Approach to cholestatic jaundice

Seminar PPT

1. Approach to cholestatic Jaundice Dr.Ram Raut -JR III (Medicine) Guide - Dr.D.B. Kadam Seminar Teacher - Dr.Nitin Pai Dr.Manoj Waghmode

2. A 45-year-old male …. C /O – Yellowish discoloration of eyes, itching & low-grade intermittent fever since 3 months. Swelling over the feet, abdominal distension and abdominal pain since last month. Past alcoholic but had stopped since one year. Denied any high-risk sexual behavior. Jaundice

3. Normal Bilirubin Metabolism

4. Definition – Conjugated hyperbilirubinemia due to : Impaired bile formation (hepatocytes) Impaired bile flow (bile ducts/ductules) Consequences - Secondary liver damage Bile acid-induced hepatocyte injury Secondary biliary cirrhosis Failure of substances secreted in bile to reach intestine Bile acid deficiency in gut Fat malabsorption/fat-soluble vitamin malabsorption Cholestasis-

5. Screening tests that suggest cholestasis – Color change in skin/sclera/stool/urine Biochemical tests (Alkaline Phosphatase , Bilirubin) Sinusoidal blood Biliary canaliculus Towards central hepatic vein Towards Interlobular Bile duct Liver cell Endoplasmic reticulum Bilirubin, Bile salts, & Phospholipids N C Obstruction

6. Clinically - Pruritus, Fatigue, Xanthomas, Hepatic Osteodystrophy: back pain from osteoporosis, Pale stools, or steatorrhea Evidence of fat-soluble vitamin deficiency. Enlarged liver with a firm smooth non-tender edge . Histologically - Bile plugs (bilirubinostasis), F eathery degeneration of hepatocytes (cholate stasis), S mall-bile-duct destruction, P eri cholangitis, P ortal edema, B ile lakes and infarcts (typically with extrahepatic obstruction), F inally , biliary cirrhosis. After 3–5 yrs of jaundice , liver cell failure indicated by deep jaundice, ascites, edema and a lowered serum albumin develops. Pruritus lessens and the bleeding is not controlled by vitamin K. Hepatic encephalopathy is terminal.

7. Xanthomas Scratch marks & pruritus Sceral icterus Cholestasis : Retained bile pigments & bilirubin in hepatocytes

8. EVALUATION OF CHOLESTATIC JAUNDICE The first question -whether the cholestasis is from intrahepatic or extrahepatic process. Clues to extrahepatic obstructions – Abdominal pain, Palpable GB or upper abdominal mass, Evidence of cholangitis, and H/O- past biliary surgery. Clues to intrahepatic cholestasis- Pruritus, as in primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC) patient

9. Extrahepatic causes of cholestatic jaundice Benign Choledocholithiasis Postoperative biliary strictures Primary sclerosing cholangitis Chronic Pancreatitis AIDS cholangiopathy Mirizzi’s Syndrome Parasitic Disease (Ascariasis) Malignant Cholangiocarcinoma Pancreatic cancer Gall Bladder Cancer Ampullary Cancer Malignant involvement of the porta hepatis lymph nodes

10. Intrahepatic causes of cholestatic jaundice Viral Hepatitis Fibrosing cholestatic hepatitis – Hep. B &C Hep.A, EBV, CMV Alcoholic Hepatitis Drug toxicity Pure cholestasis- Anabolic & contraceptive steroids Cholestatic hepatitis- chlorpromazine, erythromycin, Amoxiclav Chronic cholestasis- chlorpromazine & prochloperazine Primary Biliary cirrhosis Primary Sclerosing cholangitis Vanishing Bile duct Syndrome Chronic rejection of liver transplant Sarcoidosis Drugs Non hepatobiliary Sepsis Benign post-operative cholestasis Para neoplastic Syndrome Veno-occlusive disease GVHD Inherited Progressive familial intrahepatic cholestasis Benign recurrent cholestasis Cholestasis of pregnancy Total Parenteral Nutrition Infiltrative diseases TB Lymphoma Amyloidosis Infections Malaria Leptospirosis

11. Risk factors - Alcohol intake, Medications, Pregnancy Sexual contact, drug abuse, needle punctures. ICU – Sepsis, shock liver & TPN . After BM transplantation- Veno occlusive disease or GVHD family history – Benign recurrent intrahepatic cholestasis (BRIC). Details – Onset, duration, Intermittent or progressive, Associated symptoms like dark urine, acholic stools, arthralgia, rash, wt loss, fever, chills, and pain in RHC.

