crash course: when the liver starts talking jaundice

© UEG. 2018

Presentation by

Crash course: When the liver starts talking

Jaundice

23/10/2018

George N Dalekos Room E1

Prof. George Ν. Dalekos, MD, PhD

Institute of Internal Medicine and

Hepatology, Department of Medicine and

Research Laboratory of Internal Medicine

University Hospital of Larissa, Greece

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Crash course: When the liver starts talking Jaundice

Nothing to declare for this presentation

Jaundice | Presentation by George N Dalekos 2

Disclosure of Conflicts of Interest

© UEG. 2018 3

Crash course: When the liver starts talking Jaundice: Clinical Case 1

Jaundice | Presentation by George N Dalekos

♦ 41 ys female from Corfu island - Torturous pruritus since 45d - Antihistamines, medrol, local

creams for scabies (GP) - PE: icteric (Bil: 21.8 mg/dL;

Dir: 15 mg/dL) with scratches - AST: 50; ALT: 50; γ-GT: 28;

ALP: 304 (ULN: 120 U/L) - Viral serology (A-E): negative

- Autoimmune serology: neg

- Past history: spontaneous haematomas (thighs)

- Supplements, vitamins up to 9 mo before admission; No alcohol misuse

- Family history: brother with OLT 20 ys ago (UK, 17 ys)

© UEG. 2018

• 61 ys male with AIH/PBC variant in tapering PRE + MMF + URSO in complete response (normal IgG, AST and ALT)

• New-onset icteric hepatitis (Bil: 6.7 mg/dl; Dir: 4.1 mg/dl; AST: 689 U/L; ALT: 515 U/L; γ-GT: 358 U/L) accompanied by diarrhoea and fatigue

• No supplements, medicines, herbals, toxins, alcohol

• Past history: autoimmune thrombocytopenia

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© UEG. 2018

Jaundice or Icterus • Jaundice: From the Latin word “galbinus” (yellow-green)

• Icterus: From the Greek word “ikteros”

• Bilirubin deposition

sclera, skin, mucosa

(> 2.5 – 3 mg/dL) 5



© UEG. 2018

Jaundice or Icterus

• Is not a disease but a sign of many underlying diseases

• Is not an uncommon clinical problem

• NHAMC survey (1995-2004): 400000/1 bil visits ED

6 Jaundice | Presentation by George N Dalekos


© UEG. 2018

• Understanding the fundamental metabolism of bilirubin

• Differential diagnosis (risk factors, epidemiology and pathophysiology of common causes of jaundice)

• Serologic and imaging studies used in the work-up of jaundiced patients



Assessment of Jaundice

© UEG. 2018 8 Jaundice | Presentation by George N Dalekos

Abnormality at any of these steps can

lead to jaundice

Crash course: When the liver starts talking Bilirubin metabolism (I)


Biliary tree obstruction at any

level from the canals of Hering up

to the ampulla of Vater can lead to

jaundice

Crash course: When the liver starts talking Bilirubin metabolism (II)


Crash course: When the liver starts talking Jaundice: Differential Diagnosis (I)

♦ Is the hyperbilirubinemia

predominantly conjugated

or unconjugated?

♦ Are other LFTs abnormal?

♦ Is the underlying disease likely to be related to:

- isolated disorders of bilirubin production or metabolism?

- intrinsic liver disease?

- biliary tree obstruction?


Crash course: When the liver starts talking Jaundice: Differential Diagnosis (II)

♦ Risk factors for LD - being health care worker - toxins, drugs/herbals, alcohol - wild mushrooms, travels - institutionalization

- parenteral exposure (blood, transfusions, PWID, tattoos, piercing, hemodialysis, risky sexual activity)

♦ Signs of chronic LD

- ascites, caput medusae

- edema, palmar erythema

- coagulopathy, splenomegaly

- spider angiomas, varices

- gynecomastia, testicular atrophy, pleural effusion


Crash course: When the liver starts talking Jaundice: Differential Diagnosis (III)

Thorough history should be obtained to exclude

• any herbal or non-prescribed supplements

• over-the-counter medications or “health foods”

• weight loss and body building supplements

• herbal remedies used as “joint pain remedies”


Crash course: When the liver starts talking Jaundice: Differential Diagnosis (IV)

The drug your doctor prescribed contains

lead, arsenic, asbestos.. Doesn´t matter, if only no steroids…


Crash course: When the liver starts talking Jaundice: Differential Diagnosis (V)

Clinical Case 3


Crash course: When the liver starts talking Jaundice: Differential Diagnosis (VI)

Thorough history to exclude alcohol consumption

(CAGE questioning technique + family info)

• Have you wanted to Cut back on your drinking?

• Have you been Annoyed by another’s comments?

