Jaundice

In Tens of Minutes 1.0= Normal Vigilance Medical Audience Attention Span

Overview What is “jaundice”? What is “jaundice”? Types Types Etiologies Etiologies Diagnosis Diagnosis

What is jaundice? The french word jaune - yellow. The french word jaune - yellow. Icterus - yellowish discoloration Icterus - yellowish discoloration Skin, conjunctiva, sclera, mucous membranes Skin, conjunctiva, sclera, mucous membranes Appears 'top to bottom' (face to feet) Appears 'top to bottom' (face to feet) Resolves 'bottom to top'. Resolves 'bottom to top'.

Technical definition Hyperbilirubinemia Hyperbilirubinemia Normal less than 1.2 mg/ml Normal less than 1.2 mg/ml Less than 5 percent conjugated Less than 5 percent conjugated Not visual until greater than 2.5 mg/ml Not visual until greater than 2.5 mg/ml Best seen in sclera and oral mucous membranes (look at soft palate) Best seen in sclera and oral mucous membranes (look at soft palate)

Bilirubin RBC destruction RBC destruction Hemoglobin degraded to heme Hemoglobin degraded to heme Spleen turns into unconjugated bilirubin Spleen turns into unconjugated bilirubin Transported to liver Transported to liver Conjugated with glucuronic acid Conjugated with glucuronic acid Passed into bile Passed into bile Small bowel bacteria convert to stercobilinogen Small bowel bacteria convert to stercobilinogen Oxidised to stercobilin. Oxidised to stercobilin. Some reabsorbed, excreted renally as urobilinogen Some reabsorbed, excreted renally as urobilinogen Oxidised into urobilin Oxidised into urobilin

A Tale of Two Hyperbilirubinemias Unconjugated Unconjugated Overproduction Overproduction Impaired uptake Impaired uptake Conjugation abnormalities Conjugation abnormalities Mixed Mixed Hepatocellular disease Hepatocellular disease Impaired canalicular excretion Impaired canalicular excretion Obstruction Obstruction

Or… Pre-hepatic or hemolytic causes Pre-hepatic or hemolytic causes Hemolysis Hemolysis Hepatic causes Hepatic causes Conjugation problems Conjugation problems Post-hepatic or extrahepatic Post-hepatic or extrahepatic Excretion of bile disrupted Excretion of bile disrupted

Unconjugated Hyperbilirubinemia Overproduction Overproduction Hemolysis Hemolysis Extravascular vs intravascular Extravascular vs intravascular Extravasation Extravasation Dyserythropoiesis Dyserythropoiesis Reduced hepatic uptake Reduced hepatic uptake Impaired conjugation Impaired conjugation Physiologic jaundice of newborn Physiologic jaundice of newborn Consists of all three Consists of all three

Overproduction Normal liver can keep up Normal liver can keep up Bilirubin < 4-5 mg/dl Bilirubin < 4-5 mg/dl Conjugated bilirubin remains 3-5 percent Conjugated bilirubin remains 3-5 percent Hepatic disease affects canilicular excretion Hepatic disease affects canilicular excretion Bilirubin diffuses back into plasma Bilirubin diffuses back into plasma

Conjugation Function Gilbert’s Gilbert’s Crigler-Najjar Crigler-Najjar

What about Gilbert? Reduced levels of Uridinediphosphoglucuronate glucuronosyltransferases (UGTs) Reduced levels of Uridinediphosphoglucuronate glucuronosyltransferases (UGTs) Mutation in the promoter region Mutation in the promoter region Deficiency in isoform that conjugates bilirubin to glucuronic acid Deficiency in isoform that conjugates bilirubin to glucuronic acid Creates a backflow equilibrium Creates a backflow equilibrium

And Crigler-Najjar? Type I - UGT with no activity Type I - UGT with no activity Kernicterus Kernicterus Fatal without liver transplant Fatal without liver transplant Type II – UGT with reduced activity Type II – UGT with reduced activity Less severe than type I Less severe than type I

Genetic lesions in bilirubin-UGT deficiency syndromes

Are you new here? Conjugating activity low in neonates Conjugating activity low in neonates Turn over of fetohemoglobin to adult forms Turn over of fetohemoglobin to adult forms May need light therapy May need light therapy

