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Jaundice- An overviewPublished March 21, 2012 | By Namrata Chhabra
Bilirubin is the end product of heme degradation. From 70–90% of bilirubin is derived from degradation of thehemoglobin of senescent red blood cells. Bilirubin produced in the periphery is transported to the liver withinthe plasma, where, due to its insolubility in aqueous solutions, it is tightly bound to albumin.
Under normal circumstances, bilirubin is removed from the circulation rapidly and efficiently by hepatocytes.
Transfer of bilirubin from blood to bile involves four distinct but interrelated steps:
1) Hepatocellular uptake: Uptake of bilirubin by the hepatocyte has carrier-mediated kinetics.
2) Intracellular binding: Within the hepatocyte, bilirubin is kept in solution by binding as a nonsubstrate ligand to several of the glutathione-S-transferases, formerly called ligandins.
3) Conjugation: Bilirubin is conjugated with one or two glucuronic acid moieties by a specific UDP-glucuronosyl transferase to form bilirubin mono- and diglucuronide, respectively. Conjugation disrupts theinternal hydrogen bonding that limits aqueous solubility of bilirubin, and the resulting glucuronide conjugatesare highly soluble in water. Conjugation is obligatory for excretion of bilirubin across the bile canalicularmembrane into bile. The UDP-glucuronosyl transferases have been classified into gene families based on thedegree of homology among the mRNAs for the various isoforms. Those that conjugate bilirubin and certainother substrates have been designated the UGT1 family. These are expressed from a single gene complex byalternative promoter usage.
4) Biliary excretion: Bilirubin mono- and diglucuronides are excreted across the canalicular plasma membraneinto the bile canaliculi by an ATP-dependent transport process mediated by a canalicular membrane proteincalled multidrug resistance–associated protein 2 (MRP2). Mutations of MRP2 result in the Dubin-Johnsonsyndrome.
Extra hepatic Aspects of Bilirubin Disposition
Bilirubin in the Gut
Following secretion into bile, conjugated bilirubin reaches the duodenum and passes down the gastrointestinaltract without reabsorption by the intestinal mucosa. An appreciable fraction is converted by bacterialmetabolism in the gut to the water-soluble colorless compound, urobilinogen. About 80–90% of these productsare excreted in feces, either unchanged or oxidized to orange derivatives called urobilins. The remaining 10–20% of the urobilinogens are passively absorbed, enter the portal venous blood, and are reexcreted by the liver.A small fraction (usually <3 mg/dL) escapes hepatic uptake, filters across the renal glomerulus, and is excretedin urine.(See figure 1)
Figure-1 – showing formation and fate of bilirubin
Unconjugated bilirubin ordinarily does not reach the gut except in neonates or, by ill-defined alternativepathways, in the presence of severe Unconjugated hyperbilirubinemia [e.g., Crigler-Najjar syndrome, type I(CN-I)]. Unconjugated bilirubin that reaches the gut is partly reabsorbed, amplifying any underlyinghyperbilirubinemia.
Renal Excretion of Bilirubin Conjugates
Unconjugated bilirubin is not excreted in urine as it is too tightly bound to albumin for effective glomerularfiltration and there is no tubular mechanism for its renal secretion. In contrast, the bilirubin conjugates arereadily filtered at the glomerulus and can appear in urine in disorders characterized by increased bilirubinconjugates in the circulation.
Jaundice
Jaundice is a yellow discoloration of the skin, mucous membranes, and sclera caused by increased amountsof bilirubin in the blood. Jaundice is a sign of an underlying disease process.
Jaundice results from the accumulation of bilirubin. Hyperbilirubinemia may be due to abnormalities in the
formation, transport, metabolism, and excretion of bilirubin. Total serum bilirubin is normally 0.2–1.2 mg/dL(mean levels are higher in men than women and higher in whites and Hispanics than blacks), and jaundice maynot be recognizable until levels are about 3 mg/dL.
