Hepatic

Unit 16. liver diseases.  Overload – pre hepatic haemolysis.  Hepatic – poisonings, infections, loss of liver cells.  Post hepatic - blockage of bile ducts.

Jaundiced patient 

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History: family history, contacts, immigrant status, occupation, sexual practices, drug use, alcohol etc Physical examination: stigmata, systemic, auscultation, gall bladder problems. Laboratory investigations, abdominal X ray, Ultrasound.

Hepatocellular disease with “prodrome” – no jaundice!       

Anorexia, Nausea, Malaise, Abdominal pain, Liver tenderness, Faeces: pale, may float. Urine: dark.

Liver functions:        

Protein homeostasis Carbohydrate homeostasis Lipid homeostasis Erythrocyte: make and destroy Waste: metabolize and excrete Digestion: make bile salts Blood clotting factors made Speciality proteins made and destroyed.

Liver function tests 

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s-AST and s-ALT indicate hepatocellular damage s-bilirubin and s-ALP indicate cholestasis In chronic disease s-albumin is measured.

LFT: serum transaminases, ALT and AST.   

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Clinically sensitive but not clinically specific Both are found in many tissues. s-ALT is more increased in liver disease than sAST s-ALT has fewer false positive results. Increased by overload of liver, infections, shock, severe hypoxia, acute and chronic cardiac failure

Distribution of ALT and AST in normal human adult tissue ALT Serum Lung Spleen Kidney Heart Skeletal muscle Liver

AST 1

1

44 75 1200 450 300 2750

500 700 4550 7800 4950 7100

LFT: serum bilirubin   

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Breakdown product from haem. Insoluble in water, transported bound to albumin Liver makes it into mono and diglucuronide (“direct” or conjugated bilirubin) Conjugated bilirubin is secreted into the bile Altered in the gut to stercobilin (urobilin) Normal is <17 umol/L but jaundice is seen when bilirubin is >40 umol/L

Serum alkaline phosphatase    

Membrane transport protein Increases in blood in cholestasis Increases in cancer and cirrhosis Also found increased in diseases of the bone, small intestine, kidney and the placenta.

Serum gamma glutamyl transferase  

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Microsomal enzyme Increased in cholestasis but is somewhat increased in all liver diseases Ethanol and Phenytoin etc users have increased serum levels of gamma glutamyl transferase [GGT].

Serum albumin  

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Transport protein Most abundant protein made by the liver Low levels in chronic liver disease, starvation and shock.

Prothrombin time: 

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Liver made clotting protein decreased in liver disease. Increased prothrombin time may be the first sign of liver damage Short half life – the only LFT that gives the “current” situation

Serum globulins or total protein 

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In hepatitis there is broad spectrum (polyclonal) increase in serum gamma globulins. In autoimmune hepatitis similar broad gamma band is seen on serum protein electrophoresis. Could be estimated by s-protein and/or salbumin.

Liver function tests summary:  

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Cell damage = s-ALT (or s-AST) increased Bile blocked = s-bilirubin, s-ALP, s-GGT increased Serial tests for monitoring and prognosis. s-GGT increase may indicate hepatocellular enzyme induction by drugs or alcohol.

Rarer liver function tests: 

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Alpha foetoprotein; usually used as a cancer marker but also increases in liver regeneration. Alpha-1-antitrypsin: juvenile cirrhosis.

Serum ceruloplasmin 

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Anti inflammatory protein – increased in inflammation. Decreased in Wilson’s disease Increased tissue and urinary copper Leads to juvenile cirrhosis 1 in 30,000 Europeans

Liver serology, tertiary LFTs Virus . Test A B

Indication

IgM anti-HAV

Acute infection

IgG anti-HAV

Prior infection

HBsAg, anti-HBs

Acute infection

HBc, anti-HBc

Prior infection

HBV DNA

Detection, response to therapy

Anti-HBe

Response to therapy

Liver serology (continued) Virus

Test

Indication

Anti-HCV

Previous infection

HCV RNA

Presence of viral replication

D

Total anti-HDV

Acute or chronic infection

E

Anti-HEV

Infection

C

Hepatitis: Haemolytic(pre)

Hepatocellular Cholestasis (post)

s-bilirubin >75 nonconjugated u-bilirubin 0

s-bilirubin late s-bilirubin conjugated. u-bilirubin u-bilirubin

b-reticulocytes

s-ALT, AST

b-Hb decreased

s-ALP up later s-ALP increased

b-haptoglobin decreased s-LD may increase

s-ALT, AST

Gilbert’s disease:   

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Defective conjugation. Benign or very mild disease. Most obvious in infections, operations, when fasting. Quebec 1 in 60 “pure laine”. Differential diagnosis confusion.

