Hepatology lecture 1. Tomas Koller, Doc. MUDr. PhD.

Liver anatomy

Liver histology

Clinical manifestation of liver disease

❖ fatigue

❖ right upper quadrant tenderness

❖ petechiae and bleeding

❖ increase in abdominal circumference

❖ edema

❖ pruritus

❖ hematemesis

❖ melena

❖ jaundice

❖ dark urine

❖ caput medusae

❖ palmar erythema

❖ spider angiomas

❖ ascites

❖ flapping

❖ malnutrition

❖ sarcopenia

❖ fever

LATE !

Clinical syndromes in liver disease

Acute hepatitis

❖ fatigue

❖ right upper quadrant tenderness

❖ petechiae and bleeding

❖ increase in abdominal circumference

❖ edema

❖ pruritus

❖ hematemesis

❖ melena

❖ jaundice

❖ dark urine

❖ caput medusae

❖ palmar erythema

❖ spider angiomas

❖ ascites

❖ flapping

❖ malnutrition

❖ sarcopenia

❖ fever

Hepatic insufficiency

❖ fatigue

❖ right upper quadrant tenderness

❖ petechiae and bleeding

❖ increase in abdominal circumference

❖ edema

❖ pruritus

❖ hematemesis

❖ melena

❖ jaundice

❖ dark urine

❖ caput medusae

❖ palmar erythema

❖ spider angiomas

❖ ascites

❖ flapping

❖ malnutrition

❖ sarcopenia

❖ fever

Cholestasis impairmant of bile formation or transport

❖ fatigue

❖ right upper quadrant tenderness

❖ petechiae and bleeding

❖ increase in abdominal circumference

❖ edema

❖ pruritus

❖ hematemesis

❖ melena

❖ jaundice

❖ dark urine

❖ caput medusae

❖ palmar erythema

❖ spider angiomas

❖ ascites

❖ flapping

❖ malnutrition

❖ sarcopenia

❖ fever

Portal hypertension increased blood pressure in the portal and corresponding veins

❖ fatigue

❖ right upper quadrant tenderness

❖ petechiae and bleeding

❖ increase in abdominal circumference

❖ edema

❖ pruritus

❖ hematemesis

❖ melena

❖ jaundice

❖ dark urine

❖ caput medusae

❖ palmar erythema

❖ spider angiomas

❖ ascites

❖ flapping

❖ malnutrition

❖ sarcopenia

❖ fever

Acute liver injury

Acute liver injury

❖ Asymptomatic liver test elevation

❖ Acute hepatitis (>5-8x) upper limit of normal

❖ cytolytic (AST, ALT)

❖ cholestatic (ALP)

❖ mixed (both ALP and ALT)

❖ Acute severe hepatitis (PT<50%)

❖ Acute liver failure (PT<30% and HE)

❖ =fulminant

❖ Death

❖ Asymptomatic liver test elevation

❖ Acute hepatitis (>5-8x) upper limit of normal

❖ cytolytic (AST, ALT)

❖ cholestatic (ALP)

❖ mixed (both ALP and ALT)

❖ Acute severe hepatitis (PT<50%)

❖ Acute liver failure (PT<30% and HE)

❖ =fulminant

❖ Death

Liver function

%

Prevalence

%

Acute liver injury common causes

❖ Viral hepatitis A, B, C, E

❖ Drug induced idiosyncratic (autoimmune) injury

❖ Dose unrelated

❖ Toxic hepatitis (Amanita poisoning, paracetamol, isoniazid, methylprednisolone)

❖ Dose related

❖ Wison’s disease

❖ Ischemic hepatitis (low cardiac output)

❖ Hepatic vein thrombosis (Bud-Chiari syndrome)

Acute hepatitis

Right upper quadrant dyscomfort

ALT, ALT

Hepatomegaly

Cause of ALD ALT

AST

time

upper limit of normal

Acute hepatitis management

Viral hepatitis A, B, C, E no therapy, HBV antivirals

Drug induced idiosyncratic reaction (antibiotics, NSA, hormones...) drug withdrawal

Toxic hepatitis (Amanita, paracetamol, isoniazid, methylprednisolone) drug withdrawal+antidotes*

Wison’s disease penicillamin

Ischemic hepatitis (low cardiac output) increase cardiac output

Hepatic vein thrombosis anticoagulants

*Antidotes:

Amanita poisoning: G-PNC iv, or silymarin iv

Paracetamol and other drugs: N-acetyl cystein iv

Acute severe hepatitis management (PT<50%)

❖ Transfer to the liver unit 🚑

❖ Liver support systems

❖ MARS, Prometheus, Bioartificial liver🐷

❖ Bridging to LT

❖ Urgent liver transplantation

❖ PT<30% and hepatic encefalopathy

❖ No other contraindications

Chronic liver injury

Chronic liver injury

❖Chronic mild liver test elevation +++ (<2xULN)

