Bilirubin Metabolism PDF

Syndromes of liver injury. Approach to the patient with abnormal liver biochemical tests. Bilirubin metabolism. Differential diagnosis of jaundice Ilona Savlan, Vilnius University 2024/2025  Liver The largest gland in...

Syndromes of liver injury. Approach to the patient with abnormal liver biochemical tests. Bilirubin metabolism. Differential diagnosis of jaundice Ilona Savlan, Vilnius University 2024/2025  Liver The largest gland in the human body Weight about 1,5kg Under the diaphragm, within the rib cage in the upper right quadrant of the abdomen Only human organ can self- regenerate Performs >500 functions  The functions of the liver METABOLIC Metabolism of carbohydrates, lipids, proteins (glucose→glycogen; amino acids→ammonia, urea; fatty acids→energy; lipids→GNG) EXCRETORY The synthesis of bile in the liver emulsifies lipids and fat-soluble vitamins in the intestines to help digestion and preventing cholesterol to precipitate in the gallbladder. The synthesis and excretion of bile help in reducing excess cholesterol. SYNTHETIC It produces and regulates triglycerides, phospholipids, lipoproteins and cholesterol. Synthesis of proteins (100% albumin, 75-90% α globulins, 50% β globulins, Ƴ globulins (RES)). Proteins are converted to non-essential amino acids and functional proteins for clotting, ferritin for the transport of iron, lipoprotein for the transport of cholesterol, albumin for maintaining oncotic pressure and globulins for immune function. DETOXIFICATION Converts ammonia to urea. Detoxification of alcohol, synthetic and natural drugs, steroidal and non-steroidal hormones such as corticosteroids, testosterone, progesterone, oestrogen and thyroid hormones, insulin and growth hormones. STORAGE It stores fat-soluble vitamins (A, D, E, K) , B12 and other vitamins and minerals such Zn, Fe, Cu, Mg. IMMUNE Synthesis of immunoglobins in RES, Kupffer cells  Liver biochemical tests (LBTs) Liver function tests (LFTs) OR liver biochemical tests can be used to screen for liver disease distinguish among different types of liver disease assess severity prognosis response to treatment LFTs term - is entrenched in the medical literature - misleading term - includes several LBTs, which reflect liver injury, not liver function (liver function - serum albumin, bilirubin, prothrombin time) - abnormal values can be caused by diseases unrelated to the liver - tests may be normal in patients who have advanced liver disease  LFTs classification according to liver functions Synthetic function plasma proteins (albumin, globulins), prothrombin time, INR Detoxification ammonia Excretion serum bilirubin, urine bilirubin, urine and fecal urobilinogen Storage function vitamins A, D, E, K, B 12 Metabolic function serum proteins, cholesterol Liver enzymes evaluation (AST, ALT, ALP, LDH, Ƴ-GT)  Location of enzymes in hepatocyte AST - mitochondria, cytosol ALT - cytosol Alanine aminotransferase (ALT) ALP – canalicular surface Ƴ-GT – canalicular surface, microsomes Gamma LDH - cytosol Alkaline glutamyl transferase phosphatase Lactat dehydrogenase Aspartate aminotransferase (AST)  Classification of liver syndromes Hepatocellular ↑AST – aspartate aminotransferase ↑ALT – alanine aminotransferase Cholestatic ↑alkaline phosphatase (ALP) ↑Ƴ-glutamyl transpeptidase (Ƴ-GT) ↑bilirubin Liver failure ↑bilirubin ↓albumin ↑prothrombin time Inflammatory syndrome ↑serum proteins, globulins, Ƴ-globulins, IgA, IgM, IgG, positive antibodies (anti-DNR, ANA, SMA, LKM-1, AMA, SLA) Infiltrative (cancer, amyloidosis, Hodgink’s disease, granulomatous diseases) ↑ ALP, Ƴ-GT, tumour markers (Ca19.9, αFTP)  Hepatocellular liver syndrome ↑AST – aspartate aminotransferase ↑ALT – alanine aminotransferase disproportionate elevation in the ↑LDH serum aminotransferases compared ↑iron, ferritin with ALP ↑B12 The R value determine type of liver injury (hepatocellular vs. cholestatic) in patients with elevated aminotransferases and alkaline phosphatase R value = (ALT ÷ ULN ALT) / (ALP ÷ ULN ALP) The R value is interpreted as follows: ≥5: Hepatocellular injury >2 to 55 y/o), elevation lower of the cutoff serum values ALT level havemay (and Ƴ-GT) only mild liverwith be associated all-cause and cardiovascular mortality disease or no