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

13. S/o chronic liver disease , temporal & proximal muscle weakness. S/o Cholesterol deposition (Xanthomas, xanthelasmas) flat or slightly raised, yellow and soft , usually around the eyes, in the Palmar creases, below the breast and on the neck, chest or back. Anemia – GI blood loss, nutritional deficiency, hypersplenism Itching marks , clubbing , and lymphadenopathy. Virchow’s node or sister Mary Joseph's nodule- abdominal malignancy. Jugular venous distension – hepatic congestion. S/o 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) S/O Hepatic Osteoarthropathy – loss of height, back pain, collapsed vertebrae & fractures particularly of ribs with minimal trauma. Physical Examination –

14. xanthelasma

15. Stigmata of Chronic Liver Disease Palmar erythema Spider nevi Parotid enlarged Gynecomastia Muscle atrophy Asterixis Dupuytren’s contracture LL edema

16. Hepatomegaly Alcoholic liver disease, primary or secondary hepatic neoplasm, infiltrative disease, and primary biliary cirrhosis. Enlarged tender liver - Viral ,alcoholic hepatitis, infiltrative process, or chronic passive congestion of liver. Murphy’s Sign – Cholecystitis, Ascending cholangitis Enlarged gallbladder – Non- calculous biliary obstruction Hard & nodular hepatomegaly – ? metastatic malignancy. Other abdominal masses – Primary ca stomach or colon. Abdominal Examination

17. Ascites + Jaundice - Cirrhosis or malignancy with peritoneal spread. Rectal examination and sigmoidoscopy may indicate carcinoma. Marked splenomegaly- Cirrhosis + portal HTN or lymphoproliferative disease Stools - loose, pale, bulky and offensive , sticky to the pan & non flushable Our Case – O/E – Pallor +, icteric , B/L pedal edema. 1 x 1 cm firm lymph node in left axilla. P/A – Tender hepatomegaly - 3 cm with a smooth surface. Investigations – Total bilirubin 10 mg% (D= 4.2). ALP (1923 IU/L) & GGT 85 IU/L- raised. AST and ALT normal. Albumin of 2.4 gm%. PT INR 1.7 corrected by Vit.K suppl. Hb 10 gm/dl .Normal PBS Urine positive for BS & BP

18. Laboratory work up CBC – Anaemia - infection, blood loss or malignant disease. PMN leucocytosis - cholangitis or underlying neoplasm. LFTs - Alkaline Phosphate out of proportion to ALT/AST Albumin linked Bilirubin ( δ Fraction / biliprotein) Low albumin - chronic process (cirrhosis/ cancer) Normal Albumin - acute process ( viral hepatitis/ choledocholithiasis) Elevated PT – Vit K Deficiency RFTs - Sepsis , HRS, malignancy .

19. Enzymes raised in cholestasis Alkaline Phosphatase (ALP), gamma-glutamyl transpeptidase (GGT) & 5’-nucleotidase (5’NT). ALP isoenzymes are also present in bone & placenta. Increase in ALP, GGT & 5’NT  hepatobiliary origin. GGT levels – Fatty liver, alcoholic liver disease.

20. Proteins : Albumin : Decreased – advanced cirrhosis & signify severe hepatic dysfunction. Usually normal - acute hepatitis Globulins: Non-specific elevation – Chronic liver disease . Disproportionate elevation IgG in autoimmune hepatitis, IgM in PBC & IgA in alcoholic liver disease .

21. Prothrombin time (PT) & ( INR ) An increasing INR/PT - hepatocellular dysfunction. May be deranged in cholestasis , But due to the malabsorption of Vit. K Rapidly corrected by Parenteral administration of Vit K.

