Liver function tests.

Hepatocellular injury, ALT. 7 to 55 units per liter.

necrosis, swelling. Metabolise proteins.
AST. 8 to 48 U/L.
Metabolise alanine. (found in liver, muscles, heart,
brain, kidneys).
Total, conjugated & unconjugated bilirubins.
Cholestasis. ALP. (enzyme in the liver, bile ducts and bone). 45 to 115 U/L.
GGT. 9 to 48 U/L.
5'-nucleotidase. 2 to 15 U/L.
Bilirubin (total). 0.2 – 1.2 mg/dL.
Conjugated bilirubins. 0.1-0.4 mg/dL.
conjugated with glucuronic acid by the
enzyme glucuronyltransferase – water soluble.
Unconjugated bilirubins. Difference.
Synthesis. Albumin.
(blood osmotic pressure & enzyme carriers). 35-50 g/L.
Globulins. 23 to 35 g/L.
Total proteins. 6 and 8.3 gm/dL.
Prothrombin time. 11-14 seconds.
(vitamin K–dependent process.). (INR 0.8 to 1.2).
Aminotransferases (AST, ALT).
ALT. Very specific to hepatic injury.
AST. If AST alone is elevated, probable causes – heart, muscles, kidney, brain
damages.
Alcoholic. Ratio AST/ ALT 2.0 & GGT elevated.
ALP & GGT together Liver diseases.
elevated.
ALP alone elevated. Intestine or bone injuries.
Breath tests.
The rate of conversion of orally or intravenously radiolabeled carbon 14 (14 C), which is converted to CO2, is
subsequently exhaled, can be collected and quantified as a measure of liver function.

The decreased clearance of aminopyrine (aminopyrine breath test), that correlates with the decreased rate
of 14CO2 – liver cirrhosis.

The methacetin breath test was introduced to measure fl ow-dependent hepatic microsomal function. The
substrate, 13 C methacetin, is metabolized in the liver by O-demethylation to 13 CO 2 and acetaminophen.
Materials clearance tests.
Indocyanine green (ICG). IGC is a dye with high clearance from healthy hepatic. To measure the
hepatic blood fl ow using the Fick equation. More retention implies less
functional hepatic.
Galactose clearance. These reduced in patients with cirrhosis and chronic hepatitis.
Monoethylglycinexylidide (MEGX) formation tests.

MEGX, the fi rst-pass metabolite of lidocaine, formation is the measure of liver function/ hepatic blood flows.
The Lidocaine, when administered intravenously at a subtherapeutic dose (1 mg/kg), is rapidly cleared and
metabolized by the liver to MEGX.
The biles & bile formation with contents.
- elimination of lipid-soluble toxins.
- secretion of bile acids.
- Transport of cholesterol into the gastrointestinal (GI) tract.
- absorption of fats and fat-soluble vitamins, in addition to drugs, toxins, and heavy metals (through the
formation of micelles) (Micelles are formed by bile acids and by cholesterol, phosphatidyl choline, and
lecithin).
- excretion of bilirubin. The conjugation failures/ excretion failures may result in the jaundice.
- Excretion of copper (regulation of copper in the body). Wilson’s disease – failure of copper excretions
by the mutation of ATPB7 genes.
- Others: steroid hormones, certain vitamins, cytokines such as tumor necrosis factor-a, and leukotrienes
and divalent cations.
- Other proteins: albumin, lysosomal enzymes, and haptoglobins.
The bilirubins/ hepatic ions transporters (e.g., mdr2/MDR3), responsible for biliary secretion and transport of
these substances.
The activation of the nuclear receptors such as the FXR, PXR, CAR, VDR, RAR, LRH, PPARa and GR, in the
cholestatic conditions may enhance the bile flows.
Bile flow obstruction → bile reflex & hepatocellular injuries → liver cirrhosis.
1. Increased bile acids in the blood stream (no recirculations).
2. Increased ALP.
3. Due to the non – availability of bile acids in the GIT – low fat absorption (malnutritions), Vit. D
deficiency (calcium def. & osteoporosis), Vit. K malabsorption (prothrombin formation deficiencies).
1. Reduced protein synthesis & clotting factors by the hepatocytes. Weight loss (less proteins), easy
bruising (less prothrombins).
2. Increased ALP.
3. Increased bilirubins in circulations.
1. Increased portal veins pressures. Further obstructions.
2. Hepatic encephalopathy, Spider angiomas, Bleeding varices, Caput medusae & Ascites.
The bile duct obstruction will cause jaundice only if the obstruction is between the confluence of the right
and left hepatic ducts and the tip of the papilla of Vater.
But the serum alkaline phosphatase (ALP) or total serum cholesterol levels may be elevated in the absence
of jaundice.
Obstructions (extrahepatic ducts) – the Intrinsic obstructive tumors
Physical signs to identify the liver diseases.
1. jaundice, dark urine, light stools.
2. Clubbing of the fingers, and whitening of the nail beds – cirrhosis.
 3. Icterus (the deep staining of the skin, sclerae, and mucous membranes) – both hepatic &
obstructive. The prehepatic (hemolytic) will not have the deep staining of skins.
4. Pre – hepatic: No bilirubins in urine, but urobilinogen (dark urine). Dark stool.
5. The enlarged or tender liver.
6. congestive heart failure (CHF) or constrictive pericarditis – the enlarged, tender livers.
7. Liver massively enlarged and nodular - biliary cirrhosis, fatty liver, or primary or secondary hepatic
neoplasms.
8. The portal hypertension: splenomegaly, ascites, and caput medusae.
9. severe itching of the skin (pruritus) - cholestatic liver disease (increased bile salts in circulations). Also
combined with high cholesterols.
10. Presacral and ankle edema: Low albumins & sodium retentions.
11. Intermittent fever – cirrhosis.

