions in ca pancreas. The diagnostic role of ERCP is to collect tissue for biopsy in periampullary growths or brush cytology samples. The exact level of the block and the severity of backpressure changes can also be ascertained.

43. Biliary stricture due to cholangiocarcinoma

44. EUS sensitivity 89%-97% and 67%-98% specificity Advantage of permitting biopsy and aspiration of suspected malignant lesions Most useful in circumstances in which the patient is thought to be at high risk for complications of ERCP. Imaging of bile ducts via EUS is superior to USG and CT.

45. Requires passage of a needle through the skin and subcutaneous tissues into the liver and advancement into a peripheral bile duct. When bile is aspirated, a catheter is introduced through the needle, and radiopaque dye is injected. The sensitivity and specificity of percutaneous THC for the diagnosis of biliary tract disease are comparable with those for ERCP. Interventional procedures like balloon dilation and stent placement can be performed and cholangioscopy is also feasible by this route. Particularly technically advantageous when the level of biliary obstruction is proximal to the common hepatic duct or altered anatomy precludes ERCP . Percutaneous Transhepatic Cholangiography

46. PITT’S PROGNOSTIC SCORE Parameters (one point per factor) Type of obstruction (benign or malignant) Age >60 years Serum albumin < 3gm/dl Serum bilirubin > 10 mg% Serum Alkaline phosphatase > 100 IU Serum creatinine > 1.3 mg% TLC > 10000/mm 3 Haematocrit < 30 score mortality 0% 3 4% 4 7% 5 44% 6 67% 8 100% score mortality 0% 3 4% 4 7% 5 44% 6 67% 8 100%

47. THERAPEUTIC APPROACH The therapy is directed at diagnosed condition. In a patient with bile duct obstruction, therapy is directed at relieving the obstruction. Interventional endoscopic or radiologic approaches include sphincterotomy, balloon dilation of focal strictures, and placement of drains or stents. Surgery should be considered for neoplasms, if feasible. Preoperative stenting to relieve jaundice is of great help in preparing the patient for surgery. In inoperable cases, palliative stenting is done.

48. Thank you