22. Other tests: Serological/ replicative markers – specific diagnosis of acute or chronic viral hepatitis . Anti mitochondrial antibody (AMA) for PBC (90%) P-ANCA in PSC (65%) Antinuclear factor (ANA), Anti-smooth muscle antibody (ASMA) & Anti-liver kidney microsome (LKM) antibody Alpha- feto protein, which is raised in HCC & Other Malignancies – CEA, CA19.9, PSA S. Ceruloplasmin for Wilson disease. seen in autoimmune hepatitis;

23. Serum drug levels Urine dipstic test (Ictotest) - Conjugated bilirubin +ve. X rays- changes of osteomalacia Bone mineral density by dual energy x-ray absorptiometry (DEXA).

24. Imaging RUQ Ultrasound CT scan ERCP PTC Endoscopic Ultrasound Endoscopic CT MR cholangiography Dilated bile ducts Non- dilated bile ducts CT/MRCP/ERCP/PTC ? Intra hepatic cholestasis MRCP/ liver biopsy Liver Biopsy Serologic studies AMA Hepatitis serologies Hep -A, CMV, EBV Review drugs Negative AMA Positive USG USG abdomen – Normal size liver & echo pattern With intrahepatic biliary radical dilatation (IHBRD) in left lobe, splenomegaly (18 cm), Normal CBD and gallbladder. Minimal free fluid. No focal lesions

25. Imaging USG First-line imaging Inexpensive No ionizing radiation GB stones readily detected. Absence of biliary dilatation suggests intrahepatic cholestasis & oppositely extrahepatic cholestasis Limitations Distal CBD, bowel gas, Obesity False negative – Partial obstruction, cirrhosis, scarring d/t PSC Except mass lesion in the head of the pancreas, USG usually does not identify the type of obstruction.

26. Gall bladder wall thickening. Stones in the GB

27. Other tests – Viral serologies – Ve for HIV, HBV and HCV . Blood culture sterile. Sputum AFB , CXR - NAD. Weil-felix, Paul-Bunnel and Brucella serologies negative. Ascitic fluid - Transudative no cells & negative ADA. Provisional diagnosis - Alcoholic liver disease with ? Biliary malignancy A contrast CT abdomen – Multiple ill-defined nonenhancing lesions in the liver, largest 1.4 cm x 1.0 x 1.0 cm rounded lesion (? necrotic lymph node) at the porta hepatis with IHBRD seen above this level in left lobe. Multiple small para-aortic, periportal and mesenteric lymph nodes present. Our Case

28. Dilated bile ducts and gallbladder Gallbladder Dilated bile ducts Mass in head of the pancreas CT Scan Localizes level of the obstruction, in about 90% cases. First choice in lymphoma, for retroperitoneal lymph node involvement

29. When clinical suspicion is supported by CT or USG, MRCP - Noninvasive screening ,rapid and comfortable. Failed or incomplete conventional ERCP. Variant biliary duct anatomy/ congenital duct abnormalities. Post operative anatomy where ERCP would be difficult. Evaluating changes of chronic pancreatitis or sclerosing cholangitis. Distal CBD Stone PSC

30. Direct cholangiography (PTC and ERCP) Direct visualization 99% sensitivity & specificity. Therapeutic interventions . ERCP is the procedure of choice in suspected ampullary or duodenal lesions in ca pancreas & when gallstone obstruction is suspected, where sphincterotomy & stone extraction can be implemented.

31. ERCP

32. Normal ERCP

33. Sclerosing cholangitis Multiple CBD Stones Ascariasis in CBD

34. Biliary stricture due to cholangiocarcinoma Alk phos = 669 IU Bili = 17.5 mg/dl AST = 68 IU ALT = 38 IU Bile duct obstruction from chronic pancreatitis

35. PTC is preferred when obstructing lesion is high C/I - Marked ascites and coagulopathy. PTC and ERCP may be used together across a difficult obstruction. Sometimes hepatobiliary scintigraphy, may help in evaluating biliary leaks & congenital malformations. Endoscopic CT & MRCP – Biliary obstruction, specially in setting of liver transplantation.