Prehepatic jaundice Unconjugated hyperbilirubinaemia  Newborn: HbF replaced by HbA  s-bilirubin > 300 umol/L then blood transfusion to avoid brain damage  Glucose-6-phosphatase deficiency, membrane defects, severe trauma, sepsis 

Hepatic jaundice   

s-bilirubin, ALT, AST, ALP increased. Poisonings or vial. Commonest poisonings: Tylenol (Acetaminophen), Carbon tetrachloride, Phenytoin (Dilantin), Valproate, Halothane, Plant and fungi.

15 year old woman suicidal, took pills 2 hours ago   

s-bilrubin 15 umol/L (2-17) s-ALT 100 U/L (<35) s-ALP 100 U/L (<100)

What next?

Viral hepatitis transmission, after Botticelli 1486: Venus

Transmission

Viral hepatitis

sexual

B and D

Giant clam Shellfish,water

A and B

Sea Wind Pregnant

Blood salivary neonate

B B, Epstein-Barr B

Mosquito

needles, blood supply B and C.

Hepatitis tests for:  

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Prodrome: s-ALT, u-urobilinogen. Bilirubin increases and s-AST, s-ALT remain increased until cure. No u-urobilinogen until recovery. During cholestatic phase faeces is pale and floats. Diagnosis by serology.

Hepatitis A        

Single strand RNA Transmission: faecal-oral Incubation period: 2-4 weeks North America: children Diagnosis: s-IgM against hepatitis A Death rate: 1 in 5,000 No chronic hepatitis results. Vaccine available.

15 year old boy boarding school, ‘flu. Pain in right upper quadrant     

p-bilirubin 17 umol/L (<17) p-ALT 325 U/L (<35) p-ALP 100 U/L (<100) p-Albumin 39 g/L (30-50) p-Protein 65 g/L (60-85)

What indicates hepatitis A? How do you confirm this?

Hepatitis B        

DNA virus, Transmission: by body fluids Incubation: 2-6 months World wide prevalence: 5-6% Neonates at most risk. Diagnosis: s-HBsAg Vaccine exists, hands on health, day care workers should have it. Leads to recovery or carrier state and/or liver cancer eventually.

Hepatitis C      

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Transmission: in North America by blood Incubation: 7 weeks Mild illness but 85% get chronic liver disease s-ALT and s-AST fluctuate widely Screen by s-ALT, anti-HCV High rate of spontaneous mutation so no vaccine likely. Liver cancer likely.

HCV

Hepatitis D   

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Transmission: in some cases, at least, sexual Requires co-infection with HBV for replication First noted in Italy, pockets of it exist in Russian and Sweden IgG, A, M anti HDV (total) Goes to severe liver disease

HDV

40 year old man returned from vacation in southern Italy.      

5 days of increasing jaundice. p-bilirubin 200 umol/L (<17) p-ALT 2,640 U/L (<35) p-ALP 500 U/L (<100) p-protein 66 g/L (60-80) p-albumin 37 g/L (35-50)

Indicators of severity? Diagnosis?

Hepatitis E 

Transmission: faecal-oral Major epidemic in Far East and India

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Diagnosis by antibodies to HEV antigens.

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May be fatal to pregnant women

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Epstein-Barr virus (EBV): 

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Infectious mononucleosis, Transmission: is oral, “kissing disease” Incubation period: is 28 days. Mild hepatitis with the usual prodrome Laboratory tests: Monospot (heterophil IgM antibodies), EBV titre, nuclear, capsid and early antigen antibodies.

