Jaundice resident survival guide

Jaundice Resident Survival Guide
Overview
Causes
Diagnosis
Treatment
Do's
Don'ts

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Roghayeh Marandi, M.D.[2]

Synonyms and keywords: Approach to jaundice, Jaundice workup, Jaundice management

Overview

The classic definition of jaundice is a serum bilirubin level higher than 2.5 to 3 mg per dL (42.8 to 51.3 μper L) in conjunction with clinical evidence of yellow skin and sclera. The causes of jaundice can be classified by measuring total bilirubin. The conjugated and unconjugated levels determine whether there is dysfunction of bilirubin metabolism.

Causes

Life Threatening Causes

Life-threatening causes include conditions that may result in death or permanent disability within 24 hours if left untreated.

• Ascending cholangitis
• Sepsis
• Acute liver failure (the combination of jaundice with hepatic encephalopathy)

Common Causes

Common causes of acute Jaundice

• Gilbert syndrome
• Alcoholic hepatitis
• Viral hepatitis
• Obstructive Jaundice due to choledocholithiasis or malignancy
• Decompensated chronic liver disease

Common causes of chronic progressive jaundice

• Cirrhosis
• Pancreatic cancer

Diagnosis

Shown below is an algorithm summarizing the diagnosis of jaundice.
Abbreviations: ALT:Alanine transaminase, AST:Aspartate transaminase, ALP: Alkaline phosphatase, INR:International normalized ratio, ERCP:Endoscopic retrograde cholangiopancreatography, HAV: Hepatitis A virus, HBV: Hepatitis B virus, HCV: Hepatitis C virus, TIBC:Total iron binding capacity,Hb: Hemoglobin, LDH: lactate dehydrogenase, HbA1C:Hemoglobin A1c, CBC:Complete blood count, LFT: Liver function tests, MRCP: Magnetic resonance cholangiopancreatography, G6PD:Glucose-6-phosphate dehydrogenase deficiency

Characterize the jaundice duration and frequency ❑Duration: short vs long ❑Frequency: episodic vesus constant

Ask about associated symptoms ❑ Abdominal pain (episodic or constant) ❑ Abdominal distension ❑ Fever ❑ Clay colored stool ❑ Dark urine ❑ Weight gain or loss ❑ Anorexia ❑ Dyspepsia ❑ Arthralgia ❑ Myalgia ❑ Back pain ❑ Rash ❑ Confusion

Inquire about ❑ Past medical history ❑ Blood disorder ❑ Liver diseases ❑ Biliary diseases ❑ Pancreatic disease ❑ Cardiac disease ❑ Infectious disease ❑ HIV ❑ Malaria ❑ Etc ❑ Family history of ❑ Hemolytic anemias ❑ Congenital hyperbilirubinemia ❑ Wilson disease ❑ Medication history ❑ Parentral exposure ❑ Blood transfusion ❑ IV drug abuse ❑ Recent travel history ❑ Social history ❑ Excess alcohol intake ❑ Sexual history

Examine the patient General Appearance ❑ Check for: ❑ Pale skin (hemolysis/cancer/cirrhosis) ❑ Gross weight loss (cancer/severe malabsorption) ❑ Fetor hepaticus ❑ Flapping tremor (impending hepatic coma) Skin exam ❑ Check for: ❑ Scratch marks ❑ Melanin pigmentation ❑ Xanthoma of eyelids (chronic cholestasis) ❑ Signs of liver disease: spider nevi, palmar erythema ❑ Bruising, purpuric spots, clotting defects due to thrombocytopenia of cirrhosis Cardiac exam ❑ Check JVP (right sided heart failure) Full abdominal exam ❑ Size and consistency of liver and spleen ❑ A grossly enlarged nodular liver or an obvious abdominal mass suggests malignancy ❑ Small liver can be seen in (severe hepatitis/cirrhosis) ❑ An enlarged tender liver could be due to: ❑ Viral hepatitis ❑ Alcoholic hepatitis ❑ An infiltrative process such as amyloidosis ❑ Acutely congested liver secondary to right-sided heart failure) ❑ Check gallbladder area if it is tender ❑ Positive murphy sign due to choledocholithiasis ❑ Palpable, visibly enlarged gallbladder can be due to pancreatic cancer ❑ Splenomegaly can be seen in hemolytic states, Hodgkin’s lymphoma, portal hypertension ❑ Ascites due to cirrhosis/abdominal malignancy caput medosa Extremity examination ❑ Ankle edema due to: ❑ Cirrhosis ❑ IVC obstruction due to hepatic or pancreatic malignancy

Order ❑ Blood tests ❑ CBC ❑ Total Bilirubin ❑ Conjugated or unconjugated bilirubin ❑ Metabolic panel ❑ LFT ❑ Albumin ❑ γ-glutamyltransferase ❑ INR ❑ prothrombin time ❑ Urine ❑ Bilirubin ❑ Urobilinogen ❑Urine positive for bilirubin in conjugated hyperbilirubinemia ❑Urine Negative for bilirubin in unconjugated hyperbilirubinemia

