Chronic Liver Disease (CLD)

Symptoms:

1.       Right hypochondrial pain due to stretching of liver capsule as a result of hepatomegaly.

2.       Ankle swelling due to fluid retention.

3.       Gynaecomastia (enlargement of male breast), loss of libido and amenorrhea due to endocrine dysfunction.

4.       Pruritus due to cholestasis, this is often and early symptoms of primary biliary cirrhosis.

5.       Hematemasis and melena from GIT hemorrhage.

6.       Confusion and drowsiness due to neurological complicatin (hepatic encephalopathy).

Signs:

Skin

·         Palmar erythema: Indicating hyperdynamic circulation. (may also occur in pregnancy, thyrotoxicosis, rheumatoid arthritis, CO2 retention and old age).

·         Clubbing: occasionally occur.

·         Dupuytren’s contracture: (often in alcoholic cirrhosis).

·         Spider nevi: These are telangiectasias that consist of a central arteriole with radiating small vessels. They are found in the distribution of the superior vena cava (i.e. above the nipple line).

Abdomen

·         Initial hepatomegaly followed by small liver in well established cirrhosis.

·         Splenomegaly: Indicating portal hypertension.

Endocrine system

·         Testicular atrophy

·         Gynecomastia: enlargement of male breast occurs due to decreased estrogen metabolism in diseased liver, it also results from treatment with spironolactone, a diuretic commonly used for edema and edema and ascites in cirrhosis.

With complications:

·         Jaundice

·         Encephalopathy: (drowsiness, stupor, flapping tremor of outstretched hands and fetor hapaticus)

·         Collateral veins e.g. veins around the umbilicus forming caput medusae

·         Peripheral edema

·         Ascites 

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NORMAL LIVER FUNCTIONS (Health tips)

Recognition of normal liver functions is necessary to understand the manifestations that develop when liver becomes abnormal due to disease process.

SYNTHETIC FUNCTION (Health tips)  

Protein synthesis

Liver is the principal site of synthesis of all circulating proteins except gamma-globulins, which are produced in the reticuloendothelial system. Plasma contains 6-8 mg/dl of proteins, mainly in the form of albumin, globulin and fibrinogen. Liver also synthesizes complement factors, transferin, haptoglobin, caeruloplasmin, protease inhibitors (a 1-antitrypsin), and a-fetoprotein.

Albumin has half-life of 16-24 days and 10-12g is synthesized daily. Its main functions are to maintain the intravascular colloid osmotic pressure and to transfer water-insoluble substances such as bilirubin, hormone, fatty acids and drugs.

• Albumin synthesis is reduced in chronic liver disease and malnutrition. It can be lost in nephritic syndrome and in protein-losing enterpathy.
• Hypoalbuminemia results in edema.

Coagulation proteins

Liver also synthesizes all coagulation factors (other than factor VIII) such as fibrinogen, prothrombin, factors V, VII, IX, X and XII.

• Deficiency of coagulation factors results in bleeding tendency.

METABOLIC FUNCTIONS

Carbohydrate metabolism

Liver is the main source of plasma glucose as it is the main body storage site for glycogen. In the fasting state glucose is derived from glycogen breakdown of (glycogenolysis) and gluconeogenesis (formation of glucose from amino acids and fatty acids).

• Liver damage can lead to hypoglycemia.

Fat metabolism

Liver synthesizes triglycerides, cholesterol, phospholipids and lipoproteins.

Protein metabolism

In addition to its synthetic function, liver is the central organ in protein catabolism and synthesis of urea formation. Ammonia is produced by the degradation of amino acids that is converted into urea. Urea is secreted by the liver into plasma for excretion by the kidney. This is the major pathway for the elimination of nitrogenous waste.

• Ammonia level becomes high in severe liver disease that is harmful for brain and may lead to hepatic encephalopathy.

EXCRETORY FUNCTION

Liver is responsible for excretion of many substances in the bile.

Bilirubin metabolism

Bilirubin is produced mainly from the breakdown of mature in Kuffer cells of the liver in the reticuloendothelial system. Biliverdin is formed form haem after removal of iron;  this Biliverdin is reduced to form bilirubin. The bilirubin produced unconjugated and water-insoluble, and is transported to the liver attached to albumin. Bilirubin dissociates from albumin and is taken up by the hepatic cells, where it is conjugated red cells with glucuronic acid and is excreted in bile.

• In liver disease there may be obstruction to excretion of bilirubin manifesting as jaundice.

This conjugated bilirubin enters in intestine within bile, and is not absorbed because of its large molecular size in the terminal ileum. Bacterial enzymes hydrolyze the molecule, releasing free bilirubin, which is then reduced to urobilinogen. Some off this is excreted in the stools as stercobilinogen and the remainder is absorbed by the terminal ileum, passes to the liver via enterohapatic circulation and is re-excreted in bile. Urobilinogen bound to albumin enters the circulation and is excreted in the urine via kidneys.

Bile acids metabolism

Bile acids are synthesized in hepatocytes from cholesterol. They are excreted in bile and then pass into the duodenum. Bile acids are detergents, causing fat solubilization that is necessary for absorption of lipids and lipid-soluble vitamins such as vitamin A, D, E and K.

• Decreases excretion of bile salts in liver disease causes:

-          Pruritus (itching)

-          Bleeding disorder: deficiency of vitamins such as vitamin K leads to decreased formation of vitamin K dependent coagulation factors resulting in bleeding tendency.

-          Steatorrhea (fatty stool) due to fat malabsorption.