In the normal adult the rate of systemic bilirubin production is equal to the rates of hepatic uptake, conjugation,and biliary excretion. Jaundice occurs (bilirubin levels may reach 30-40 mg/dL in severe disease) when theequilibrium between bilirubin production and clearance is disturbed by one or more of the followingmechanisms (1) excessive production of bilirubin, (2) reduced hepatic uptake, (3) impaired conjugation, (4)decreased hepatocellular excretion, and (5) impaired bile flow (both intra hepatic and extra hepatic). The firstthree mechanisms produce unconjugated hyperbilirubinemia, and the latter two produce predominantlyconjugated hyperbilirubinemia. More than one mechanism may operate to produce jaundice, especially inhepatitis, which may produce Unconjugated and conjugated hyperbilirubinemia. In general, however, onemechanism predominates, so that knowledge of the predominant form of plasma bilirubin is of value inevaluating possible causes of hyperbilirubinemia
Classification of jaundice
1) Pre-hepatic (before bile is made in the liver)
Jaundice in these cases is caused by rapid increase in the breakdown and destruction of the red blood cells(hemolysis), overwhelming the liver’s ability to adequately remove the increased levels of bilirubin from theblood.
Examples of conditions with increased breakdown of red blood cells include:
Jaundice in these cases is caused by the liver’s inability to properly metabolize and excrete bilirubin.
Causes
-Viral – hepatitis A, B, or C, yellow fever, Bacterial sepsis, tuberculosis,
-Alcohol, Drugs e.g. estrogens, contraceptive pills and Pregnancy
-Carcinoma: metastases. Lymphoma. Adenocarcinoma of kidney (non-metastatic)
-Preoperative hypo perfusion/shock
-Chronic active hepatitis
3) Post-hepatic (after bile has been made in the liver)
Jaundice in these cases, also termed obstructive jaundice, is caused by conditions which interrupt the normaldrainage of conjugated bilirubin in the form of bile from the liver into the intestines. The obstruction may beintrahepatic or extra hepatic
Causes of obstructive jaundice include:
a) Intra hepatic Obstruction
-Biliary atresia
-Primary Biliary Cirrhosis
-Malignant infiltration of ducts
b) Extra hepatic obstruction
-Gallstones in the bile ducts,
-cancer (pancreatic and gallbladder/bile duct carcinoma),
-strictures of the bile ducts,
-Pressure on the common bile duct from enlarged lymph nodes,
-cholangitis,
-congenital malformations,
-pancreatitis,
-parasites,
-pregnancy, and
-Newborn jaundice.
Congenital conditions that may cause jaundice
1) Crigler-Najjar syndrome: an inherited condition that may lead to severe Unconjugated hyperbilirubinemia(high bilirubin concentrations); a gene mutation leads to a deficiency in an enzyme necessary for bilirubinconjugation.
2) Dubin-Johnson syndrome: an inherited disorder that causes the retention of conjugated bilirubin (and othercompounds that turn the liver black) in liver cells; patients may have intermittent jaundice.
3) Rotor’s syndrome: an inherited conjugated hyperbilirubinemia that causes intermittent jaundice; similar toDubin-Johnson without the retention of other compounds or a black liver.
4) Gilbert syndrome-There is compensatory hemolysis, impaired uptake and conjugation of bilirubin.
Figure-2- showing the causes of jaundice
Physiologic Neonatal Jaundice
Bilirubin produced by the fetus is cleared by the placenta and eliminated by the maternal liver. Immediatelyafter birth, the neonatal liver must assume responsibility for bilirubin clearance and excretion. However, manyhepatic physiologic processes are incompletely developed at birth. Levels of UDP –Glucuronyl Transferaselevels are low, and alternative excretory pathways allow passage of unconjugated bilirubin into the gut. Sincethe intestinal flora that convert bilirubin to urobilinogen are also undeveloped, an enterohepatic circulation ofUnconjugated bilirubin ensues. As a consequence, most neonates develop mild unconjugatedhyperbilirubinemia between days 2 and 5 after birth. Peak levels are typically <85–170 mol/L (5–10 mg/dL) anddecline to normal adult concentrations within 2 weeks, as mechanisms required for bilirubin disposition mature.Prematurity, with more profound immaturity of hepatic function, or hemolysis, results in higher levels ofunconjugated hyperbilirubinemia.