Other Effects on Activity Decreased UGT activity Decreased UGT activity Antibiotics Antibiotics Hepatitis Hepatitis Chronic hepatitis Chronic hepatitis Advanced cirrhosis Advanced cirrhosis Wilson’s disease Wilson’s disease Hyperthyroidism Hyperthyroidism Ethinyl Estradiol Ethinyl Estradiol Increased activity Increased activity Progestational and estrogenic steroids Progestational and estrogenic steroids

Conjugated Hyperbilirubinemia Intrahepatic cholestasis Intrahepatic cholestasis Extrahepatic cholestasis/obstruction Extrahepatic cholestasis/obstruction Hepatocellular injury Hepatocellular injury

Dubin-Johnson Autosomal recessive Autosomal recessive Human canalicular multispecific organic anion transporter (cMOAT) mutation (multidrug resistance protein 2 (MRP2)) Human canalicular multispecific organic anion transporter (cMOAT) mutation (multidrug resistance protein 2 (MRP2)) Impaired transport Impaired transport Accumulation of hepatocellular pigment. Accumulation of hepatocellular pigment. Rare, Sephardic Jews Rare, Sephardic Jews Prevalence 1:1300. Prevalence 1:1300. Life expectancy normal Life expectancy normal Reduced prothrombin and factor VII activity Reduced prothrombin and factor VII activity Nonpruritic jaundice in teenage years. Nonpruritic jaundice in teenage years.

Rotor Syndrome Rare, Autosomal Recessive Rare, Autosomal Recessive Mechanism not clear Mechanism not clear chronic mixed hyperbilirubinemia chronic mixed hyperbilirubinemia Storage defect Storage defect Benign Benign Labs and histology normal Labs and histology normal Biopsy not required Biopsy not required Urinary coproporphyrin 250 to 500% normal, 65% coproporphyrin I Urinary coproporphyrin 250 to 500% normal, 65% coproporphyrin I Dubin-Johnson syndrome - urinary coproporphyrin normal, 80% coproporphyrin I Dubin-Johnson syndrome - urinary coproporphyrin normal, 80% coproporphyrin I Normal – urinary porphyrins 75% coproporphyrin III Normal – urinary porphyrins 75% coproporphyrin III

Bilirubin throughput in hepatocytes

Obstruction Bilirubin retained Bilirubin retained Glucuronidation reversed Glucuronidation reversed Unconjugated bilirubin diffuses into plasma Unconjugated bilirubin diffuses into plasma Mixed bilirubin transported into plasma by MRP transporters. Mixed bilirubin transported into plasma by MRP transporters.

Primary Sclerosing Cholangitis

Cholangiocarcinoma

Differential Dx Cholelithiasis Cholelithiasis Tumors Tumors Primary sclerosing cholangitis Primary sclerosing cholangitis Parasites Parasites Pancreatitis Pancreatitis Strictures (benign/malignant) Strictures (benign/malignant) AIDS cholangiopathy AIDS cholangiopathy

AIDS Cholangiopathy Cryptosporidium Cryptosporidium CMV CMV HIV HIV Biopsies or bile cultures for dx Biopsies or bile cultures for dx

Other HIV Possibilities Viral Hepatitis Viral Hepatitis HSV HSV EBV EBV Tumors Tumors Lymphoma Lymphoma Kaposi’s Kaposi’s Drugs Drugs Mycobacterium TB Atypical mycobacterium Fungi Cryptococcus Histoplasma Candida Coccidioides Pneumocystis carinii

Intrahepatic Cholestasis Jaundice Jaundice Bile ducts are patent Bile ducts are patent

Etiologies Viral Hepatitis Viral Hepatitis Alcoholic Hepatitis Alcoholic Hepatitis Non-Alcoholic Steatohepatitis Non-Alcoholic Steatohepatitis Primary Biliary Cirrhosis Primary Biliary Cirrhosis Drugs Drugs Toxins Toxins End-stage liver disease End-stage liver disease Sepsis Low perfusion states Malignancy Liver infiltration TPN Post-operative Post-transplant Sickle Cell disease Pregnancy

Alcoholic Hepatitis Cholestasis Cholestasis Fever Fever Leukocytosis Leukocytosis History of EtOH History of EtOH AST to ALT exceeds 2.0 AST to ALT exceeds 2.0 AST and ALT each less than 500 AST and ALT each less than 500

NASH Similar to EtOH but NO EtOH Similar to EtOH but NO EtOH Obesity Obesity DM DM Female Female Amiodarone Antiviral drugs (nucleoside analogues) Aspirin / NSAIDS Statins Corticosteroids Methotrexate Nifedipine Perhexiline Tamoxifen Tetracycline Valproic acid