Isolated unconjugated hyperbilirubinemia]

Isolated conjugated hyperbilirubinemia

Unconjugated & conjugated hyperbilirubinemia

❑ Inquire about any recent trauma hematoma blood transfusion

❑ Dubin-Johnson syndrome ❑ Rotor syndrome

If none of them

With Liver enzyme changes

with ↑ INR,↓ Albumin,↓ Platelet

❑ Check Hb,LDH,Haptoglobin,Recticulocyte count

If ⇈AST/ALT out of proportion to ALP

If ⇈AlP out of proportion to AST/ALT

Suggestive of cCirrhosis Additional tests to find the cause of cirrhosis Hepatitis serology Iron panel Abdominal Ultrasound Workup for Automimmune hepatitis, NAFLD, Hemochromatosis & other causes of cirrhosis

Abnormal

Normal

Hepatocellular pattern

Cholestatic pattern

Start workup of hemolytic anemia with blood smear & coombs test

❑ Gilbert syndrome ❑ Crigler-Najjar type I,II

Additional work-up for specific diseases Viral hepatitis serology(e.g. HAV,HBV,HCV) Toxicology screen Acetaminophen level Cereuloplasmin if patient<40 years of age Autoantibodies (ANA,Anti-sm,LKM,...) Ferritin & TIBC HbA1c Pregnancy test a1-antitrypsin ❑Consider work-up for rare cases Liver biopsy if results negative

Ultrasound

Consider following based on the results: ❑ Sickle cell disease ❑ Hereditary spherocytosis ❑ G6PD deficiency ❑ Medications effect (Rifampicin, Probencid) ❑ Immune-mediated hemolysis

Consider following based on the results: ❑ Viral hepatitis ❑ NAFLD (Non-alcoholic liver disease) ❑ ppAlcoholic liver disease]] ❑ Metabolic/genetic diseases Hereditary hemochromatosis Wilson's disease Alpha-1 antitrypsin deficiency ❑ Drug-induced and supplemental-induced injury Acetaminophen, kavakava, Vinyl cholride ❑ Pregnancy AFLP,HELLP syndrome ❑ Autoimmune hepatitis ❑ Ischemic hepatitis

Bile ducts dilated

Bile ducts not dilated

ERCP/CT

Additional work-up for intrahepatic cholestasis Hepatitis serology Autoantibodies for autoimmune hepatitis Review medications MRCP/Liver biopsy

❑ Common bile duct stones ❑ Biliray stricture ❑ Worms/flukes ❑ Extrahepatic sources: ❑ Cholangiocarcinoma ❑ Pancreatic cancer

Consider following based on the results: Primary biliary Cirrhosis PSC Drugs TPN Sepsis Infiltrative diseases: Sarcoidosis Amyloidosis Malignancy

