LIVER DISEASES & LFTs.

Major Metabolic Functions of the Liver

• Synthetic Function – Plasma proteins (albumin, globulins), cholesterol,

triglycerides and lipoproteins

• Detoxification and excretion – Ammonia to urea (urea cycle), bilirubin, cholesterol,

drug metabolites

• Storage Function – Vitamins A, D, E, K and B12

• Production of bile salts – Helps in digestion

LFT

• LFTs are a group of blood tests that detect inflammation and damage to the liver. They can also check how well the liver is working. Liver enzyme testing includes ALT, AST, alkaline phosphatase and GGT.

• Other liver function tests include PT, PTT,

albumin, and bilirubin.

Why Check Liver Function?

• LFTs done if: You are taking a medication that can

harm the liver You have liver disease You have symptoms of liver or bile system

disease (abdominal pain, nausea and vomiting, or yellow skin)

You drink alcohol excessively Liver tests may be done together in a

panel or tested separately routinely in annual physical.

LIVER FUNCTION TESTS

• ALT (SGPT)

• AST (SGOT)

• ALKALINE PHOSPHATASE

• GGT

• BILIRUBIN ( Total & Direct )

• Albumin, Globulins & Total Proteins

• PT

Liver Enzyme Tests

• When liver cells are damaged or destroyed, the enzymes in the cells leak out into the blood, where they can be measured by blood tests.

• Aspartate aminotransferase (AST), formerly called SGOT. The AST enzyme is also found in muscles and many other tissues besides the liver.

• Alanine aminotransferase (ALT), formerly called SGPT. ALT is almost exclusively found in the liver.

• If ALT and AST are found together in elevated amounts in the blood, liver damage is most likely present.

Transaminitis: < 5 x normal

• ALT predominant – Chronic Hep B / C

– Acute A-E, EBV, CMV

– Steatosis / Steatohep

– Hemochromatosis

– Medications / Toxins

– Autoimmune Hepatitis

– Alpha-1-antitrypsin

– Wilson’s Disease

– Celiac Disease

• AST predominant

– Alcohol-related liver dz

– Steatosis/ Steatohep

– Cirrhosis

• Non-hepatic source

– Hemolysis

– Myopathy

– Thyroid disease

– Strenuous exercise

Severe AST & ALT Elev: >15x

• Acute Viral Hepatitis

– does not predict outcome

– Bili > 20 poor prognosis

• Ischemic Hepatitis

– hypotension

– sepsis

– hemorrhage

– MI

• Autoimmune Hepatitis

• Wilson’s Disease

• Acute bile duct obstr

• Hepatic Artery ligation

• Budd-Chiari Syndrome

• Medications / Toxins

– acetaminophen

– CCl4

BILIRUBIN

• Water insoluble product of heme metabolism

• Taken up by liver and conjugated to become water soluble so it can be excreted in bile and into bowel.

• Patient looks Jaundiced if bilirubin >2.5 mg/dl

• If patient is vomiting GREEN, then they have bowel obstruction below the level of the Ampulla of Vater.

WHAT IS THE DEAL WITH DIRECT AND INDIRECT BILIRUBIN?

• Prehepatic disease (eg hemolysis) causes high bilirubin which is non conjugated ie. Indirect fraction higher

• Hepatic disease causes increased conjugated and unconjugated bilirubin

• Post hepatic disease eg. Gallstones have increased conjugated (direct) bilirubin and lead to dark urine and pale stool.

ALKALINE PHOSPHATASE

• Found in hepatocytes that line the bile canaliculi • Level is raised in Biliary obstruction (causes stretch of

the bile canaliculi) • BUT also found in BONE and PLACENTA • GGT is also found in bile canaliculi and therefore can

be used in conjunction with Alk Phos for predicting liver origin

• BUT GGT can be raised by many drugs including Alcohol and therefore non specific

• Alkaline Phosphatase (ALP), 5’ Nucleotidase, and GGT • Another of the liver's key functions is the

production of bile, which helps digest fat. Bile flows through the liver in a system of small tubes (ducts), and is eventually stored in the gallbladder.

• ALP is found in several body tissues, including the liver. Kids and teens normally have higher levels of ALP than adults because of bone growth. But ALP levels that are higher than normal can be a sign of liver diseases or blocked bile ducts.

• When bile flow is slow or blocked, blood levels of certain liver enzymes rise:

• Alkaline phosphatase

• 5' nucleotidase

• Gamma-glutamyl transpeptidase (GGT)

• Liver tests may check for any or all of these enzymes in the blood. Alkaline phosphatase is by far the most commonly tested of the three.

• If alkaline phosphatase and/or 5' nucleotidase and GGT are elevated, a problem with bile flow is most likely present. Bile flow problems can be due to a problem in the liver, the gallbladder, or the ducts connecting them.