A rapidly rising Unconjugated bilirubin concentration, or absolute levels >340 mol/L (20 mg/dL), puts theinfant at risk for bilirubin encephalopathy, or kernicterus. Under these circumstances, bilirubin crosses animmature blood-brain barrier and precipitates in the basal ganglia and other areas of the brain. Theconsequences range from appreciable neurologic deficits to death. Treatment options include phototherapy,which converts bilirubin into water-soluble photo isomers that are excreted directly into bile, Administration ofinducing agents(Phenobarbitone), Albumin infusion and exchange transfusion. The canalicular mechanismsresponsible for bilirubin excretion are also immature at birth, and their maturation may lag behind that of UGT,this can lead to transient conjugated neonatal hyperbilirubinemia, especially in infants with hemolysis.
Maternal-fetal blood group incompatibility (Rh, ABO)
This form of jaundice occurs when there is incompatibility between the blood types of the mother and the fetus.This leads to increased bilirubin levels from the breakdown of the fetus’ red blood cells (hemolysis).
Breast milk jaundice
This form of jaundice occurs in breastfed newborns and usually appears at the end of the first week of life.Certain chemicals in breast milk are thought to be responsible for inhibition of UDP Glucuronyl transferase. Itis usually a harmless condition that resolves spontaneously.
Clinical Features
1) Unconjugated Hyperbilirubinemia (Pre hepatic jaundice)Stool and urine color are darker than normal,and there is mild jaundice and indirect (Unconjugated) hyperbilirubinemia with no bilirubin in the urine.Splenomegaly occurs in hemolytic disorders except in sickle cell anemia.
2) Hepatocellular disease (Hepatic jaundice)
Malaise, anorexia, low-grade fever, and right upper quadrant discomfort are frequent. Dark urine, jaundice, and,in women, amenorrhea occur. An enlarged tender liver, depending on the cause, severity, and chronicity of liverdysfunction is observed
There may be right upper quadrant pain, weight loss (suggesting carcinoma), jaundice, dark urine, and light-colored stools. Symptoms and signs may be intermittent if caused by stone, carcinoma of the ampulla, orcholangiocarcinoma. Pain may be absent early in pancreatic cancer. Occult blood in the stools suggests cancerof the ampulla. Hepatomegaly and a palpable gallbladder (Courvoisier’s sign) are characteristic, but neitherspecific nor sensitive, of a pancreatic head tumor. Fever and chills are more common in benign obstruction withassociated cholangitis.
Diagnosis
The goal of testing is to determine the cause of the jaundice and to evaluate the severity of the underlyingcondition. The initial step is to obtain appropriate blood tests to determine if the patient has an isolated elevationof serum bilirubin. If so, is the bilirubin elevation due to an increased Unconjugated or conjugated fraction? Ifthe hyperbilirubinemia is accompanied by other liver test abnormalities, is the disorder hepatocellular orcholestatic? If cholestatic, is it intra- or extra hepatic? All of these questions can be answered with a thoughtfulhistory, physical examination, and interpretation of laboratory and radiologic tests and procedures.
Laboratory Studies
Measurement of Serum Bilirubin
The terms direct- and indirect-reacting bilirubin are based on the original van den Bergh reaction. This assay, ora variation of it, is still used in most clinical chemistry laboratories to determine the serum bilirubin level. Inthis assay, bilirubin is exposed to diazotized sulfanilic acid, splitting into two relatively stable dipyrrylmetheneazopigments that absorb maximally at 540 nm, allowing for photometric analysis.
The direct fraction is that which reacts with diazotized sulfanilic acid in the absence of an accelerator substancesuch as alcohol. The direct fraction provides an approximate determination of the conjugated bilirubin in serum.The total serum bilirubin is the amount that reacts after the addition of alcohol. The indirect fraction is thedifference between the total and the direct bilirubin and provides an estimate of the Unconjugated bilirubin inserum.
With the van den Bergh method, the normal serum bilirubin concentration usually is 17 mol/L (<1 mg/dL). Upto 30%, or 5.1 mol/L (0.3 mg/dL), of the total may be direct-reacting (conjugated) bilirubin. Total serumbilirubin concentrations are between 3.4 and 15.4 mol/L (0.2 and 0.9 mg/dL) in 95% of a normal population.
Measurement of Urine Bilirubin
Unconjugated bilirubin is always bound to albumin in the serum, is not filtered by the kidney, and is not foundin the urine. Conjugated bilirubin is filtered at the glomerulus and the majority is reabsorbed by the proximaltubules; a small fraction is excreted in the urine. Any bilirubin found in the urine is conjugated bilirubin. Thepresence of bilirubinuria implies the presence of liver disease. A urine dipstick test (Ictotest) gives the sameinformation as fractionation of the serum bilirubin. This test is very accurate. A false-negative test is possible inpatients with prolonged cholestasis due to the predominance of conjugated bilirubin covalently bound toalbumin.