36. Technique of PTC & corresponding Cholangiogram

37. Major indications – chronic hepatitis, cirrhosis, Unexplained abnormal LFT, hepatosplenomegaly of unknown etiology, suspected infiltrative / Granulomatous disease Complications Minor – Prolonged RHC pain, (6%). Major - intra-abdominal bleeding, mortality ( 0.01%). Contraindications – Bleeding tendencies, INR>1.5 or PT >3 sec above the control, Severe thrombocytopenia Marked ascites . Transjugular liver biopsy or no biopsy at all are alternatives. Liver Biopsy

38. Adapted from Gordon Flynn, Wikimedia Commons Intrahepatic Perihilar Distal extrahepatic Duodenum Ampulla Of Vater Common bile duct Gallbladder Common hepatic duct Liver Cholestatic liver disease is broadly categorized as extra-hepatic or intrahepatic.

39. CHOLEDOCHOLITHIASIS Mechanism of jaundice – Impaction & edema of the common duct (Mirizzi syndrome) Direct inflammation of porta hepatis. CBD stones retained after cholecystectomy may produce jaundice in the immediate postoperative period or even several years later . Pain (biliary colic or from acute pancreatitis). Rapid rise & rapid decline within 72 hours in aminotransferases . If Cholangitis in choledocholithiasis – Fever with chills, abdominal pain, & jaundice. ( Charcot’s triad )

40. BENIGN STRICTURES OF THE BILE DUCTS In adults most common after surgery. PSC -multiple or diffuse strictures. Chronic alcoholic pancreatitis - a long stricture in the intrapancreatic portion of the common duct. Ampullary stenosis - trauma during passage of a stone & AIDS. Cholangitis - frequent in benign than in malignant one.

41. Pancreatic carcinoma commonest Other tumors - Cholangiocarcinoma, ampullary tumors, and carcinoma of GB Abdominal pain Loss of appetite and weight , Progressive deep & painless jaundice. Klatskin’s tumor NEOPLASTIC OBSTRUCTION Macro cystic adenocarcinoma of the pancreatic head.

42. Tumors producing complete obstruction of CBD may be accompanied by marked, palpable dilatation of the gallbladder ( Courvoisier’s law ). Ampullary tumors produce intermittent jaundice because of sloughing and partial relief of the block. Highest surgical cure of all tumors presenting as painless jaundice. Metastatic cancer may obstruct the bile duct, as may lymphoma. Hepatocellular carcinoma rupture into the biliary system throwing tumor emboli obstructing common duct. Compression by adjacent tumor/ peribiliary lymph node infiltrated by lymphoma, or metastatic ca breast. Direct infiltration by lymphoma.

43. UNCOMMON CAUSES OF OBSTRUCTIVE JAUNDICE Choledochal cyst . Duodenal diverticulum Hemobilia, (biliary colic, jaundice & GI bleeding). Ascaris ,liver flukes (Fasciola, Clonorchis or Opisthorchis). Secondary sclerosing cholangitis d/t opportunistic infections in immunodeficiency. Cryptosporidium parvum, cytomegalovirus (CMV), and Microsporidia most frequently found.

44. Intrahepatic causes of cholestatic jaundice

45. Drug-induced cholestasis. Clinically mimic viral hepatitis or biliary tract disease. Serum-sickness-like features (rash , arthralgia,& eosinophilia) Only practical approach is to eliminate the drug and monitor. Antimicrobial agents Augmentin , cloxacillin, erythromycin , ethambutol, dapsone, fluconazole, griseofulvin, ketoconazole Cardiovascular agents Disopyramide β -blockers, ACE inhibitors, ticlopidine, warfarin, methyldopa Endocrine agents Sulfonylureas, estrogens, tamoxifen, androgens, niacin, OCPs, anabolic steroids HAART- Zidovudine, Protease Inhibitors ( Indinavir, Ritonavir) Immunosuppressive agents – Azathioprine, cyclosporine, gold salts, NSAIDs Psychopharmacologic agents Tricyclic antidepressants, BZDs, Phenothiazines, Phenytoin, halothane Direct hepato-toxic Idiosyncratic

46. Alcoholic hepatitis . Marked tender hepatomegaly & e/o liver cell failure . Viral hepatitis. Acute phase of viral hepatitis; Most commonly hepatitis A, Hepatitis C, and hepatitis E. Though jaundice may be profound up to 6 months, complete recovery is the rule.