PBC Cholestatic and hepatocellular injury picture Cholestatic and hepatocellular injury picture Antimitochondrial antibodies Antimitochondrial antibodies Present in 95 percent Present in 95 percent 95 percent sensitive, 98 percent specific 95 percent sensitive, 98 percent specific Anti-nuclear antibodies Anti-nuclear antibodies In 70 percent of patients In 70 percent of patients

Drugs Dose related Dose related Allergic reactions Allergic reactions Idiosyncratic Idiosyncratic Mixed hepatocellular/cholestatic picture Mixed hepatocellular/cholestatic picture Thorough drug history imperative Thorough drug history imperative

Low Perfusion States Sepsis Sepsis Hyperbilirubinemia can promote sepsis Hyperbilirubinemia can promote sepsis CHF CHF Hypotension Hypotension Hypoxemia Hypoxemia

Paraneoplastic Syndromes Stauffer’s Syndrome Stauffer’s Syndrome Uncommon in RCC Uncommon in RCC Absence of metastases Absence of metastases Cholestasis, elevated alkaline phosphatase. Cholestasis, elevated alkaline phosphatase. Fever Fever Weight loss Weight loss Fatigue Fatigue Poor prognosis Poor prognosis Related to tumor cytokines Related to tumor cytokines Nephrectomy may ameliorate Nephrectomy may ameliorate Recurrence - maybe more cancer or metastases Recurrence - maybe more cancer or metastases

Infiltration Amyloidosis Amyloidosis Sarcoidosis Sarcoidosis Lymphoma Lymphoma TB TB

TPN Steatosis Steatosis Lipidosis Lipidosis Cholestasis (after 2-3 weeks of Rx) Cholestasis (after 2-3 weeks of Rx) Bacterial overgrowth Bacterial overgrowth

Post Operative Multifactorial Multifactorial Transfusions Transfusions Hematomas Hematomas Hemolysis Hemolysis Sepsis Sepsis TPN TPN Drugs (anesthetics) Drugs (anesthetics) Hypoxia Hypotension Viral Hepatitis Renal Failure

Post Transplant Bone Marrow and Liver mostly Bone Marrow and Liver mostly TPN TPN Drugs Drugs Immunosuppressives Immunosuppressives Radiation Radiation Chemotherapy Chemotherapy Graft rejection Graft rejection Preservation injury Operative complications

Sickle Cell Disease Chronic hemolysis Chronic hemolysis Hepatic dysfunction Hepatic dysfunction Cirrhosis Cirrhosis Secondary hemochromatosis Secondary hemochromatosis Hepatic crisis Hepatic crisis Hepatomegaly and tenderness Hepatomegaly and tenderness Severe hyperbilirubinemia Severe hyperbilirubinemia Bilirubin microliths, sludge, stones common Bilirubin microliths, sludge, stones common Obstruction rare Obstruction rare

Intrahepatic Cholestasis of Pregnancy (IHCP) Third Trimester Third Trimester Possibly genetic Possibly genetic Pruritus >> cholestasis >> Jaundice Pruritus >> cholestasis >> Jaundice Maybe more premature/still births Maybe more premature/still births Distinguish from acute fatty liver and HELLP Distinguish from acute fatty liver and HELLP

Acute Fatty Liver of Pregnancy microvesicular fatty infiltration of hepatocytes microvesicular fatty infiltration of hepatocytes 1 in 7000 to 1 in deliveries 1 in 7000 to 1 in deliveries Second half of pregnancy, usually third trimester Second half of pregnancy, usually third trimester Nausea, vomiting, abdominal pain, anorexia, and jaundice, preeclampsia Nausea, vomiting, abdominal pain, anorexia, and jaundice, preeclampsia Delivery is curative (and mandatory!) Delivery is curative (and mandatory!)

HELLP Hemolysis, Elevated Liver enzymes, Low Platelets Hemolysis, Elevated Liver enzymes, Low Platelets 1 of 1000 pregnancies 1 of 1000 pregnancies 10 to 20 percent with preeclampsia or eclampsia 10 to 20 percent with preeclampsia or eclampsia Diagnosed between 28 and 36 weeks of gestation Diagnosed between 28 and 36 weeks of gestation 70 percent occurred prior to delivery 70 percent occurred prior to delivery Delivery is mandatory! Delivery is mandatory!