Liver cirrhosis.
The chronic injury to the liver parenchyma, alteration of hepatic architecture and the formation of small or
large nodules.
This may lead to portal hypertension with ascites, esophageal varices, and necrosis.
The hepatic fibrogenesis due to inflammatory mediators. The hepatic stellate cells are the primary storage
site for retinoids, and upon stimulation by inflammatory or other noxious factors, stellate cells become
contractile and are activated, demonstrating features of myofibroblasts and releasing cytokines and other
inflammatory mediators.
1. Thrombocytopenia, Leukocytosis, anemia caused by hypersplenism (portal hypertensions).
2. ascites, esophageal varices, and the dilatation of abdominal veins (caput medusae) – due to portal
hypertensions.
3. Peripheral neuropathy (due to malnutritions).
4. Severe jaundice is seen in only a minority of patients.
5. Chills, high fever.
6. ankle edema (due to the Hypoproteinemia and compression of the inferior vena cava by ascites).
7. The mildly to moderately decreased platelet count and associated splenomegaly.
8. Bleeding/ bruisings.
9. The excess circulating estrogen resulting from decreased clearance by the liver - Testicular atrophy,
gynecomastia, female escutcheon, pectoral and axillary alopecia, and marked reddening of the
thenar and hypothenar. increased estrogenic activity appear more in men. In women, hair loss and
spider nevi are seen most often, but some masculinizing effects, such as hirsutism.
10. The Cutaneous spider nevi are found mainly on the upper half of the body, usually the neck,
forearm, and dorsum but sometimes the mucous membranes, and consist of a central arteriole from
which many small vessels radiate.
Pathogenesis & structural changes.
From the hepatic stellate cells.
The deposition of extracellular matrix results in fibrosis, development of scar tissue, vascular obstruction, and
sinusoidal hypertension, followed by portal hypertension and eventually hepatic failures.
The progression of this can be slowed by immunomodulator therapy (e.g., corticosteroids) or elimination of
the inciting agent (e.g., interferon-a for hepatitis C).
Cytokines that play a key role in stellate cell proliferation and activation include transforming growth factor-
ß, interleukins, hepatocyte growth factor, and platelet-derived growth factor. These cytokines have multiple
effects; some are fibrogenetic, whereas others may promote fibrinolysis. Some are primarily proinflammatory
and others are anti – inflammatory.

Fibrinogen formation: These characterized by increased deposition of extracellular matrix, ongoing

inflammations and an imbalance in favor of fibrogenetic rather than the fibrinolytic pathways. The fibroblasts
are also involved in the development of hepatic fibrosis.
Diagnosis: Biopsy & laparoscopy.
The Trichrome stain system to evaluate the degree of fibrosis: stages 1 and 2 represent periportal or septal
fibrosis, whereas stages 3 and 4 are used to describe bridging fibrosis and cirrhosis, respectively.
Innovative avenues.
1. The anti – fibrotic agents/ therapies.
2. The use of noninvasive serum markers of fi brogenesis to classify the degree of scarrings.