❖Most common

❖ Chronic hepatitis (liver test elevation >2xULN/4-6 months)

❖ Cytolytic (dominant ALT elevation)

❖ Cholestatic (dominant ALP elevation)

❖ Vascular liver lesions

❖ Bud-Chiari syndrome, portal vein occlusion, venooclusive dis., regenerative nodular hyperplasia

❖ Focal liver lesions

❖ Benign (cysts, hemangioma, focal nodular hyperplasia)

❖ Malignant (metastasis, primary liver cancer)

Chronic liver injury common causes

Alcoholic liver disease

Non-alcoholic fatty liver disease

Chronic viral hepatitis B, C, D, (E)

Primary biliary cholangitis

Autoimmune hepatitis

Primary sclerosing cholangitis

Wilson’s disease

Hereditary hemochromatosis

Liver lobulus

Chronic liver disease progression Regardless of the cause

❖ Increase in liver fibrosis

❖ Increase in liver stiffness*

❖ Increase in hepatic venous

pressure gradient (HVPG)**

❖ Abnormal laboratory findings

❖ AST>ALT

❖ Low platelets

**

*

Chronic liver injury Fibrosis progression stages

Stage F1, mild fibrosis Stage F2, significant fibrosis Stage F3, advanced fibrosis Stage F4. cirrhosis

Liv

er

his

tolo

gy

Ela

sto

gra

phy

<7.5 kPa >7.5 kPa >13 kPa >13 kPa

HV

PG

<5 mmHg <5 mmHg 5-9 mmHg >10 mmHg

Alcoholic liver disease

The risk of liver disease after the1st. drink

Alcohol GBD, Drug Use C. The global burden of disease attributable to alcohol and drug use in 195 countries and territories, 1990-2016: a systematic analysis for the Global Burden of

Disease Study 2016. Lancet Psychiatry. 2018;5(12):987-1012.

Alcoholic liver disease (ALD)

Risk factors for alcohol-induced liver damage:

• Amount of alcohol/day or per setting

>20g/day, or 4-5 (binge) drinks in few hours

• Time of exposure

• Females

• Genetic background (PNPLA3 polymorphism)

• Other toxins – trace elements in home-made a.

• Other liver diseases – steatosis, viral …..

Alcoholic liver disease Patterns of progression

Driving force: alcohol consumption, obesity, viral hepatitis

abstinenc

Alcoholic liver disease

Clinical: asymptomatic+++, portal hypertension a

late manifestation

Laboratory: AST>ALT, ↑ ↑ ↑ GGT, >MCV,

carbohydrate def. transferin, urine

ethynil glucuronide

Diagnosis: clinical history, objective history, AUDIT

C questionaire

Treatment: abstinence, psychological support

Prognosis: very good in case of abstinence, if

not - cirrhosis 30-40%/10-15

years

Audit C questionnaire

Alcoholic hepatitis

❖ Clinical: jaundice+++, fever, abstinence syndrome, hepatomegaly ++

❖ Laboratory: AST>>>ALT, >MCV, high conjug. Bilirubin, elevated WBC, CRP

❖ Diagnosis: laboratory pattern, exclusion of biliary obstruction (US), (histology)

❖ Severity: Mild or Severe (Maddrey score, Lille model)

❖ Treatment: abstinence, severe: steroids

❖ Prognosis: mild: good, severe: mortality 30-50%, refractory to steroids>50%

Non alcoholic fatty liver disease (NAFLD)

❖ Projected the most common chronic liver disease world-wide

❖ The fastest growing liver disease in terms of prevalence

❖ The second most common indication for LT in the USA

❖ Has recently been proposed to change its name to:

❖ “Metabolic associated fatty liver disease (MAFLD)”

Non-alcoholic (metabolic) fatty liver disease Patterns of progression

Driving force: obesity, diabetes (insulin resistance)

Weight loss

TK1

Snímka 34

TK1 Tomas Koller; 8. 5. 2021

❖ Clinical: asymptomatic, obese, diabetic

❖ Laboratory: ALT>AST, ↑GGT, normal bilirubin, elevated ferritin

❖ Diagnosis: proof of liver fat (ultrasound or MRI), exclusion of significant alcohol intake, viral, AI and other etiologies, NASH – histology++

❖ Severity: depends on the fibrosis stage, histology or elastography

❖ Treatment: weight loss, exercise, control of diabetes, cholesterol, specific targeted drugs in the pipeline (liraglutide……)

❖ Prognosis: depends on the fibrosis stage, good up-to F2, bad in F3-4

Non-alcoholic (metabolic) fatty liver disease

Chronic viral hepatitis

❖ Clinical: asymptomatic, rare extrahepatic manisfestations, cryoglobulinemia, glomerulonephritis