End Stage Liver Disease Supportive Care Supportive Care Transplant Transplant

Hepatocellular Injury Neoplasms Neoplasms Viral Viral Bacterial Bacterial Congenital Congenital Parasitic Parasitic Fungal Fungal Systemic Systemic Immunologic Immunologic Toxic Toxic

Viral Hepatitis A, B, C, D, E Hepatitis A, B, C, D, E HSV HSV Hemorrhagic viruses Hemorrhagic viruses Adenoviruses Adenoviruses Enteroviruses Enteroviruses

Bacterial TB TB Leptospirosis Leptospirosis Syphilis Syphilis Brucella Brucella Rickettsia Rickettsia Tropheryma Whippelii Tropheryma Whippelii Rochalimea Rochalimea

Congenital Wilson’s disease (rare after age 40) Wilson’s disease (rare after age 40) Alpha-1-antitrypsin deficiency Alpha-1-antitrypsin deficiency Hemochromatosis Hemochromatosis Porphyrias (a 24 hour urine for porphyrins is best test to rule out all the porphyria subtypes) Porphyrias (a 24 hour urine for porphyrins is best test to rule out all the porphyria subtypes)

Systemic Acute Ischemia Acute Ischemia Cardiac causes Cardiac causes Thromboembolic disease Thromboembolic disease Telangiectasias Telangiectasias Amyloid Amyloid Sarcoid Sarcoid

Immunologic Autoimmune Hepatitis Autoimmune Hepatitis PBC PBC PSC PSC

Diagnosis History History Diseases/therapies Diseases/therapies Medications/herbals/exposures Medications/herbals/exposures Risk factors/HIV status/travel Risk factors/HIV status/travel Surgeries Surgeries Complications Complications Physical Physical Screening labs Screening labs Differential Differential Further testing Further testing

Findings Primary biliary cirrhosis Primary biliary cirrhosis Xanthomas Xanthomas Viral Hepatitis Viral Hepatitis Anorexia Anorexia Malaise Malaise Myalgias Myalgias Liver failure/portal HTN Liver failure/portal HTN Ascites Ascites Splenomegaly Splenomegaly Spider Angiomata Spider Angiomata Gynecomastia Gynecomastia

Overload Findings Hyperpigmentation Hyperpigmentation Hemochromotosis Hemochromotosis Kayser-Fleischer rings Kayser-Fleischer rings Wilson’s disease Wilson’s disease

Labs Transaminases – biliary or hepatic injury Transaminases – biliary or hepatic injury Alkaline Phosphatase Alkaline Phosphatase obstruction or intrahepatic cholestasis obstruction or intrahepatic cholestasis TB TB Sarcoid Sarcoid GGT/5’-nucleotidase - biliary tract (overly sensitive test) GGT/5’-nucleotidase - biliary tract (overly sensitive test) Prothombin time Prothombin time Correctable with vitamin K? Correctable with vitamin K? Albumin – hepatic synthetic insufficiency Albumin – hepatic synthetic insufficiency

Non-obstructed Viral hepatitis Viral hepatitis AMA AMA ASMA and LKM ASMA and LKM Iron panel and ferritin (ferritin is an APR, can be elevated for multiple causes); iron saturation is key Iron panel and ferritin (ferritin is an APR, can be elevated for multiple causes); iron saturation is key Ceruloplasmin level Ceruloplasmin level Alpha-1-antitrypsin activity Alpha-1-antitrypsin activity

Obstructed? US US EUS EUS Helical CT/CT Helical CT/CT ERCP ERCP 0.2% mortality, pancreatitis 3 % 0.2% mortality, pancreatitis 3 % MRCP – non-therapeutic, interpretation difficult MRCP – non-therapeutic, interpretation difficult Pecutaneous Transhepatic Cholangiography Pecutaneous Transhepatic Cholangiography Good for proximal lesions or if ERCP not available Good for proximal lesions or if ERCP not available

Emergencies Massive hemolysis (sepsis, malaria) Massive hemolysis (sepsis, malaria) Ascending cholangitis Ascending cholangitis Fever Fever Chills Chills RUQ pain RUQ pain Prior biliary surgery Prior biliary surgery Neonates Neonates Fulminant hepatic failure Fulminant hepatic failure

Summary Many etiologies for jaundice Many etiologies for jaundice History and physical is key History and physical is key Medical history Medical history Medications Medications Risk factors Risk factors Surgeries Surgeries Labs Labs Differential Differential Further testing Further testing Diagnosis Diagnosis