• Have you ever felt Guilty about your drinking?

• Have you ever needed an Eye opener in the morning?


Crash course: When the liver starts talking Jaundice: Differential Diagnosis (VIII)

Careful history & physical examination = not contributory Initial LFTs evaluation apart from BIL = normal

ISOLATED DISORDERS OF BILIRUBIN PRODUCTION AND METABOLISM


Crash course: When the liver starts talking Jaundice: Differential Diagnosis (IX)

Hemolytic anemias

Hematoma resorption

Blood transfusions

Ineffective erythropoiesis

Gilbert or Crigler

Najjar syndromes

Increased heme load or

Impaired conjugation

Predominant indirect

hyperbilirubinemia

Predominant direct hyperbilirubinemia with normal LFTs consider Dubin-

Johnson or Rotor syndrome


Crash course: When the liver starts talking Jaundice: Differential Diagnosis (X)

Careful history & physical examination = contributory Initial LFTs evaluation apart from BIL = abnormal

Liver disease (mixed or conjugated BIL)

Extrahepatic cholestasis (predominant conjugated BIL)

Hepatocellular damage (predominant AST/ALT)

Intrahepatic cholestasis (predominant γ-GT/ALP)


Crash course: When the liver starts talking Jaundice: Differential Diagnosis (XI)

Hepatocellular damage

Intrahepatic cholestasis

Careful history & physical examination = contributory Initial LFTs evaluation apart from BIL = abnormal

vs.

R ratio: (ALT value/ALT ULN) / (ALP value/ALP ULN)

R ratio: > 5 = hepatocellular injury < 2 = cholestatic injury 2-5 = mixed pattern ACG CPC Am J Gastroenterol 2017


Crash course: When the liver starts talking Jaundice: Differential Diagnosis (XII)

♦ Viral hepatitis (A-E); Alcoholic liver disease ♦ NAFLD/NASH; DILI; Liver cirrhosis ♦ Autoimmune hepatitis ♦ Genetic diseases (Wilson disease, HFE) ♦ Ischemic hepatitis; Pregnancy related

Acute or chronic hepatocellular damage (predom AST/ALT)


Crash course: When the liver starts talking Jaundice: Differential Diagnosis (XIII)

♦ Intrahepatic mass lesions (HCC, IHC, metastasis; abscess)

♦ PBC; DILI; Sepsis; Post-operative; GVHD; TPN; PFIC/BRIC

♦ Diffuse infiltrative disorders (lymphomas, sarcoidosis, tuberculosis, amyloidosis, brucellosis, etc.); ICP

♦ Atypical presentations of viral, autoimmune, alcoholic hepatitis

Intrahepatic cholestasis (predominant γ-GT/ALP)


Crash course: When the liver starts talking Jaundice: Differential Diagnosis (XIV)

♦ Choledocholithiasis (the most common); pancreatic cancer

♦ Cholangitis (bacterial, primary or secondary sclerosing)

♦ Cholangiocarcinoma; Klatskin tumor; Postoperative strictures

♦ Mirizzi syndrome; Choledochal or Pancreatic cysts

♦ Biliary-vascular fistula; Biliary atresia; HIV cholangiopathy

Extrahepatic cholestasis (predominant direct Bil)



Overview of basic laboratory tests in the work-up of jaundice

Test Significance CBC Peripheral smear

To check haemoglobin concentartion For signs of haemolysis (particularly if LFTs normal)

ALT Primarily cytosolic, more specific for liver damage AST Cytosolic and mitochondrial; less sensitive and specific ALP Primarily in bile canaliculi (also bone, placenta, kidney) γ-GT In biliary epithelium; poor specificity INR Synthetic liver function



Additional laboratory tests in the work-up of jaundice (I) Test Significance IgM anti-HAV HBsAg, IgM anti-HBc HBsAg, IgG anti-HBc Anti-HCV, HCV RNA IgM anti-HDV, HDV RNA (HBsAg pos) IgM anti-HEV, HEV RNA

Acute HAV infection Acute HBV infection Chronic HBV infection HCV infection HDV infection Acute HEV infection

Other viral serologies CMV, VZV, EBV, HSV, HIV AMA, PBC-specific ANA (sp100, gp210) Primary biliary cholangitis



Additional laboratory tests in the work-up of jaundice (II)

Test Significance Protein electrophoresis, γ-globulins, IgG, ANA, SMA, SLA/LP, LKM1, LC1

Autoimmune hepatitis

24h urinary Cu, ceruloplasmin, free Cu Wilson disease Iron saturation, ferritin, HFE gene testing Haemochromatosis Measurement of α1-antitrypsin activity or serum protein electrophoresis