Liver biochemical tests: changes in three types of jaundice.
Serum alanine and aspartate aminotransferase (ALT and AST) levels vary with age and correlate with bodymass index. Elevated alkaline phosphatase levels are seen in cholestasis or infiltrative liver disease (such as
tumor or granuloma). Alkaline phosphatase elevations of hepatic rather than bone, intestinal, or placental originare confirmed by concomitant elevation of γ-glutamyl transpeptidase or 5ʹ′-nucleotidase levels. The differentialdiagnosis of any liver test elevation includes toxicity caused by drugs, herbal remedies, and toxins.
Liver Biopsy
Percutaneous liver biopsy is the definitive study for determining the cause and histological severity ofhepatocellular dysfunction or infiltrative liver disease.
Imaging
Demonstration of dilated bile ducts by ultrasonography or CT scan indicates biliary obstruction (90–95%sensitivity). Ultrasonography, CT scan, and MRI may also demonstrate hepatomegaly,intrahepatic tumors, andportal hypertension. Magnetic resonance cholangiopancreatography (MRCP) is a sensitive, noninvasive methodof detecting bile duct stones, strictures, and dilation; however, it is less reliable than endoscopic retrogradecholangiopancreatography (ERCP) for distinguishing malignant from benign strictures.
Treatment
The treatment is entirely dependent on the cause of the jaundice. In some cases it will be curative e.g. surgicalremoval of a gallstone blocking the common bile duct. Viral infections e.g. hepatitis A, may recoverspontaneously. In other cases treatment will modify the disease process and the jaundice will improve ordisappear. Treatment may be purely symptomatic e.g., drugs to relieve itching or palliative as in malignantdisease. Some types of advanced liver disease-causing jaundice may be treated by liver transplantation.
Phototherapy for Neonatal Jaundice
The goal of therapy is to lower the concentration of circulating bilirubin or keep it from increasing. Phototherapy achieves this by using light energy to change the shape and structure of bilirubin, converting it tomolecules that can be excreted even when normal conjugation is deficient
Phototherapy converts bilirubin to yellow photo isomers and colorless oxidation products that are less lipophilicthan bilirubin and do not require hepatic conjugation for excretion. Photo isomers are excreted mainly in bile,and oxidation products predominantly in urine.
Prognosis- is fairly good in the treated cases, except in cases of malignant obstruction of common bile duct.
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Case studies – JaundicePublished March 20, 2012 | By Namrata Chhabra
Case study-1
A 24 –year –old male suffering from Malaria was put on Primaquine. He developedmalaise, fatigue and yellow discolouration of sclera and skin.
On examination – There was pallor- ++, icterus ++, Pulse – 100/min., Temperature 102°F.Liver and spleen were palpable.
What is the relationship of primaquine intake and the present manifestations?
Case Details- This is a case of primaquine induced Hemolytic anemia, progressing tojaundice. Glucose-6-P dehydrogenase deficiency seems to be the underlying defect. Highfever is due to malaria, while pallor and icterus are due to hemolytic anemia and underlyingjaundice as apparent from low Hb and high bilirubin levels. Indirect positive Van Den Berghindicates Uncinjugated Bilirubinemia. Urine is positive for hemoglobin and urobilinogenindicating the underlying hemoglobinuria and hemolytic jaundice
Primaquine being an oxidant drug precipitates the underlying defect to induce hemolysis.(See the details below).The liver has the capacity to conjugate and excrete over 3000 mg ofbilirubin per day, whereas the normal production of bilirubin is only 300mg/day. The excesscapacity allows the liver to respond to increased haem degradation with a correspondingincrease in conjugation and secretion of bilirubin diglucuronide.
However massive lysis of red blood cells, as in Glucose-6 –phosphate dehydrogenasedeficiency, may produce bilirubin faster than it can be conjugated. More bilirubin isexcreted in to the bile, the amount of urobilinogen entering the enterohepatic circulation isincreased and urinary urobilinogen is also increased. Unconjugated bilirubin levels becomeelevated in the blood causing jaundice.