identifiable cause of the abnormal laboratory values. Benefit of the proposed modifications is unclear since it would translate into a large increase in the absolute number of patients who would require evaluation for an uncertain clinical benefit  AST, ALT location, clearance ALT found primarily in liver AST Liver > Cardiac muscle> Skeletal muscle > Kidneys > Brain > Pancreas> Lungs > Leukocytes > Erythrocytes AST less specific than ALT for liver disease Hepatocyte necrosis is not required for release of enzymes. Liver cells membrane damage – increases permeability The major site of transaminases clearance is the hepatic sinusoidal cell (RES) Elimination half-life AST T½ 17h, ALT T½ 47h  The De Ritis Ratio (AST/ALT) Normal ≤1 “ Inflammatory” type Viral hepatitis, NAFLD ≤ 1 “Necrotic ” type *Alcoholic hepatitis, fulminant Wilson d., drugs, toxins, non-hepatic causes, ishemic hepatitis >2 **Liver cirrhosis>1 *Alcoholic hepatitis - >AST more severe injury, mitochondrial level damage, reduction of ALT synthesis due to B6 deficit **Chronic viral hepatitis, alcoholism, NAFLD, an elevated AST/ALT ratio is predictive of long terms complications Mera JR, Dickson B, Feldman M including fibrosis and cirrhosis Dig Dis Sci. 2008 Mar; 53(3):799-802. Correlation BMI, gender and transaminases Alcoholic/nonalcoholic fatty liver disease score (ANI score) AST ALT Gender Weight MCV ANI score =.....% http://www.mayoclinic.org/gi-rst/mayomodel10.html  Elevation of aminotransferase concentrations in hepatocellular injury The highest elevations due to extensive hepatocellular injury: acute viral hepatitis ischemic hepatitis (=hypoxic hepatitis, shock liver) acute drug- or toxin- induced liver injury (acetaminophen) Other causes of massive elevations in AST include NAFLD, nonalcoholic fatty liver disease. rhabdomyolysis and heat UEGW, 2017 stroke  Causes of sever elevations in aminotransferase levels Acetaminophen (paracetamol) toxicity Idiosyncratic drug reactions Acute viral hepatitis (hepatitis A, B, C, D, E; herpes simplex virus; varicella zoster virus; EBBV; CMV; other viral infections; an acute exacerbation of chronic viral hepatitis (hepatitis B) Alcoholic hepatitis Autoimmune hepatitis >15 times the upper limit of normal Wilson disease Ischemic hepatitis Budd-Chiari syndrome Sinusoidal obstruction syndrome (veno-occlusive disease) HELLP (hemolysis, elevated liver enzymes, low platelets) syndrome and occasionally acute fatty liver of pregnancy Malignant infiltration (breast cancer, small cell lung cancer, lymphoma, melanoma, myeloma) Partial hepatectomy Toxin exposure, including mushroom poisoning Sepsis Heat stroke Muscle disorders (acquired muscle disorders [eg, polymyositis], seizures, and heavy exercise [long distance running])  Evaluation of markedly elevated aminotransferases (1) Acetaminophen level, toxicology screen Acute viral hepatitis serologies (IgM anti-hepatitis A virus, Hepatitis B surface antigen (HBsAg), IgM anti-hepatitis B core antigen (anti-HBc), antibody to HBsAg, Anti-hepatitis C virus antibody (HCV), hepatitis C viral RNA, anti-herpes simplex virus antibodies, anti-varicella zoster antibodies, anti-CMV antibodies, CMV IgM, Epstein-Barr IgM Serum pregnancy test in women of childbearing potential who are not already known to be pregnant Autoimmune markers (antinuclear antibodies, anti-smooth muscle antibodies, anti-liver/kidney microsomal antibodies type 1, IgG) Transabdominal ultrasonography with Doppler imaging to look for evidence of vascular occlusion (Budd-Chiari syndrome)  Evaluation of markedly elevated aminotransferases (2) Additional tests: Ceruloplasmin level and urinary copper quantitation in patients suspected of having Wilson disease Hepatitis D virus antibodies in patients with acute or chronic hepatitis B Hepatitis E virus antibodies in patients from endemic areas, in pregnant patients (because of the high rates of acute liver failure in pregnant women with hepatitis E) Urinalysis to look for proteinuria in women who are pregnant Serum creatinine kinase or aldolase in patients with risk factors for or symptoms of muscle disorders Testing negative → liver biopsy (the acute elevation, aminotransferases fail to decline, appears to be developing acute liver failure) If the elevation is