Approac h to cholestatic jaundice

EVALUATION OF CHOLESTATIC JAUNDICE

1. Approach to Cholestatic Jaundice

2. Introduction Clinical & Diagnostic evaluation Intrahepatic vs Extrahepatic causes PBC PBC- AIH overlap PSC PSC – AIH Overlap DILI ICP Clinical Case

3. Introduction Cholestasis is an impairment of bile formation and/or bile flow which may clinically present with fatigue, pruritus and, in overt form, jaundice. Cholestasis is considered chronic if it lasts >6 months. Chronic cholestatis often have an asymptomatic course over months or years, and can be identified by elevated serum ALP.

4. Serum ALP can have different sources (e.g. liver, intestine, bone, placenta ). Therefore, its elevation can be caused not only by cholestatic liver disease, but also rapid bone growth in children (e.g. Paget’s disease), extrahepatic diseases .vitamin D deficiency or pregnancy. In clinical practice, the hepatic origin of elevated serum ALP is usually supported by simultaneous elevation of serum GGT (or 5’ nucleotidase ) A cholestatic pattern is defined by an R ratio of <2 (calculated as ALT/ALT ULN ÷ ALP/ALP ULN)

5. MECHANISM OF CHOLESTASIS Bile formation originates in hepatocytes with the uptake and production of organic anions, bilirubin and bile salts. Multiple factors contribute to the impairment of bile flow: Endotoxins are potent stimuli for activating cytokine production from macrophages and have acute cholestatic effects on hepatic bile production.

6. The cut-off levels of serum ALP and GGT requiring diagnostic work-up are debated. However follwing is proposed- ALP >1.5 times the ULN and GGT levels >3 ULN

7. A. Hepatocellular cholestasis Sepsis, endotoxemia -induced cholestasis viral hepatitis Alcoholic or non-alcoholic steatohepatitis Drug- or parenteral nutrition-induced cholestasis Genetic disorders: e.g., BRIC, PFIC, ABCB4 deficiency, intrahepatic cholestasis of pregnancy (ICP), erythropoietic protoporphyria Malignant infiltrating disorders: e.g., hematologic diseases, metastatic

8. Benign infiltrating disorders: e.g., amyloidosis , sarcoidosis hepatis and other granulomatoses , storage diseases Paraneoplastic syndromes: e.g., Hodgkin disease, RCC Nodular regenerative hyperplasia Vascular disorders: e.g., Budd– Chiari syndrome, veno -occlusive disease, congestive hepatopathy Cirrhosis (any cause)

9. B. Cholangiocellular cholestasis Primary biliary cholangitis Primary sclerosing cholangitis IgG4-associated cholangitis Secondary sclerosing cholangitis , e.g. due to cholangiolithiasis , ischemia (Shock, polytrauma , intensive care therapy), telangiectasia , vasculitis , Cystic fibrosis Drug-induced cholangiopathy ‘ Ductal plate malformations’: von Meyenburg complexes ( biliary hamartomas ), Caroli syndrome, congenital liver fibrosis Graft-vs.-Host disease Idiopathic ductopenia Langerhans cell histiocytosis

10. 2. Extrahepatic Cholestasis INTRINSIC AIDS cholangiopathy Ampullary cancer Autoimmune pancreatitis Cholangiocarcinoma Choledocholithiasis CMV, Cryptosporidiosis Cholangitis Malignancy Microsporidiosis Parasitic infections PSC EXTRINSIC Gallbladder cancer Malignancy Metastases, including portal adenopathy from metastases Mirizzi syndrome Pancreatic cancer Pancreatic pseudocyst Pancreatitis

11. Clinical History & cause of cholestasis 1. Pain - duct stones, tumor or gallbladder disease. 2. Arthralgia , myalgia predating jaundice -hepatitis (viral/drug related) 3 . Fever and rigors- cholangitis d/t duct stone or traumatic stricture (Charcot’s intermittent biliary fever). Or systemic infection 4. Contaminated foods/alcohol consumption. 5. H/o hepato -toxins - Drugs /chemicals/ occupational 6. Parenteral exposures (Bl. Transfusions, drug abuse/ tattoos , sexual activity) 7. H/o Ulcerative colitis - ? PSC

12. Risk factors- 1. Alcohol intake, 2. Medications, 3. Pregnancy 4. Sexual contact, drug abuse, needle punctures. 5. ICU – Sepsis, shock liver & TPN . 6. After BM transplantation- Veno occlusive disease or GVHD • Family history – Benign recurrent intrahepatic cholestasis (BRIC).