Case study-2
A 10 –year- old boy received a sulfonamide antibiotic as prophylaxis for recurrenturinary tract infections. Although he was previously healthy and well nourished, hebecame progressively ill and presented with pallor and irritability. A blood countrevealed that he was severely anaemic with jaundice due to hemolysis of the red bloodcells.
What is the problem with the boy?
What is the cause of anemia and jaundice in this boy?
What is the simplest way for the diagnosis of this problem?
Case details The child is suffering from Glucose-6-phosphate dehydrogenase deficiency.The individuals with G-6-P-D deficiency present with excessive hemolysis on exposure tocertain drugs like antibiotics, analgesics and Antimalarials. Acute HA can develop as a resultof three types of triggers: (1) fava beans, (2) infections, and (3) drugs. Glucose 6-phosphatedehydrogenase (G6PD) is an enzyme critical in the redox metabolism of all aerobic cells .Inred cells, its role is even more critical because it is the only source of reduced nicotinamideadenine dinucleotide phosphate (NADPH), which, directly and via reduced glutathione (GSH),defends these cells against oxidative stress.
figure showing the role of G-6-P-Dehydrogenase in Glucose metabolism.
NADPH is a required cofactor in many biosynthetic reactions which also maintainsglutathione in its reduced form. Reduced glutathione acts as a scavenger for dangerousoxidative metabolites in the cell. With the help of the enzyme glutathione peroxidase,reduced glutathione converts harmful hydrogen peroxide to water. The inability todecompose hydrogen peroxide results in free radical induced membrane disruption andreduced life span as a result of haemoglobin formation.G6PD deficiency is a prime exampleof a haemolytic anemia due to interaction between an intracorpuscular and anextracorpuscular cause, because in the majority of cases hemolysis is triggered by anexogenous agent. People deficient in glucose-6-phosphate dehydrogenase (G6PD) are notprescribed oxidative drugs, because their red blood cells undergo rapid hemolysis underthis stress. Although in G6PD-deficient subjects there is a decrease in G6PD activity in mosttissues, this is less marked than in red cells, and it does not seem to produce symptoms.
Clinical manifestations The vast majority of people with G6PD deficiency remainclinically asymptomatic throughout their lifetime.
However, all of them have an increased risk of developing neonatal jaundice (NNJ) and arisk of developing acute HA when challenged by a number of oxidative agents. Typically, ahaemolytic attack starts with malaise, weakness, and abdominal or lumbar pain. After aninterval of several hours to 2–3 days, the patient develops jaundice and often dark urine,due to hemoglobinuria. The onset can be extremely abrupt, especially with favism inchildren. The anemia is moderate to extremely severe, usually normocytic andnormochromic, and due partly to intravascular hemolysis; hence, it is associated withhaemogobinemia, hemoglobinuria, and low or absent plasma Haptoglobin. Jaundice isprehepatic.
The laboratory workup for glucose-6-phosphate dehydrogenase (G6PD) deficiency includesthe following:
Measure the actual enzyme activity of G6PD rather than the amount of glucose-6-
phosphatase dehydrogenase (G6PD) protein.Obtain a complete blood cell (CBC) count with the reticulocyte count to determine thelevel of anemia and bone marrow function.Indirect bilirubinemia occurs with excessive hemoglobin degradation and can produceclinical jaundice.Urinary urobilinogen is high
Treatment- Identification and discontinuation of the precipitating agent is critical in casesof glucose-6-phosphate dehydrogenase (G6PD) deficiency. Affected individuals are treatedwith oxygen and bed rest, which may afford symptomatic relief. Prevention of drug-inducedhemolysis is possible in most cases by choosing alternative drugs. When acute HA developsand once its cause is recognized, no specific treatment is needed in most cases. However, ifthe anemia is severe, it may be a medical emergency, especially in children, requiringimmediate action, including blood transfusion.
Case study-3
A 50 –year-old woman had 8 day history of loss of appetite, nausea and flu-likesymptoms. She had noticed that her urine had been dark in color over the past twodays. On examination she had tenderness in the right upper quadrant.
Laboratory investigations showed;
Serum Total bilirubin 4.5 mg%
Direct bilirubin 2.5 mg%
Indirect bilirubin 2.0 mg%
Serum AST- 40 IU/L
Serum ALT-115 IU/L
Serum ALP- 20 Units (KA)
What is the probable diagnosis?