Treatment

Type of hyperbilirubinemia	Diagnostic Indicators	Management Recommendations
Managment of isolated unconjugated jaundice, hemolytic	Any history of recent trauma, hematoma or blood transfusion Any recent travel Inquire about medications that can cause hemolysis Any positive family history of hemolytic anemia	Work-up and detect the cause of hemolysis, if low Hb, high LDH, Low haptoglobin, and reticulocytes present. G6PD deficiency - the majority recover on their own, if progress to hemolytic anemia, oxygen therapy, or blood transfusion may be required. Avoid precipitants and etiological factors Spherocytosis[-[phototherapy]] and/or exchange transfusion for infants, folic acid for maintaining erythropoiesis. Splenectomy is the definitive treatment Sickle cell anemia- reduce pain and prevent complications, blood transfusions and supplemental oxygen, as well as a bone marrow transplant. Immune-related hemolysis – corticosteroids, folic acid is the first line of treatment Parasitic Infections like malaria are treated with antimalarial drugs like chloroquine, artesunate, lumefantrine,amodiaquine Ineffective erythropoiesis- iron and folic acid & vitamin B12 supplementation, repeated blood transfusions.
Managment of isolated unconjugated jaundice, Non-hemolytic	Gilbert's syndrome does not produce symptoms or adverse effects and patients have a normal life span Crigler-Najjar type I is fatal in early life due to development of kernicterus. Crigler-Najjar type II is compatible with a normal life.|	Phenobarbital can decrease serum bilirubin by enzymatic induction of UDPGT (Uridine Glucuronosyltransferase) in Crigler-Najjar type II.
Managment of isolated conjugated jaundice	Dubin-Johnson syndrome- doesn't produce any symptoms and compatible with a normal life span. Rotor's syndrome is a harmless chronic hyperbilirubinemia |	Suspect for Dubin-Johnson syndrome before considering surgery if the healthy patient with long-standing conjugated hyperbilirubinemia, other normal liver function tests, and a non visualized gallbladder. Hepatic architecture is normal but there is an accumulation of hepatic pigment compatible with melanin in patients with Dubin-Johnson syndrome In Rotor's syndrome the gallbladder opacifies normally with cholecystographic dye and no pigmentation be seen in the liver.
Managment of conjugated & unconjugated hyperbilirubinemia jaundice with ⇈AST/ALT out of proportion to ALP'	History of recent travel Social history: alcohol, sexual history Family history of Wilson's disease or hemochromatosis Review medications Pregnancy test HELLP syndrome, AFLP Toxicology screen Acetaminophen level Mild elevation in aminotransferase levels in female patients with concomitant autoimmune disorders (e.g., autoimmune thyroiditis, connective tissue diseases) is suggestive of autoimmune hepatitis. Consider work-up for rare cases Liver biopsy if results negative Ischemic acute liver damage is more likely in patients with concomitant clinical conditions such as sepsis or low-flow hemodynamic state or right-sided heart failure|	Viral hepatitis Hepatitis A: mostly self-limiting Hepatitis B treated with antiviral medications Hepatitis C is treated with interferons Other viral infections like EBV, CMV, HSV are treated with Antiviral medications Alcohol hepatitis: Alcohol abstinence, glucocorticoids, pentoxifylline Wilson"s disease: chelating agents such as D-penicillamine Drug toxicity treatment(e.g. Acetaminophen, Isoniazid Autoimmune hepatitis treatment with glucocorticoids
Managment of conjugated & unconjugated hyperbilirubinemia jaundice with ⇈ AlP out of proportion to AST/ALT	History of intermittent right upper quadrant pain radiating to the back or right shoulder favors gallstones, fever and chills suggest cholangitis. History of biliary tract surgery within 2 years should alert the physician to possible biliary stricture. History recent weight loss, constant epigastric or right upper quadrant pain radiating to the back suggests malignancy Icteric patient with extrahepatic obstruction due to gallstones or postsurgical biliary stricture has usually had acute symptoms for less than 2 weeks Those with carcinoma, chronic pancreatitis, or primary sclerosing cholangitis have had symptoms of longer duration A middle-aged woman with a history of itching and autoimmune disease raises the suspicion of primary biliary cirrhosis More than half the people with primary biliary cirrhosis do not have any symptoms when diagnosed. Symptoms develop over the next five to 20 years. Those who do have symptoms at diagnosis typically have poorer outcomes. Commonly used drugs such as antihypertensives (e.g., angiotensin-converting enzyme inhibitors) or hormones (e.g., estrogen) may cause cholestasis Abnormal ALP levels may be a sign of metastatic cancer of the liver, lymphoma or infiltrative diseases such as sarcoidosis. History of inflammatory bowel disease (most commonly ulcerative colitis) suggests the presence of primary sclerosing cholangitis since about 70% of these cases are associated with inflammatory bowel disease TPN is associated with ↑ AlP and GGT level.|	Obstruction removal by ERCP, PTC, Surgery (e.g.Cholecystectomy or Palliative Bypass procedures such as hepaticojejunostomy if stenting has failed in patients with tumors) Primary biliary cholangitis management: no cure for primary biliary cholangitis, but medications are available for slow the progression and prevent complications of the disease: Ursodeoxycholic acid (UDCA), Obeticholic acid (Ocaliva), Fibrates, Liver transplantation may help prolongs life. Treatments for primary sclerosing cholangitis focus on managing complications and monitoring liver damage. None of the medications have been found to slow or reverse the liver damage associated with this disease.
Managment of conjugated & unconjugated hyperbilirubinemia jaundice with ↑ INR,↓ Alb,↓ PLT |	Cirrhotic patients with MELD Score> 15 should be referred to liver transplant center Patients with MELD Score< 15 should be treated depending on compensated cirrhosis or decompensated one|	Compensated cirrhosis Mangament Alochol abstinence Antiviral medications for viral hepatitis avoidance of hepatotoxic medications vaccination Decompensated cirrhosis Managment Managment of complications: Varices, Ascites, Hepatorenal syndrome, Hepatic encephalopathy(Acute liver failure)

Do's

• Alcohol Use: screen for alcohol use disorders in all patients.
• Medications: discuss the safety of limited (2 gram/day) acetaminophen use, review pharmacologic history, and discontinue medications that cause hemolysis or drug-induced hepatitis.
• Treat underlying disease conditions.
• Liver Transplant Referral: refer early when a patient requires liver transplant.
• Palliative Care: address goals of care and refer to palliative care early especially for patients with tumors.

Don'ts

• Forget to discuss medication to avoid, especially in patients with G6PD or drug-induced hepatitis.
• Delay palliative care until the patient is in a critical state.
• Delay referring a patient to the liver transplant center until the patient is hospitalized in life-threatening condition.