DETOXIFICATION FUNCTION

Liver plays a vital role in detoxifying nitrogenous compounds derived from intestine, as well as many hormones, drugs and chemicals.

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LEAD POISONING ( Health Tips)

 Lead is used in a variety of industrial and commercial products such as paints, cans, plumbing fixtures, leaded gasoline, improperly glazed ceramics, lead crystals, leafy vegetables grown in lead contaminated soil and storage batteries.

Lead produces adverse effects on CNS, GIT and blood.

METABOLISM

Lead is absorbed into the blood where 95-99% is sequestered in red cells, where it is bound to hemoglobin. Therefore lead is measured in whole blood rather than in serum. The largest proportion of absorbed lead is incorporated into skeleton; however it also appears in nails, hair, sweat, saliva and breast milk.

Toxicity occurs due to its affinity for cell membrane and mitochondria. Therefore it interferes mitochondrial phosphorylation. Na+ K+ and calcium ATPase.

CLINICAL FEATURES

CHILDREN

Symptomatic

Symptomatic toxicity in children develops usually at blood level of 80 ug/dl and is characterized by:

• Abdominal pain and irritability followed by lethargy, anorexia, pallor (due to anemia), ataxia and slurred speech.
• Convulsion, coma and death due to generalized cerebral edema and renal failure occur in severe cases.

Subclinical toxicity

Subclinical toxicity occurs at blood level>30ug/dl and causes learning disorders in children and motor neuropathy.

It presents with mental retardation, selective deficits in language, cognitive function, balance, behavior and school performance. Maximum impact occurs at around age 2 years.

ADULTS

Symptomatic

Symptomatic toxicity in adults develops when the blood lead level is >80ug/dl for period of weeks and is characterized by:

• Abdominal pain, headache, irritability, joint pain, fatigue, anemia, peripheral motor neuropathy (e.g foot drop, wrist drop), deficits in short-term memory and ability to concentrate.
• Lead-line appears on gingival-tooth border after prolonged high level exposure.

Chronic Subclinical

• Chronic Subclinical intoxication causes:
• Interstitial nephritis, tubular damage, hyperuricemia (with increased risk of gout) and chronic renal failure.
• Hypertension.

FOR BOTH CHILDRENAND ADULTS

• Increased bone level is a risk factor for bone diseases, anemia and hypertension.
• Hyperthyroidism may causes lead toxicity by mobilizing stores of lead in bones.

INVESTIGATIONS

1. Blood lead level:

·         Less than 10 ug/dl is considered non-toxic.

• Levels between 10-25 ug/dl is associated with impaired neurobehavioral development in children.
• Levels of 25-50 ug/dl may be associated with headache, irritability and Subclinical toxicity.
• Levels of 50-70 ug/dl are associated with moderate toxicity.
• Levels >70-100 ug/dl are associated with severe poisoning.

2. Blood CP: microcytic anemia with basophilic stippling.
3. Blood protoporphyrin: elevated.
4. Gamma aminolevillinic acid (heme precursor) increases in plasma and urine.
5. Nerve conduction velocity (NCV): prolonged nerve conduction time due to peripheral demyelination usually of extensor muscles of hand and feet.
6. X-ray bone: increased density at metaphyseal plate and growing long bones (lead lines) can develop in children.
7. UCE: adults chronically exposed to lead can develop elevated serum creatinine.

MANAGEMENT

Emergency measure

Coma: maintain airway, other management of unconscious patient.

Convulsion: anticonvulsion therapy.

Activated charcoal and endoscopic removal for recent acute ingestion.

Chelating agents

EDTA, dimercaprol and penicillamine.

Indications for chelation: blood lead level > 55 ug/dl in children and 80 ug/dl in adults.

                                                                                 

BENZODIAZEPINE POISONING (Health tips)

• Benzodiazepines are used as tranquilizers and as sleeping pills.
• Poisoning is usually due to attempted suicide.
• Alprazolam (Xanax), lorazepam (Ativan), bromazipam (Lexotanil) are commonly used benzodiazepines.

CLINICAL FEATURES

Features develop within 30 min of an over-dose and include:

• Weakness, ataxia, dilated pupil, dysarthria and drowsiness.
• Nystagmus and confusion are also observed. Minor hypotension may occur.
• Coma and respiratory depression can occur with short acting benzodiazepine such as midazolam (Dormicum) or if benzodiazepines are combined with other CNS depressants such as tricyclic antidepressants.

MANAGEMENT

• Gastric lavage is not advised in pure benzodiazepine overdose.
• Activated charcoal should be given repeatedly to decontaminate GIT.
• Impaired consciousness requires particular attention to maintain airway. Pulse oximetry is needed to monitor oxygen saturation.
• Observation should be for at least 6 hours post-ingestion.

Flumazenil

            (Inj. Anexate 0.1mg) a competitive benzodiazepine receptor antagonist can reverse CNS and respiratory depression. It is given IV as incremental dose of 0.2, 0.3 and 0.5 mg at 1 min intervals until the desired effect is achieved or a total dose of 3-5 mg has been given.

Flumazenil is not given routinely in mild to moderate poisoning (required when there is CNS or respiratory depression). It is expensive, costs more than Rs. 3000/injection.

Flumazenil should not be given in patients who are chronic dependent on benzodiazepine or who have taken tricyclic antidepressants with benzodiazepine; in these patients seizure may be precipitated. Removal of drug through dialysis is not possible because 85 to 99% or drug is protein bound in the plasma.

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