What will be the observation regarding bile pigments in urine?
Case details Flu like symptoms are indicative of viral hepatitis. Damage to liver cells cancause unconjugated bilirubin to increase in the blood as a result of decreased conjugation.The bilirubin that is conjugated is not efficiently secreted in to the bile, but instead diffusesin to the blood. Urobilinogen is increased in urine because hepatic damage decreases theenterohepatic circulation of this compound allowing more to enter blood, from which it isfiltered in to the urine. The urine thus becomes dark in color, whereas stools are palecolored. Plasma levels of AST and ALT are elevated. This is a case of hepatic jaundice.
Case-4
Based on the following clinical laboratory data, give the most probable diagnosis
Serum bilirubin 4 mg%
Direct bilirubin 0.2 mg%
Serum Alkaline phosphatase 6 units( KA)
SGOT- 30 IU/L
SGPT- 26 IU/L
Urine Bilirubin- Negative
Urine urobilinogen-Positive
Urine Bile Salts- Negative
Case details- Normal enzyme profile, Hyperbilirubinemia, absence of urinary bilirubin andpositive urobilinogen are indicative of Hemolytic jaundice.
Case study-5
A 40 –year- old, fat female, presents with intolerance to fatty foods, pain in the rightside of abdomen, yellowing of eyes and passage of clay colored stools.
Laboratory Investigations revealed
Serum
Total Bilirubin – 20 mg%
Direct Bilirubin- 16 mg%
ALP- 800 U(KA)
SGPT- 90 IU/L
Urine
Color- deep yellow
Bilirubin- ++
Urobilinogen- absent
Stools
Clay colored
Stercobilnogen- absent
What is the likely diagnosis?
Which other enzymes are likely to increase?
Case details This is a case of obstructive jaundice due to gall stones. This patient fits the“classic” criteria of gallbladder disease: female, middle-aged, overweight. Gallstones arecollections of solid material (predominantly crystals of cholesterol) in thegallbladder. Gallstones may cause pain. Pain develops when the stones pass from thegallbladder into the cystic duct, common bile duct, or ampulla of Vater and block the duct.Then the gallbladder dilates, causing pain called biliary colic. The pain is felt in the upperabdomen, usually on the right side. Eating a heavy meal can trigger biliary colic, but simplyeating fatty foods does not.
In this instance jaundice is not due caused due to overproduction of bilirubin, but insteadresults from obstruction of the bile duct from the gall stones. The liver regurgitatesconjugated bilirubin in to the blood (Hyperbilirubinemia)
High direct bilirubin (Conjugated hyperbilirubinemia), high alkaline phosphatase (marker ofcholestasis),slightly increased SGPT level are suggestive of post hepatic or obstructivejaundice. Furthermore the diagnosis is supported by the presence of bilirubin (since it isconjugated) and absence of urobilinogen (Since there is obstruction to the out flow of bile)in urine. Due to the same reason of obstruction stool is clay colored as stercobilnogen isabsent.
Treatment is based on the relieving the obstruction surgically. Prolonged obstruction of thebile duct can lead to liver damage and a subsequent rise in unconjugatedhyperbilirubinemia and a rise in SGPT levels.
Case Study- 6
An Rh negative mother delivers a baby who develops jaundice immediately after birth.
General Examination reveals
Heart Rate 80/min
Icterus +
Irritability +
Liver Palpable
Laboratory Investigations
Serum
Bilirubin
Total 10 mg%
Indirect 7 mg%Direct 3 mg%
Alkaline phosphatase 50 U/L
Urine
Urobilinogen +++
Feces
Stercobilnogen +++
What is your likely diagnosis?
Case details This is a case of haemolytic jaundice due to Rh incompatibility. Indirect hyperbilirubinemia (Unconjugated hyperbilirubinemia), high urinary urobilinogen and fecalstercobilnogen are indicative of haemolytic jaundice. Typically bilirubin is absent in urinesince unconjugated bilirubin being water insoluble and albumin bound (macromolecule),can not pass through glomeruli to appear in urine.