Cytomegalovirus:   

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Herpes type 80% of adults show evidence of infection Serological Test for cytomegalovirus – not conclusive. Rapid screen exists. IgM levels in primary infections Hepatitis is mild and does not progress to chronic disease. A problem in pregnancy, could cause CNS damage to foetus.

Treatment of viral hepatitis:  

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Nothing really works. Alpha interferon is being tried but has to be taken continuously. Isolate the patient. Universal (body fluid) precautions. Supportive care.

Post hepatic jaundice (Cholestasis)  

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Gallstones can partly or fully block the bile duct. Complete block: s- bilirubin and s-ALP increased, no u-urobilinogen, faeces pale and float. Partial block: s-ALP increased but sbilirubin could be normal Increased s-conjugated bilirubin.

60 year old man jaundiced with no pain.    

Weight loss, pale faeces, drinker, no drugs p-bilirubin 250 umol/L (<17) p-ALT 90 U/L (<35) p-ALP 900 U/L (<100)

Diagnosis? What further tests?

Outcomes of hepatitis Complete recovery or  Acute hepatic failure or  Chronic hepatic damage. 

Etiology of chronic active hepatitis: HBV

HCV

Unknown

USA

Auto -immune 20

27

21

32 %

UK

58

6

4

32

Australia Italy France Iraq

30 2 28 5

36 49 17 92

4 15 2 0

30 34 53 3

Chronic hepatic damage:  

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Alcoholic fatty liver Chronic active hepatitis following virus infection. Autoimmune disease May progress to cirrhosis.

35 year old woman had hepatitis 9 months before. Results now:     

p-bilirubin 45 umol/L (<17) p-ALT 350 U/L (<35) p-ALP 400 U/L (<100) p-protein 115 g/L (60-85) p-albumin 30 g/L (30-50)

Evidence for CAH? What additional laboratory work?

Probable causes of jaundice in different age groups: Hepatitis Cancer Gall stones Drugs Alcohol Other

1-30yrs

30-60yrs

>60yrs

80 5 2 3 10

30 10 15 5 30 10

5% 45 25 10 10 5

Cirrhosis    

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Terminal event in liver disease. Not reversible. 30% of alcoholics get it. Multiple childbirth may be factor in autoimmune hepatitis, primary biliary cirrhosis. No good markers for early stage. Diagnosis by biopsy. Little or no treatment that works is known

(Too) Late cirrhosis       

Increasing jaundice Mental changes, flapping tremour asterixis. Ascites Bleeding Terminal liver failure Immune suppression Itching (bile salts).

Cirrhosis

50 year old labourer, vomited blood lifting a beam.       

Blood haemoglobin 102 g/L (125-175) Haematocrit 0.4 (0.4-0.52) Urine: tea coloured Faeces: occult blood positive Serum bilirubin, ALT, ALP increased Serum protein decreased. History of alcohol abuse.

Rarer causes of cirrhosis   

Wilson’s disease. Haemochromatosis. Alpha-1-antitrypsin deficiency.

Boy dies from liver failure.  

Serological tests all negative Liver copper much increased (found at autopsy)

What laboratory investigations on his younger sister?

Hepatic failure 

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Electrolyte imbalances, s-Na, Ca, glucose decreases, severe acidosis. Renal failure, toxins? b-ammonia increased s-albumin decreased p-Clotting factors decreased Recovery may take weeks.

Summary 

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Severe acute liver damage may progress to liver failure s-bilirubin, s-ALT and albumin followed over time Cirrhosis is end point LFT little or no use in late stages Biopsy needed to diagnose late stages.

Liver cancers: 

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Primary – hepatoma caused by hepatitis B or C, aflatoxin, steroids, haemochromatosis. Secondary – spread from other cancers Screening markers: s-AFP and ultrasound each 6 months. s-GGT spread to liver from colon e.g.

60 year woman, breast cancer was treated, now has bone pain:    

s-bilirubin 7 umol/L (<17) s-ALT 40 U/L (<35) s-ALP 900 U/L (<100) s-GGT 30 U/L (<30)

Explain these results? What laboratory work next?

Let your liver live with clean living.