13. Examination 1 ) Liver- Enlarged / tender /consistency 2) Cholesterol deposition ( Xanthomas , xanthelasmas ) usually around the eyes, Palmar creases, below breast and on the neck, chest. 3) Anemia – GI blood loss, nutritional deficiency, hypersplenism 4 ) Itching marks , clubbing, and lymphadenopathy . 5 ) Virchow’s node or sister Mary Joseph's nodule- abdominal malignancy.

14. 6) Jugular venous distension – hepatic congestion. 7) Fat soluble vitamin deficiency – Vit.D ( osteomalacia , Demineralized bone, Kyphosis , Fractures), Vit.E ( cerebellar ataxia, posterior column dysfunction, peripheral neuropathy), Vit.K (Puncture hematoma, Spontaneous bruising ) Vit.A (night blindness, thick skin) 8) Hepatic Osteoarthropathy – loss of height, back pain, collapsed vertebrae & fractures particularly of ribs with minimal trauma.

15. USG The first step to exclude dilated intra- and extrahepatic ducts. Advantage 1. First-line imaging 2. Inexpensive 3. No ionizing radiation 4. GB stones readily detected . 5. Absence of biliary dilatation suggests intrahepatic cholestasis & oppositely extrahepatic cholestasis Limitations Distal CBD, bowel gas,Obesity . operator dependent and abnormalities of bile ducts may be missed.

16. CT Localizes level of the obstruction, in about 90% cases. First choice in lymphoma , retroperitoneal lymph node involvement. less interpreter-dependent, but is associated with radiation exposure .

17. MRCP Noninvasive screening ,rapid and comfortable. Variant biliary duct anatomy/ congenital duct abnormalities. Post operative anatomy where ERCP would be difficult. Evaluating changes of chronic pancreatitis or sclerosing cholangitis . (EUS) is equivalent toMRCP in the detection of bile duct stones and lesions causing extrahepatic obstruction. Distal CBD

18. ERCP The gold standard for visualizing the biliary tract and treating extrahepatic biliary obstruction . 99% sensitivity & specificity. But even in experienced hands it carries a significant complication rate [pancreatitis in 3–5%, cholangitis 1%, procedure-related mortality 0.4%]

19. Percutaneous Transhepatic Cholangiography [PTC] PTC is preferred when obstructing lesion is high C/I- Marked ascites and coagulopathy

20. Liver Biopsy Should be considered in patients with otherwise unexplained intrahepatic cholestasis and a negative AMA test . Particular attention to the condition of bile ducts is critical in the histologic evaluation and a biopsy of adequate quality should contain >10 portal fields because of the high degree of sampling variability in patients with small bile duct disease. [ EASL ]

21. Primary billiary cholangitis Why its called Cholangitis in stead of cirrhosis ?

22. With increased awareness and better diagnostic tools, most pts are diagnosed at early disease stages. The term primary biliary cholangitis better reflects the most current natural history of the disease, in which fewer than a third of pts have cirrhosis at the time of presentation and removes the stigma a/w such terminology.

23. Primary Biliary Cirrhosis Autoimmune chronic , non- suppurative cholangitis leading to Progressive destruction of interlobular bile ducts AMA positivity in 95% & ANA 30% cases. Predominantly middle aged female 30-60 yrs . M : F ratio 9:1 Predisposition to developing PBC is influenced by both genetic background and environmental exposures. The strongest risk factor is a family HX of PBC or other autoimmune disease.