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Case study- PorphyriaPublished March 19, 2012 | By Namrata Chhabra
A 30-year-old woman had severe abdominal pain, nausea, vomiting and diarrhea. Evaluations includingupper and lower endoscopies did not establish any intestinal infection. She gradually improved and wasdischarged after 2 weeks. 2 years later she was admitted to a psychiatric unit with acute mental changesand hallucinations, she had to be transferred to the emergency department due to abdominal pain, agrand mal seizure and hyponatremia.
Her pulse was 120 and BP 174/114 mm Hg. She was disoriented but had no focal neurological signs. MRIshowed sub cortical abnormalities, and the spinal fluid was normal. After cholecystectomy for adistended gallbladder, she was discharged but she stayed with a family member in another city becauseher symptoms were worse and muscle weakness had developed. She was hospitalized and progressed toquadriparesis, respiratory failure and aspiration pneumonia. Urinary porphobilinogen (PBG) wasreported as 44 mg/24 hours (reference range 0-4).
How is the diagnosis done and what is its prognosis?
What is the genetic basis of this disease?
Case Discussion
The patient is suffering from acute intermittent Porphyria as evident from the typical combination ofabdominal pain, motor neuropathy, psychiatric symptoms and increased amounts of urinary Porphyrins andtheir precursors. Acute intermittent Porphyria (AIP) is a rare autosomal dominant metabolic disorder affectingthe production of heme. It is characterized by deficiency of enzyme porphobilinogen deaminase.
Basic concept
Haem synthesis
Heme is required for a variety of haemoproteins such as hemoglobin, myoglobin, respiratory Cytochromes, andthe cytochrome P450 enzymes (CYPs). Hemoglobin synthesis in erythroid precursor cells accounts forapproximately 85% of daily heme synthesis in humans. Hepatocytes account for most of the rest, primarily forsynthesis of CYPs, which are especially abundant in the liver endoplasmic reticulum, and turn over morerapidly than many other haemoproteins, such as the mitochondrial respiratory cytochromes.
Heme biosynthesis involves eight enzymatic steps in the conversion of glycine and succinyl-CoA to heme(Fig.1). These eight enzymes are encoded by nine genes, as the first enzyme in the pathway, 5ʹ′-aminolevulinatesynthase (ALA-synthase), has two genes that encode unique housekeeping (ALAS1) and erythroid-specific(ALAS2) isozymes. The first and last three enzymes in the pathway are located in the mitochondrion, whereasthe other four are in the cytosol. As shown in Fig.1, pathway intermediates are the porphyrin precursors, ALAand PBG, and porphyrins (mostly in their reduced forms, known as porphyrinogens). At least in humans, theseintermediates do not accumulate in significant amounts under normal conditions or have important physiologicfunctions.
Figure-1- showing the steps of Haem synthesis
Steps of Haem synthesis
1) The first and rate-controlling step is the condensation of glycine and succinyl–coenzyme A (CoA) to form δ-aminolevulinic acid (ALA). The enzyme, ALA-synthase is activated by Pyridoxal phosphate. In the liver, thisrate-limiting enzyme can be induced by a variety of drugs, steroids, and other chemicals. Defects in the
erythroid gene, cause X-linked Sideroblastic anemia (XLSA).
2) The ALA formed is transported into the cytoplasm, where the second enzyme, ALA dehydratase (alsoknown as porphobilinogen synthase), condenses two molecules of ALA to form the monopyrroleporphobilinogen.
3) The third enzyme, porphobilinogen deaminase (also known as hydroxymethylbilane synthase), forms alinear tetrapyrrole, hydroxymethylbilane, which is normally rapidly converted, mainly to the cyclic intermediateUroporphyrinogen III, by the enzyme Uroporphyrinogen III synthase (also known as Uroporphyrinogencosynthase). When Uroporphyrinogen III synthase is deficient, as in congenital erythropoietin Porphyria(Guenther’s disease), hydroxymethylbilane rapidly undergoes nonenzymatic ring closure to formUroporphyrinogen I.
4) The enzyme Uroporphyrinogen decarboxylase carries out the stepwise decarboxylation ofUroporphyrinogen I or III to form intermediates with 7-, 6-, 5-, and 4-carboxyl groups. Coproporphyrinogen isthe common name for the 4-carboxyl–containing intermediate.