47. AIDS related cholangiopathy Cryptosporidium most frequent . Rarely Microsporidia, CMV, Mycobacterium avium complex, and Cyclospora Papillary stenosis if CD4 <100 Elevated ALP (mean 800 IU/L). Jaundice unusual , If present, suggests other disorders, like drug, alcohol abuse or neoplasm

48. Primary biliary cirrhosis. Autoimmune chronic non- suppurative cholangitis AMA positivity in 95% & ANA 30% cases. Progressive destruction of interlobular bile ducts(medium & small). Elevated ALP, IgM, and cholesterol & later on bilirubin. Predominantly middle aged female . Fatigue, pruritus, hyper pigmentation, Xanthomas. Majority have associated autoimmune disorders (Sjögren’s syndrome, scleroderma, and arthritis). Biopsy is diagnostic . UDCA- only drug, prolongs survival & improves biochemical abnormalities.

49. Bile duct

50. Primary sclerosing cholangitis. Mostly young men. Inflammatory bowel disease in >70% . So colonoscopy warranted. p -ANCA positive (up to 65%). Characteristic- Destruction & fibrosis of entire biliary tree. Diagnosis by imaging (MRCP/ERCP)– Multiple strictures & proximal dilatations ( classic beaded appearance ). Morbid complications - cholangiocarcinoma (Dreaded) & ca colon No established treatment.

51. Sclerosing Cholangitis: “ Onion-skin fibrosis ” around bile ducts very thickened bile duct wall decreases luminal diameter

52. Idiopathic adulthood ductopenia . Rare and defined by the presence of ductopenia (decrease of bile ducts in >50% of the portal triads ) and cholestasis in the absence of known cholestatic liver disease. A diagnosis of exclusion. Histology similar to primary biliary cirrhosis. UDCA may result in biochemical improvement. Autoimmune hepatitis . Females (70%) Anti LKM 1 , ANA and ASMA & hyper gammaglobulinemia in 80%. Associated autoimmune disorders include arthritis, rash, thyroiditis, Sjögren’s syndrome, and ulcerative colitis.

53. Syndromatic ductopenia (Alagille syndrome) Non- syndromatic adult ductopenia Ductal plate malformation (congenital hepatic fibrosis, biliary atresia Primary biliary cirrhosis, autoimmune cholangitis Primary sclerosing cholangitis Chronic rejection Graft-versus-host disease Sarcoidosis Cystic fibrosis Byler disease (progressive familial intrahepatic cholestasis) Histiocytosis X and Different drugs (augmentin, carbamazepine) Duct destruction after regional chemotherapy (e.g. floxuridine) Idiopathic adulthood ductopenia Causes and syndromes of ductopenia in adult

54. Decompensated chronic liver disease. Jaundice may occur in chronic hepatitis or cirrhosis. Other evidence of severe liver cell dysfunction is present & jaundice is prognostically a grave sign. Lymphoma. 3% and 10% cases of lymphoma develop jaundice . Fatty liver. Middle aged women with obesity, diabetes, and Hyper lipidemia and a variety of other medical problems. Cholestasis seen in about 5% cases.

55. Granulomatous hepatitis. Common cause of cholestatic liver disease. Sarcoidosis, infection (TB and fungal, esp. histoplasmosis), hypersensitivity reaction, malignancies, IBDs, and as a feature of other chronic liver disease . Pathologically , Granulomas are nodular infiltrates consisting of aggregates of epithelioid cells or macrophages with a rim of mononuclear cells/ Giant cells . Clinically, often asymptomatic, or Nonspecific symptoms . Routine bacterial & fungal blood culture, may be required. Benign course, with spontaneous recovery in most .

56. Hepatic Granulomas/Sarcoidosis

57. Sarcoidosis. Systemic disease characterized by non- caseating granuloma of multiple organs. 70% have hepatic granulomas. Portal granuloma result in cholestasis & destruction of interlobular bile ducts. Elevated alkaline phosphatase most characteristic abnormality & reduced with corticosteroids. Concomitant intrathoracic disease, pulmonary symptoms, and significant anemia/ leucopenia.

