Heme Proteins, Porphyrias, RDS & Cardiac Markers PDF

Heme Proteins, Porphyrias, RDS and Cardiac disease markers  Objectives At the end of the lesson students should be able to List compounds containing Heme Discuss production of Heme Compare hemoglobin and myoglobin Discuss about hemoglobin function Describe respiratory...

Heme Proteins, Porphyrias, RDS and Cardiac disease markers  Objectives At the end of the lesson students should be able to List compounds containing Heme Discuss production of Heme Compare hemoglobin and myoglobin Discuss about hemoglobin function Describe respiratory distress syndrome Discuss about cardiac disease markers  Cont. Porphyrins are cyclic compounds that readily bind metal ions—usually Fe2+ or Fe3+. The most prevalent metalloporphyrin in humans is heme, which consists of one ferrous (Fe2+) iron ion coordinated in the center of the tetrapyrrole ring of proto porphyrin IX  Cont. Heme is the prosthetic group for hemoglobin, myoglobin, the cytochromes, catalase, nitric oxi de s y n t h a s e , a n d p e r o x i d a s e. T h e s e hemeproteins are rapidly synthesized and degraded.  Biosynthesis of Heme The major sites of heme biosynthesis are the liver, which synthesizes a number of heme proteins (particularly cytochrome P450 proteins), and the erythrocyte-producing cells of the bone marrow, which are active in hemoglobin synthesis.  Cont. Formation of δ- aminolevulinic acid (ALA): All the carbon and nitrogen atoms of the porphyrin molecule are provided by glycine (a nonessential amino acid) and succinyl coenzyme A (an intermediate in the citric acid cycle) that condense to form ALA in a reaction catalyzed by ALA synthase (ALAS). End-product inhibition of ALAS1 by hemin When porphyrin production exceeds the availability of the apoproteins that require it, heme accumulates and is converted to hemin by the oxidation of Fe 2 + to Fe 3 +. Hemin decreases the activity of hepatic ALAS1 by causing decreased synthesis of the enzyme, through inhibition of mRNA synthesis and use (heme decreases stability of the mRNA), and by inhibiting mitochondrial import of the enzyme.  Effect of drugs on ALA synthase activity Administration of any of a large number of drugs results in a significant increase in hepatic ALAS1 activity. These drugs are metabolized by the micro somal cyto chrome P450 monooxygenase system—a heme protein oxidase system found in the liver.  Porphyrias Porphyrias are rare, inherited (or occasionally acquired) defects in heme synthesis, resulting in the accumulation and increased excretion of porphyrins or porphyrin precursors. Each porphyria results in the accumulation of a unique pattern of intermediates caused by the deficiency of an enzyme in the heme synthetic pathway.  Clinical manifestations The porphyrias are classified as erythropoietic or hepatic, depending on whether the enzyme deficiency occurs in the erythropoietic cells of the bone marrow or in the liver. Hepatic porphyrias can be further classified as chronic or acute.  Cont. Porphyria cutanea tarda, the most common porphyria, is a chronic disease of the liver. The disease is associated with a deficiency in uroporphyrinogen decarboxylase, but clinical expression of the enzyme deficiency is influenced by various factors, such as hepatic iron overload, exposure to sunlight, alcohol ingestion, and the presence of hepatitis B or C, or HIV infections.  Cont. Acute hepatic porphyrias: Acute hepatic porphyrias (ALA dehydratase deficiency, acute intermittent porphyria, hereditary coproporphyria, and variegate porphyria) are characterized by acute attacks of gastro intestinal, neuropsychiatric, and motor symptoms that may be accompanied by photosensitivity.  Cont. Increased ALA synthase activity: In the liver, heme normally functions as a repressor of the gene for ALAS1. Therefore, the absence of this end product results in an increase in the synthesis of ALA synthase1 (derepression). This causes an increased synthesis of intermediates that occur prior to the genetic block. The accumulation of these toxic intermediates is the major pathophysiology of the porphyrias.  Treatment During acute porphyria attacks, patients require medical support, particularly treatment for pai n and vomi t i n g. T h e s e v e r i t y o f symptoms of the porphyrias can be diminished by intravenous injection of hemin and glucose, which decreases the synthesis of ALAS1. Avoidance of sunlight and ingestion of β- carotene (a free-radical scavenger) are helpful in porphyrias with photosensitivity.  