α1-Antitrypsin deficiency



Imaging studies in the work-up of jaundice Study Advantages/Disadvantages US

First-line screening, cost-effect, low radiation but operator dependent, difficult in obese and in underlying bowel gas

MRI/CT More precise in obstructive masses and cirrhosis features MRCP PSC diagnosis, patients with low pretest probability of obstructive

lesion or multiple comobirdities before proceeding to ERCP ERCP/EUS Gold standard for extrahepatic biliary disease diagnosis, allows

therapeutic interventions PTC For higher biliary obstructions, allows therapeutic interventions



*For the diagnosis of biliary tract obstruction Test Sensitivity* (%) Specificity* (%) Morbidity (%) Mortality (%)

US 60-91 82-95 - - CT 63-96 93-100 - - MRCP 88-96 93-100 - - ERCP 88-98 89-100 3 0.2 EUS 90-98 95-100 - - PTC 98-100 89-100 3 0.2



Not all MRI/MRCP the same.....


Crash course: When the liver starts talking Diagnosis and management of jaundice (I)

Predominant unconjugated BIL

History/Physical Exam and LFTs

Review medications and assess for haemolysis and Gilbert

If persistent elevation is unexplained may consider UGT1A1 gen-test or

evaluation for uncommon etiologies (Crigler-Najar, large hematomas, ineffective erythropoiesis, etc.)

If persistent elevation is unexplained, is symptomatic, is worsening over

time and/or associated with abnormal AST/ALT values

CONSIDER LIVER BIOPSY

Adapted from ACG CPG Am J Gastroenterol 2017


Crash course: When the liver starts talking Diagnosis and management of jaundice (II)

Mixed or predominant conjug. BIL

History/Physical Exam and LFTs

Review medications/alcohol, viral hepatitis serology; IgG, AIH-related Abs or other tests (viral serology neg). DON’T MISS CLINICALLY OVERT AETIOLOGIES: Sepsis, TPN and BO

Perform upper quadrant US If ductal dilatation If NO MRCP, ERCP Check AMA & PTC or EUS PBC-specific ANA If persistent elevation is unexplained,

is symptomatic, is worsening over time and/or associated with abnormal

AST/ALT/cholestatic enzymes

CONSIDER LIVER BIOPSY

Adapted from ACG CPG Am J Gastroenterol 2017

© UEG. 2018

• US, MRI/MRCP: neg; FIBROSCAN: 14.5 kPa; K-Fring: neg

• Ceruloplasmin, iron saturation, a1-antitrypsin: normal

• Brother’s OLT due to “Cryptogenic cholestatic fibrosis”

• We performed a liver biopsy and genetic tests for PFIC

• Administration of cholestyramine (16 g/d) and rifampicin (600 mg/d) with gradual response of pruritus and jaundice

34



© UEG. 2018 35

Crash course: When the liver starts talking Case 1: Severe cholestasis (lumen + hepatocytes)


Courtesy by Prof G.K. Koukoulis, 2017

© UEG. 2018 36

Crash course: When the liver starts talking Case 1: Intense bile duct CK7-type switch


Courtesy by Prof G.K. Koukoulis, 2017

© UEG. 2018 37

Crash course: When the liver starts talking Clinical Case 1: Molecular genetics


Gene Nucleotide Status Protein effect Classification ABCB11 c.2178+1G>A Heterozygous p.? Pathogenic ABCB11 c.953A>T Heterozygous p.(Lys318lle) Likely

pathogenic DCDC2 c.123_124del Heterozygous p.(Ser42fs) Pathogenic

BSEP deficiency PFIC2 BRIC2

4 mo Tx resulted in normal LFTs (Bil: 0.9); Fibroscan: 5.2 kPa Clinical remission 9 mo f-up (ADEK suppl)

© UEG. 2018

US: no ductal dilatation; Viral serology (A-C): neg; IgG normal

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CMV, VZV, EBV, HSV, HIV serologies negative BUT…

Anti-HEV IgM high positive and HEV RNA positive

Acute HEV infection in immunocompromised patient

F-UP: HEV RNA neg 5 and 12 mo later; normal LFTs

© UEG. 2018

Department of Medicine & Research Laboratory of Internal Medicine,

University Hospital of Larissa, Greece G.N. Dalekos, Professor of Medicine, Head of the Dept. E.I. Rigopoulou, Assosiate Professor of Medicine K. Zachou, Assistant Professor of Medicine N. Gatselis, Assistant Professor of Medicine S. Gabeta, Consultant in Internal Medicine S. Saitis, Consultant in Internal Medicine K. Azariadi, PhD student, P. Arvaniti, PhD student V. Lygoura, PhD student; E. Exarchou, Technician A. Lyberopoulou, Molecular Biochemist, PhD

crash course: when the liver starts talking jaundice

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