Portal hypertension.
1. blockage in the intrahepatic portal venous system (sinusoidal portal hypertension).
2. Impaired outflow of blood from the liver (post sinusoidal portal hypertension).
 3. increased pressure in the extrahepatic portal venous system.
Above approximately 5 to 6 mm Hg. of normal range.

Alcoholic liver disease.

Complications.
1. Fatty liver (most cases reversible).
2. collagen deposition in and around central veins (the perivenular sclerosis).
3. The acute liver injury that may become recurrent or chronic.
4. sinusoidal, perivenular, and pericentral fibrosis and cirrhosis.
5. may have portal hypertension, ascites, and esophageal varices.
The oxidation to acetaldehyde by the alcohol dehydrogenase (ADH) in liver.
ethanol is oxidized within the hepatocyte cytosol to acetaldehyde, acetaldehyde is oxidized to acetate via
catalysis mainly by aldehyde dehydrogenase (ALDH) in the mitochondria, and the acetate ALDH is released
into blood and is oxidized by peripheral tissues to carbon dioxide and water.
During the process, the nicotinamide-adenine dinucleotide (NAD) is converted into NADH & this increase in
the NADH/ NAD ratios will cause - inhibition of hepatic gluconeogenesis, impairment of fatty acid oxidation,
decrease in citric acid cycle activity, and increase in conversion of pyruvate to lactic acid resulting in lactic
acidosis.

.
Fatty liver.
Ethanol oxidation to acetaldehyde increases hydrogenated nicotinamide adenine dinucleotide (NADH),
which favours triglyceride accumulation by decreasing fatty acid metabolism.

Diagnosis.
AST/ALT ratio is often greater than 2 : 1 and is frequently greater than 3 : 1.
Treatments.
- Treat portal hypertensions, if any.
- Provide thiamine, folic acid, and multivitamins.
- The electrolyte, calcium, magnesium, phosphate, and glucose levels should be strictly monitored and
corrected.
- Expecting insulin resistance. high-carbohydrate, high-fiber, and low-fat diet may reduce the insulin
resistance.
- Proteins to be given > 1 mg/kg.
- benzodiazepines (if alcohol withdrawal associated seizures and delirium tremens).
- Corticosteroids—prednisone or prednisolone (40mg.).
- The Serum levels of tumor necrosis factor (TNF) as well as IL-1, IL-6, and Il-8 to be reduced through the
Anticytokine therapy.
pentoxifylline 400 mg t.i.d. (to reduce TNF-2, IL-5, IL-10 and IL-12).
Infliximab, 10 mg per kg (daily).
Etanercept (P75-soluble TNF receptor). FC fusion protein neutralizes soluble TNF.

- Antioxidants (Vitamin E & Sadenosylmethionine (SAMe)). In cirrhosis, the SAMe synthetase’s activity is
decreased, which helps to produce the glutathione. SAMe is the amino acid of glutathione.
- Silymarin (to reduce the lipid peroxidation and lymphocyte proliferation) to improve the hepatocytes.
- Anabolic steroids (helps on protein and nucleic acid synthesis).
- Propylthiouracil (PTU) at doses of 300 mg per day for 45 days (reverse the relative tissue anoxia in the
centrilobular zone of the liver by decreasing the rate of oxygen consumption).
- The Colchicine (its antiinflammatory, antimicrotubular, and antifibrotic actions).
- The Thalidomide, misoprostol, adiponectin, and probiotics (new therapies) – the anticytokine properties.
Inherited liver disease (Wilson’s disease).
Autosomal recessive.
The progressive accumulation of copper in the liver, brain (particularly in the basal ganglia), cornea, and
kidneys, causing severe functional impairment leading to irreversible damage. If not treated, this disease is
invariably fatal, but with early diagnosis and treatment, the clinical manifestations can be prevented and
reversed.
Viral hepatitis.

Ascites.
The accumulation of fluid in the abdominal cavities, from the liver and possibly the peritoneum.