Degradation of heme After approximately 120 days in the circulation, red blood cells are taken up and degraded by the reticuloendothelial system, particularly in the liver and spleen. Approximately 85% of heme destined for degradation comes from senescent red blood cells, and 15% is from turnover of immature red blood cells and cytochromes from nonerythroid tissues.  Cont. Secretion of bilirubin into bile: Bilirubin diglucuronide (conjugated bilirubin) is actively transported against a concentration gradient into the bile canaliculi and then into the bile. This energy-dependent, rate-limiting step is susceptible to impairment in liver disease.  Cont. Varying degrees of deficiency of bilirubin glucuronyl transferase enzyme result in Crigler-Najjar I and II and Gilbert syndrome, with Crigler-Najjar I being the most severe deficiency.  Cont. A deficiency in the protein required for transport of conjugated bilirubin out of the liver results in Dubin-Johnson syndrome  Jaundice Jaundice (also called icterus) refers to the yellow color of skin, nail beds, and sclerae (whites of the eyes) caused by deposition of bilirubin, secondary to increased bilirubin levels in the blood (hyperbilirubinemia). Although not a disease, jaundice is usually a symptom of an underlying disorder.  Cont. Jaundice can be classified into three major forms described below. However, in clinical practice, jaundice is often more complex than indicated in this simple classification. For example, the accumulation of bilirubin may be a result of defects at more than one step in its metabolism.  Hemolytic jaundice The liver has the capacity to conjugate and excrete over 3,000 mg of bilirubin per day, However, massive lysis of red blood cells (for example, in patients with sickle cell anemia, pyruvate kinase or glucose 6-phosphate dehydrogenase deficiency) may produce bilirubin faster than it can be conjugated. Unconjugated bilirubin levels in the blood become elevated, causing jaundice.  Hepatocellular jaundice Damage to liver cells (for example, in patients with cirrhosis or hepatitis) can cause unconjugated bilirubin levels in the blood to increase as a result of decreased conjugation.  Urobilinogen is increased in the urine because hepatic damage decreases the enterohepatic circulation of this compound, allowing more to enter the blood, from which it is filtered into the urine. The urine thus darkens, whereas stools may be a pale, clay color. Plasma levels of AST and ALT are elevated.  Obstructive jaundice Results from obstruction of the bile duct (extrahepatic cholestasis). Patients with obstructive jaundice experience gastrointestinal pain and nausea, and produce stools that are a pale, clay color, and urine that darkens upon standing.  The liver “regurgitates” conjugated bilirubin into the blood (hyperbilirubinemia). The compound is eventually excreted in the urine. Urinary urobiloinogen is absent.  Jaundice in newborns Newborn infants, particularly if premature, often accumulate bilirubin, because the activity of hepatic bilirubin glucuronyl transferase is low at birth—it reaches adult levels in about 4 weeks. Elevated bilirubin, in excess of the binding capacity of albumin, can diffuse into the basal ganglia and cause toxic encephalopathy (kernicterus). Hemoglobin and Myoglobin Hemoglobin Cont.  MYOGLOBIN (Mb) It is seen in muscles. Myoglobin content of skeletal muscle is 2.5 g/l00 g; of cardiac muscle is 1.4 g% and of smooth muscles 0.3 g%. Mb is a single polypeptide chain. Human Mb contains 152 amino acids with a molecular weight of 17,500 Daltons.  One molecule of Mb can combine with 1 molecule of oxygen. The Hb carries oxygen from lungs to tissue capillaries, from where oxygen diffuses into tissues. In the muscles, the oxygen is taken up by Mb for the sake of tissue respiration  Mb has higher affinity for oxygen than that of Hb. The pO in tissue is about 30 mm of Hg, 2 when Mb is 90% saturated. At this pO , Hb2 saturation will be only 50%.  Hemoglobin Hemoglobin is found exclusively in red blood cells (RBCs), where its main function is to transport oxygen (O2) from the lungs to the capillaries of the tissues  Cont. Hemoglobin A, the major hemoglobin in adults, is composed of four polypeptide chains—two α chains and two β chains—held together by noncovalent interactions. Each subunit has stretches of α-helical structure, and a heme- binding pocket similar to that described for myoglobin  Transport Oxygen Carbon Dioxide Nitric oxide Hydrogen Carbon monoxide  T form The deoxy form of hemoglobin is called the “T,” or taut (tense) form. In the T form, the two αβ dimers interact through a network of ionic bonds and hydrogen bonds that constrain the movement of the polypeptide chains. The T form is the low oxygen- affinity form of hemoglobin.  