24. Histology: Florid duct lesion in PBC epithelium of the interlobular and segmental bile ducts degenerates segmentally , with formation of poorly defined, noncaseating epithelioid granulomas , is nearly diagnostic of PBC

25. Diagnosis 2 out of 3 of the following criteria are met: Chronic cholestatic liver enzyme elevation (typically ALP ≥1.5 times ULN Elevated serum AMA ( titers ≥1:40), or A liver biopsy specimen consistent with PBC. [ Sleisenger ]

26. AMA hallmark autoantibody of PBC directed against various proteins confined to the inner mitochondrial membrane, especially target the E2-subunit of the pyruvate dehydrogenase complex (PDC-E2). 9 subtypes of AMA (M1–M9) The M2 subtype was considered the most specific AMA for PBC. AMA titers of at least 1 : 40, greater or >0.1 unit are considered significant . however, the magnitude of titers does not correlate with severity of the disease.

27. ANA Anti-gp210 antibodies are only detected in 20–40% of pts with PBC are highly specific. PBC-specific types of Antinuclear Antibodies:ANA Anti gp120 Anti sp100 P62 ( Nucleoporin 62 ) Anti- centromere

28. PBC with features of AIH Around 8–10% of patients demonstrate features characteristic of AIH. PBC and AIH usually present in patients simultaneously but separate manifestations in patients with a prior diagnosis of PBC or AIH may occur even years after the primary diagnosis. Classical PBC presents with only minimal lobular and interface hepatitis activity

29. Autoantibodies against soluble liver antigen (SLA)/liver pancreas (LP) and double stranded DNA have been associated with presence of AIH in patients with PBC. EASL recommend that liver biopsy is mandatory in confirming the features of AIH

30. Patients with known diagnosis of PBC who develop features of AIH PBC patients under UDCA treatment may develop increasing hepatitis activity even years after the initial PBC diagnosis. A liver biopsy should be obtained to determine the degree of interface hepatitis

31. Patients with known diagnosis of AIH who develop features of PBC AIH patients who develop elevated cholestatic liver enzymes over time along with typical symptoms for PBC ( pruritus , sicca syndrome) should be evaluated for the presence of PBC.

32. Primary sclerosing cholangitis (PSC) chronic, cholestatic liver disease characterized by an inflammatory and fibrotic process affecting both intra and extrahepatic bile ducts Etiology – complex interplay of autoimmune and genetic susceptibilities, environmental exposures, unique dysbiosis of gut microbiota P-ANCA positive (up to 65%). male to female ratio is approximately 2:1 PSC can be seen in children as well as elderly, but mean age at diagnosis is around 40 years.

33. There is irregular bile duct obliteration, including formation of multifocal bile duct strictures. PSC is a progressive disorder that eventually develops into liver cirrhosis and liver failure. Up to 80% of PSC patients have concomitant inflammatory bowel disease (IBD)mostly ulcerative colitis (UC)

34. Signs and symptoms 50% of PSC patients are symptomatic at first presentation. Typical symptoms include pruritus , pain in RUQ, fatigue, weight loss. Hepatomegaly and splenomegaly are common Osteopenic bone disease is a complication of advanced PSC ( less cmmon than in PBC). Fat malabsorption with steatorrhea and malabsorption of fat-soluble vitamins occur only with prolonged cholestasis .

35. Diagnosis ALP – 2-3 times elevated Bilirubin - normal in 70 % pt Elevated levels of IgG - 60% of patients most frequently reported are perinuclear antineutrophil cytoplasmic antibodies ( pANCA ) (26–94%), ANA- (8– 77%) smooth muscle antibodies (SMA) (0–83%)

36. ERCP gold standard . cholangiographic findings- mural irregularities and diffusely distributed multifocal, short, annular strictures alternating with normal or slightly dilated segments producing a ‘‘ beaded” pattern .

37. PSC–AIH overlap syndrome. Ill-defined immune-mediated disorder which is predominantly found in children, adolescents and young adults. patients more commonly suffers from IBD and more often positive for atypical pANCA than those with AIH only.