❖ Risk factors: HCV (iv. drugs++, tatoo, piercing, recipient of blood products, invasive procedures), HBV (infection in mother, invasive procedures, Asian origin)

❖ Laboratory: ALT>ULN in 70%, ALT can be normal

❖ Diagnosis: screening (anti HCV, HBs Ag), proof (HCV RNA, HBV DNA)

❖ Severity: depends on the fibrosis stage, histology or elastography, HBV depends on viral load

❖ Treatment: HCV (oral direct acting antivirals 2-3 months, cure 100%), oral HBV antiviral therapy (tenofovir or entecavir) long-term, follow-up and monitoring HBV DNA, ALT, and liver fibrosis markers)

❖ Prognosis: good, depends on the fibrosis stage, and the risk of liver cancer – F3,4 – surveillance for liver cancer by liver ultrasound á 6 months needed, fibrosis and even cirrhosis can regress on treatement

❖ Prevention: HBV vaccination, HCV – testing for blood products, HCV and HBV ELIMINATION WHO goal by 2030

Primary biliary cholangitis

❖ Pathogenesis: autoimmune destruction of lobular bile ducts, trigger unknown

❖ Clinical: asymptomatic, pruritus, sicca syndrome, fatigue

❖ Laboratory: chronic cholestasis (ALP>>>ULN)

❖ Diagnosis: antiM2 (mitochondrial) autoantibodies or ANA anti-gp210

❖ Severity: depends on the fibrosis stage, histology or elastography

❖ Treatment: ursodeoxycholic acid (UDCA) 13-15 mg/kg orally (>80% success), non-response (obeticholic acid or bezafibrate), tratment of pruritus: cholestyramin, rifampin, naloxon, LT

❖ Prognosis: very good in initial stages and in responders, worse in higher fibrosis stage, LT in case of decomp. cirrhosis

Autoimmune hepatitis

❖ Pathogenesis autoimmune destruction of hepatocytes, female predominance

❖ Clinical: asymptomatic, jaundice in severe cases

❖ Laboratory: acute or chronic hepatitis, ALT>AST, ↑ bilirubin

❖ Diagnosis: high IgG, auoantibodies anti-nuclear, anti-smooth muscle, histology+++ (piece-meal necrosis, infiltration of plasma cells)

❖ Severity: depends on the fibrosis stage, synthetic liver function

❖ Treatment: steroids followed by azatioprin, 80-90% success

❖ Prognosis: good if effective therapy, depends on the fibrosis stage, monitor steroid side-effects

Primary sclerosing cholangitis

❖ Pathogenesis periductal inflammation and stenosis of segmenteal bile ducts

❖ Clinical: jaundice, diarrhea (IBD), pruritus, fever (cholangitis)

❖ Laboratory: chronic cholestasis, high bilirubin

❖ Diagnosis: any 2 of the 4: 1. chronic cholestasis, 2. IBD, 3. “dead-tree” image of bile ducts on MRCP and 4. “onion skin” bile ducts patter in liver histology

❖ Severity: depends on the fibrosis stage, occurrence of cholangitis and/or cholangiocarcinoma

❖ Treatment: none approved, UDCA given to improve the quality of life, LT in case of cirrhosis, frequent cholangitis, jaundice, or splenomegaly, LT CI in cholangiocarcinoma

❖ Prognosis: depends on the fibrosis stage and complications

Primary sclerosing cholangitis

Wilson’s disease

❖ Pathog.: failure of copper excretion in the liver, oxidative stress, AR disease

❖ Clinical: acute (even fulminant) or chronic hepatitis, neurological syndrome, neuro-psychiatric syndrome, Kayser-Fleischer ring

❖ Laboratory: high ALT, renal impairment, low ceruloplasmin

❖ Diagnosis: proof of high liver copper on histology, low ceruloplasmin, KF ring, genetic profile, MRI (liver and brain)

❖ Severity: depends on the degree of hepatitis and liver failure, and fibrosis stage

❖ Treatment: penicillamin, or triamtarene, zinc

❖ Prognosis: depends on the liver damage and fibrosis stage, good up-to F2, bad in F3-4, acute liver failure – depends on the liver function and rapidity of therapy

Wilson’s disease

Hemochromatosis

❖ Clinical: asymptomatic, arthritis, diabetes, tanned skin, heart failure

❖ Laboratory: chronic mild hepatitis, elevated ferritin and transferin saturation

❖ Diagnosis: proof of iron overload, proof of genetic muation in HFE gene

(C282Y homozygote, C282Y heterzygote, H63D, S65C)

❖ Treatment: venepuncture, chelates (less effective)

❖ Prognosis: depends on the extent of multiorgan damage (heart, cancer risk)