R form The binding of oxygen to hemoglobin causes the rupture of some of the ionic bonds and hydrogen bonds between the αβ dimers. This leads to a structure called the “R,” or relaxed form, in which the polypeptide chains have more freedom of movement. The R form is the high oxygen- affinity form of hemoglobin.  Transport of carbon dioxide At rest, about 200 ml of CO2 is produced per minute in tissues. The CO2 is carried by the following 3 ways. Dissolved Form About 10% of CO2 is transported as dissolved form. CO2 + H2O → H2CO3 → HCO3– + H+ The hydrogen ions thus generated, are buffered by the buffer systems of plasma.  Isohydric transport Isohydric transport constitutes about 75% of CO2. It means that there is minimum change in pH during the transport. The H+ ions are buffered by the deoxy-Hb and this is called the Haldane effect.  In the lungs: In lung capillaries, where the p O 2 i s h i g h , oxygenation of hemoglobin occurs. When 4 molecules of O2 are bound and one molecule of hemoglobin is fully oxygenated, hydrogen ions are released.  Carriage as Carbamino-Hemoglobin The rest 15% of CO2 is carried as carbaminohemoglobin, without much change in pH. A fraction of CO2 that enters into the red cell is bound to Hb as a carbamino complex. R–NH2 + CO2 --------- R–NH–COOH The N-terminal amino group (valine) of each globin chain forms carbamino complex with carbon dioxide. Deoxy-hemoglobin binds CO2 in this manner more readily than oxy-hemoglobin.  Lung Surfactants Normal lung function depends on a constant supply of lung surfactants. It is produced by epithelial cells. It decreases surface tension of the aqueous layer of lung and prevents collapse of lung alveoli. Constituents of surfactants are dipalmitoyl lecithin, phosphatidyl gl ycerol , chol est erol and surfactant proteins A, B and C.  Surfactants During fetal life, the lung synthesizes sphingomyelin before 28th week of gestation. But as fetus matures, more lecithin is synthesized. The lecithin-sphingomyelin (LS) ratio of amniotic fluid is an index of fetal maturity. A ratio of 2 indicates full lung maturity. Low levels of surfactant leads to respiratory distress syndrome (RDS), which is a common cause of neonatal morbidity.  RDS RDS, also known as hyaline membrane disease, is the commonest respiratory disorder in preterm infants. The clinical diagnosis is made in preterm infants with respiratory difficulty that includes tachypnea, retractions, grunting respirations and nasal flaring  Respiratory distress syndrome It is due to a defect in the biosynthesis of dipalmitoyl lecithin (DPL), the main pulmonary surfactant. Premature infants have a higher incidence of RDS because the immature lungs do not synthesize enough DPL.  Cardiac disease Diet, smoking, presence of diabetes, hypertension or hyperlipidemia, among other things, can help estimate one’s chance of having CHD or CAD, therefore measurement of blood pressure, cholesterol, blood sugar, body weight and body mass index as well as obtaining relevant medical history to collect information about one’s diet, exercise and smoking habits can be the first steps of working up a patient for possible presence of CAD.  Diagnosis of MI The “WHO criteria” were also referred to as the “WHO two out of three rule” and it was based on the presence of characteristic chest pain, elevation of cardiac enzymes such as CK, CK-MB or LD, and new abnormalities on electrocardiogram (ECG), such as a newly developed Q-wave or ST-segment elevation.  Cardiac disease Markers CK AST LDH Troponin  CK and Heart Attack i. CK value in serum is increased in myocardial infarction. The CK level starts to rise within 3-6 hours of infarction. ii. Therefore, CK estimation is very useful to detect early cases, where ECG changes may be ambiguous. A second peak may indicate another ischemic episode. Normal serum value for CK is 15-100 U/L for males nd 10-80 U/L for females.  Troponins The troponin complex is part of the regulatory apparatus of the myocyte. It consists of three components: the calcium binding troponin C, the inhibitory troponin I and the tropomyosin binding troponin T.