• GGT is elevated by large quantities of alcohol ingestion. disproportionate elevation compared to other liver enzymes (such as ALP or ALT) may indicate alcohol abuse or alcoholic liver disease. It may indicate excess alcohol consumption up to 3 or 4 weeks prior to the test.

• Numerous drugs can raise GGT levels, including barbiturates and phenytoin.

• Besides its functions in metabolism, the liver makes proteins that are essential to normal blood clotting. True liver function tests check the liver's ability to make these proteins. They include:

• Prothrombin time (PT): A test of the time it takes for a blood sample to clot, under specific conditions in a lab. If low levels of clotting factors are present, the prothrombin time is longer.

• PT is often checked together with PTT (partial thromboplastin time), which is not a liver function test. If PT and/or PTT are elevated, a problem with bleeding or clotting may be present.

Liver Function Tests: Albumin

• The liver also makes albumin, an essential protein that circulates in blood. Albumin levels are low in people with severe chronic liver disease, because the liver does not make normal amounts of albumin. However, albumin levels may fall in a variety of medical conditions.

ALBUMIN

• Albumin has a half life of 21 days, so the drop that occurs with hepatic dysfunction does not occur acutely

• That said, acute illness can cause albumin to drop rapidly – a process thought to be due to cytokines increasing the rate of albumin metabolism

• HOWEVER, don’t forget that low albumin also occurs in NEPHROTIC syndrome, so always check the urine for protein.

• Albumin and total protein. Liver function tests include measuring albumin (the major blood protein produced by the liver), as well as the total amount of all proteins in the blood. When there's a problem with the liver, there can be changes in the amounts of albumin and other proteins it produces.

PROTHROMBIN TIME/INR • Measure of the Vitamin K dependent clotting factors ie.

II, VII, IX and X.

• The liver is involved in activating Vitamin K. Therefore in liver damage, these clotting factors cannot be produced.

• Before you believe that prolonged INR is due to liver disease just make sure the patient has adequate Vitamin K by giving 10mg sc.

• Giving Vitamin K has no effect on INR if patient has impaired synthetic function.

High liver function tests • Some other possible causes of results include the

following: • Obesity puts severe stress on the liver because of the

increased blood volume and this can cause an elevation of liver function.

• Certain medications including common ones like aspirin and ibuprofen, as well as antibiotics, cholesterol lowering drugs and seizure medications can cause elevation of liver function.

• Alcohol consumption as mentioned earlier can be a major cause for elevated liver function levels, particularly if you have been consuming significant amounts of alcohol, for over a prolonged time period.

• Autoimmune disease

In some cases certain autoimmune diseases like autoimmune hepatitis and primary biliary cirrhosis could cause the immune system to launch attacks on the liver or bile ducts.

• Wilson's disease and hemochromatosis are some examples of metabolic liver disease that can cause high liver function test results. These conditions are a major cause for concern and need to be treated promptly as they can even cause liver failure if neglected.

• Viral hepatitis, in the case of acute or chronic infections, can also cause elevated levels of liver function.

• In the event of development of tumors in the pancreas, bile ducts or the liver too there would be elevated liver functions and there is also a risk of fatality, which is why such a condition needs urgent medical attention.

Toxic damage to liver

• Mitochondrial damage Drugs (antivirals, salicylate, valproate,

tetracycline) Toxins (hypoglycin, atractyloside) • Endothelial damage to hepatic veins Drugs (cytotoxic drugs) Toxins (Senecio, aflatoxin, pyrrolizidine) • Glutathione depletion and cell death Drugs (paracetamol) Hypoxic ischaemia

Clinical patterns of metabolic disease involving the liver

• Newborn acute metabolic crisis

mimics sepsis

• Severe vomiting and failure to thrive

• Recurrent episodes of vomiting and encephalopathy with acidosis

• Progressive retardation or seizures with hepatomegaly

• Hepatomegaly with/without jaundice and failure to thrive/grow normally

TYPICAL PATTERNS

• HEPATOCELLULAR

– Increased transaminases

• Viral Hepatitis

• Drugs/alcohol

• Autoimmune

• NASH

• Hemochromatosis

• CHOLESTATIC

– Increased Alk Phos and Bilirubin

– Also may cause increased transaminases

• Gallstones • Primary Biliary

Cirrhosis • Sclerosing

Cholangitis • Pancreatic C/a

Alcoholic Liver Disease

• AST > ALT

• 2:1 - 3:1 ratio

• AST < 300

• Why the discrepancy?

– ETOH AST synthesis

– Vit B6 def inhibits ALT

• ETOH

– Steatosis 90- 100%

– hepatitis 10- 35%

– cirrhosis 8- 20%

• GGT

NASH

• Non-Alcoholic Steatohepatitis

• Common cause of elevated liver function tests

• Often patients have metabolic syndrome with obesity, hyperlipidemia and diabetes

• 20-30% progress to cirrhosis

• Weight loss, control of lipids and diabetes should reduce progression.