38. Diagnosis Typical AIH features [Revised AIH score > 15 ] AMA absent Focal bile duct strictures and dilations by cholangiography Bile duct loss or damage, portal edema , and fibrous obliterative cholangitis possible on histologic examination

39. Immunoglobulin G4-associated cholangitis presents with biochemical and cholangiographic features indistinguishable from PSC, frequently involves the extrahepatic bile ducts, good responds to anti-inflammatory therapy Often associated with autoimmune pancreatitis and other fibrosing conditions M:F ratio 7 : 1 Mean age - 50 years Unlike PSC , IAC is not asoociated with IBD

40. Serum elevated IgG4 levels HPE infiltration of IgG4-positive plasma cells in bile ducts and liver tissue [>10 IgG4+ plasma cells/ hpf ] No peribiliary concentric fibrosis 2 of 3 classic lesions: Lymphoplasmacytic infiltrates, storiform fibrosis a or obliterative phlebitis Cholangiography Long strictures with prestenotic dilation Intrahepatic or hilar and distal CBD strictures

41. Drug-induced chronic cholestasis Defined by an international consensus Panel isolated elevation of ALP >2 ULN or ALT/ALP ratio <2 ( both elevated above ULN) cholestatic injury has a better prognosis than hepatocellular injury. 30% of all DILI cases are cholestatic . Temporal correlation of their use with elevation of the liver enzymeLevels , Withdrawal of the offending agent and resolution of the liver enzyme elevations is sufficient to confirm the diagnosis.

42. Most drugs that are hepatotoxic cause idiosyncratic liver injury, defined as injury that is unpredictable, occurs at therapeutic drug levels, and is infrequent.

43. Bland cholestasis Anabolic steroids Estrogens Cholestatic hepatitis ACE inhibitors: captopril , enalapril Antimicrobials: amoxicillin- clavulanic acid, ketoconazole Azathioprine Chlorpromazine NSAIDs: sulindac , piroxicam Granulomatous hepatitis Allopurinol Antibiotics: sulfonamides Antiepileptics : carbamazepine , phenytoin Cardiovascular agents: hydralazine , procainamide , quinidine Vanishing bile duct syndrome Amoxicillin- clavulanic acid Chlorpromazine Dicloxacillin Flucloxacillin Macrolides

44. Intrahepatic cholestasis of pregnancy (ICP) reversible form of cholestasis characterized by intense pruritus in pregnancy (starting in the second or third trimester of pregnancy in most patients) elevated serum ALT and fasting serum bile acid levels spontaneous relief of signs and symptoms after delivery (within 4–6 weeks)

45. Clincal features Pruritus (typically worse at night) potential fetal risks( prematurity, IUGR ) steatorrhea and postpartum haemorrhage due to vitamin K deficiency is uncommon

46. Diagnosis based on otherwise unexplained pruritus and elevated fasting serum bile acid ( ≥ 11 mmol /L) ALT activities are elevated as well. ICP patients with ABCB4 variants tend to display elevated GGT levels, which are otherwise normal in ICP.

47. Vanishing bile duct syndrome Refers to a group of acquired disorders resulting in progressive destruction and disappearance of the intrahepatic bile ducts and ultimately cholestasis . Ductopenia (a pathologic description)defined as the absence of interlobular bile ducts in >50% of portal tracts. The diagnosis is made pathologically, although it can be suggested on imaging tests such as ERCP MRCP when disease is advanced

48. Often present with cholestasis : elevated alkaline phosphatase +/- jaundice Increased ALP due to compression of small intrahepatic bile ducts by expanding granulomas CAUSES Infections Brucellosis, TB Fungal: histoplasmosis Leprosy Q fever Schistosomiasis Sarcoidosis Idiopathic granulomatous hepatitis Infiltrative/ Granulomatous Diseases

49. Hepatic Granulomas/Sarcoidosis

50. Hepatic Sarcoidosis: granulomas and giant cells

51. Benign recurrent intrahepatic cholestasis (BRIC). Characterized by. Recurrent epi . of jaundice & pruritus ,+ Symptom-free intervals. Biochemical signs of cholestasis . Histologically - canalicular stasis, normal bile ducts and absence of inflammation and fibrosis.

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