58. Bacterial infection (sepsis) Most common ly gram-negative bacteria , also Staphylococcus aureus in TSS & streptococcal pneumonia. Rarely leptospira, clostridium & borrelia. Massive ductular dilatation & retained bile at the interface of hepatic parenchyma & portal tracts, (cholangitis lenta) .

59. Total parental nutrition. When >60% calories as carbohydrates given > 3-4 weeks. Gallbladder stasis is almost universal & thereby gall stones. No oral feeding Diminished release of hormones that stimulate bile flow Diminished bile flow Direct oxidant stress to the liver. If TPN cannot be discontinued, it should be cycled around 10 hrs/day. Keeping glucose <6 g/kg/day and lipid <2 g/kg/day. Recently UDCA is found helpful.

60. Benign recurrent intrahepatic cholestasis (BRIC). Characterized by... Recurrent epi. of jaundice & pruritus,+ Symptom-free intervals. Biochemical signs of cholestasis. H istologically- canalicular stasis, normal bile ducts and absence of inflammation and fibrosis. Sporadic or familial forms (chromosome 18)- Progressive familial intrahepatic cholestasis (PFIC types 1-3) . GGT is normal with high alkaline phosphatase. Cholestatic episodes may last for many months. The episodes in BRIC eventually resolve without morphological sequelae

61. Cholestasis of pregnancy. Recurrently in 2nd & 3rd trimester of pregnancy & resolves after delivery. ? inherited & Contraceptive drugs are a risk factor. Biochemical cholestasis with pruritus, & jaundice. Histologically similar to BRIC. Increased risk of premature delivery or stillbirths. UDCA has been used with success.

62. Causes of jaundice – Viral hepatitis, Choledocholithiasis, Hepatic sickle cell crisis Hepatic sickle cell crisis- Severe RUQ pain, fever, leukocytosis, jaundice, tender hepatomegaly, and moderate elevation of alkaline phosphatase. Resolution followed by persistent cholestatic jaundice for several weeks Prevalence - 17% Causes – Sepsis, Drugs or anesthetic-induced hepatitis, Obstruction from pancreatitis, choledocholithiasis, Or direct injury to the biliary tree. “Benign postoperative cholestatic jaundice” occurs between post op day 1 to 10. Postoperative jaundice. Sickle cell anemia.

63. Nodular regenerative hyperplasia (NRH), Bone marrow transplant (BMT), Connective tissue diseases (CTD), Felty’s syndrome, Mastocytosis, Hypereosinophilic syndrome, Hyperthyroidism, Space occupying lesions. Para neoplastic syndromes of Hodgkin’s, Medullary thyroid Ca, RCC, Renal sarcoma, T cell lymphoma, Prostate Ca, Many GI malignancies. Stauffer’s Syndrome – Intrahepatic cholestasis in RCC OTHER INTRAHEPATIC CAUSES OF CHRONIC CHOLESTASIS

64. SUMMARY EVALUATION OF CHOLESTASIS AND/OR JAUNDICE Suspect cholestasis on history, physical exam , lab. Look for clues to mechanical obstruction of ducts and/or mass lesions (radiologic studies ). Visualize , diagnose and treat mechanical obstruction . Consider intrahepatic cholestasis, obtain liver biopsy.

65. Histopathology of lymph node - caseating granulomatous lymphadenitis. Liver biopsy - consistent with tuberculosis, with periportal epitheloid granulomas. The patient was started on AKT. He became afebrile on ATT with regression of jaundice and constitutional symptoms. After completing six months of AKT, complete resolution of jaundice. Repeat ultrasound showed normal liver with no IHBRD or focal lesions. What happened to our patient…

66. Treatment of cholestatic jaundice … Obstructive Jaundice : Key Principle is Decompression When cholangitis - IVF, Antibiotics, Decompression Stones - Remove stones vs. stent vs Drainage (ERCP /PTC/ surgery) Benign stricture - Endoscopic dilatation/ stent vs drainage catheter Cancer - Stent vs drainage +/- resection Medical management: UDCA Diet - MCT, Fat soluble vitamin supplementations & calcium Pruritus – Cholestyramine, anti- histaminic, phenobarbitone Bone disease – Vit.D, Bisphopshonates

67. Thank You !