Genetic Liver disease

• Wilsons

• Hemochromatosis

• Alpha-1-Antitrypsin deficiency

Hemochromatosis

• Autosomal recessive • Gene on Chromosome 6 • Increased Fe absorption from gut, depositied in tissues

causing fibrosis and functional failure. • Presentation: “BRONZE DIABETES”, but also arthralgias,

Hepatosplenomegally and stigmata of liver disease, testicular atrophy, CCF due to restrictive cardiomyopathy

• Dx: High Fe and Ferritin, low TIBC, Low testosterone, Diabetic. Joint XRays show chondrocalcinosis

• Liver Bx shows Fe staining • NB. Hemochromatosis can be secondary to B

Thalassemia and repeated blood transfusions.

Skin color of Hemochromatosis

What is this sign called and what is it associated with ?

Wilson’s Disease • Autosomal Recessive • Deletion on Chromosome 13 • Defective intrahepatic formation of caeruloplasmin

therefore failure of biliary excretion and high total body and tissue levels of copper.

• Dx High serum caeruloplasmin, increased urinary copper. • PRESENTATION: Cirrhosis, Kaiser-Fleischer rings,

hypoparathyroidism, arthropathy, Fanconi syndrome (renal tubular acidosis) CNS: Psychosis, extrapyramidal syndrome, mental retardation and seizures.

• Think of this in a young patient with strange neurology and liver disease

• Tx: Copper chelation with penicillamine, can cure with liver transplant BUT the CNS sequalae will not resolve.

α-1 Antitrypsin Deficiency

• THE AUTOSOMAL DOMINANT ONE!

• Severity of disease is dependent on which alleles are affected (ie which phenotype)

• Gene on Chromosome 14

• Intrahepatic accumulation of α-1 Antitrypsin causes liver disease and can lead to cirrhosis

• May have Lung disease (emphysema)

Budd Chiari Syndrome

• Just know that it is thrombosis of hepatic veins

• May be acute or chronic

• May be associated with hypercoagulable state therefore must do thrombophilia screen. Also look for underlying maliganacy

• Can occur with hydatid cysts

• Presentation: Nausea, Vomiting, Abdo pain, Tender hepatomegally and loss of hepatojugular reflex

• Tx: call a hepatologist: may need TIPPS or may need portocaval or splenorenal anastomosis. May be thrombolysable. Always call for help.

What is the sign…and who was it named for?

Medusa

Stigmata of liver disease • HANDS:

– Palmar Erythema – Clubbing – Dupytrens – Leuconychia – FLAPPING TREMOR

• HEENT/UPPER BODY – Jaundice – Spider Angiomata – Gynaecomastia and scant body hair – Scratch marks

• ABDOMEN – Ascites – Hepatosplenomegally – Caput Medusa – Hemorrhoids on PR - Small testes

Ascites

• Accumulation of free fluid in peritoneum

• Assessment involves taking sample of fluid and checking albumin content

• SAAG: Serum Ascites Albumin Gradient

– SAAG = Serum Albumin – Ascites Albumin

SAAG

• HIGH ie. ≥1.1

• Portal hypertension present

– Cirrhosis

– Alcoholic hepatitis

– Congestive cardiac failure

– Hepatic mets

• LOW ie <1.1

• Inflammatory causes

– Peritoneal carcinomatosis

– Peritoneal TB

– Pancreatitis

– Serositis

Management of Ascites • Salt Restrict

• Fluid Restrict

• Diuretics

– Spironolactone 100-200mg /day to increase urinary sodium excretion. Aim to reduce weight by 1Kg per day

– May also need Lasix

• Large volume paracentesis

– Should give 6g Salt poor Albumin per liter of Ascitic fluid removed in patients with HIGH SAAG otherwise can cause precipitous fall in BP and Hepatorenal syndrome.

Variceal Hemorrhage

• Varices develop at Esophagogastric junction due to portal hypertension

• First bleed has 10-30% mortality

• Early endoscopy band ligation

• Octreotide decreases the portal pressure and may stop the bleeding

• 80% rebleed within 2 years

• Bblockers esp Propranolol reduce portal pressure and may prevent rebleeding

• Serial endoscopy and banding to obliterate the varices is also indicated to prevent rebleeding

Encephalopathy

• Decreased consciousness in patient with severe liver disease

• Always look for cause • Infection

• Bleeding

• Electrolyte disturbance

• Constipation

• Increased protein intake

• Usually has increased serum ammonia – which you should check, although, it doesn’t need to be that high for pt to be encephalopathic

• Tx: Lactulose