5) Coproporphyrinogen III is transported back into mitochondria, where the enzyme Coproporphyrinogen IIIoxidase carries out the stepwise oxidative decarboxylation of two of the remaining propionate beta side chains,at positions 2 and 4 (on rings A and B, respectively), to vinyl groups, forming protoporphyrinogen IX.
6) Next, the enzyme protoporphyrinogen oxidase carries out the oxidation of protoporphyrinogen IX to formprotoporphyrin IX, after which the enzyme Ferrochelatase (also called heme synthase) inserts ferrous ironinto the protoporphyrin IX macrocycle to form the end product heme. (See figure-1)
Regulation of Heme Biosynthesis
Regulation of heme synthesis differs in the two major heme-forming tissues, the liver and erythron. In the liver,“free” heme regulates the synthesis and mitochondrial translocation of the housekeeping form of ALA-synthase.Heme represses the synthesis of the ALA-synthase mRNA and interferes with the transport of the enzyme fromthe cytosol into mitochondria. Hepatic ALA-synthase is increased by many of the same chemicals that inducethe cytochrome P450 enzymes in the endoplasmic reticulum of the liver. Because most of the heme in the liveris used for the synthesis of cytochrome P450 enzymes, hepatic ALA-synthase and the cytochrome P450s areregulated in a coordinated fashion, and many drugs that induce hepatic ALA-synthase also induce CYPs. Theother hepatic heme biosynthetic enzymes are presumably expressed at constant levels, although their relativeactivities and kinetic properties differ. For example, normal individuals have high activities of ALA-dehydratasebut low activities of HMB-synthase, the latter being the second rate-limiting step in the pathway.
In the erythron, novel regulatory mechanisms allow for the production of the very large amounts of hemeneeded for hemoglobin synthesis. The response to stimuli for hemoglobin synthesis occurs during celldifferentiation, leading to an increase in cell number. The erythroid-specific ALA-synthase is expressed athigher levels than the housekeeping enzyme, and erythroid-specific control mechanisms regulate other pathwayenzymes as well as iron transport into erythroid cells.
PORPHYRIAS
The Porphyrias are a group of rare metabolic disorders arising from reduced activity of any of the enzymes inthe heme biosynthetic pathway. The disorders may be either acquired or inherited through a genetic defect in agene encoding these enzymes. These deficiencies disrupt normal heme production, and produce symptomswhen increased heme is required. Porphyrin precursors, overproduced in response to synthetic pathway
blockages, accumulate in the body and cause diverse pathologic changes thereby becoming the basis fordiagnostic tests.
The diagnosis of acute porphyrias can be confirmed by repeating the quantitation of urinary porphyrin during anacute episode and finding elevated levels (2–5 times of normal) of porphobilinogen.
Incidence
The prevalence of this condition is unknown, but probably ranges from 1 in 500 to 50,000 worldwide. Certaintypes of porphyrias are more common in specific populations, such as whites in South Africa andScandinavians.
Classification
The Porphyrias can be classified as either hepatic or erythropoietic, depending on whether the hemebiosynthetic intermediates that accumulate arise initially from the liver or developing erythrocytes, oras acute or cutaneous, based on their clinical severity.
Inheritance
Most of the Porphyrias are inherited. Inheritance patterns depend on the type of porphyria. Some forms of thecondition are inherited in an autosomal dominant pattern, which means one copy of the altered gene is sufficientto cause the disorder. Other Porphyrias are inherited in an autosomal recessive pattern, which means two copiesof the gene must be altered for a person to be affected by the condition.
Typically, patients with the autosomal dominant varieties present initially in adulthood, and those withhomozygous variants present in early childhood. Symptomatic porphyria is thought to be more common infemale than male patients with a female-male ratio of 5 to 1.
A) The Hepatic Porphyrias
1) ALA-Dehydratase Deficient Porphyria (ADP)
ADP is a rare autosomal recessive acute hepatic porphyria caused by a severe deficiency of ALA-dehydrataseactivity. The clinical presentation depends on the amount of residual ALA-dehydratase activity. Symptomsresemble those of AIP (Acute intermittent Porphyria) including abdominal pain and neuropathy. Infant withmore severe disease manifest failure to thrive beginning at birth. Diagnosis is confirmed by significantlyelevated levels of plasma and urinary ALA, urinary coproporphyrin III and ALAD activity in erythrocytes<10% of normal.
The treatment of ADP acute attacks is similar to that of AIP.
2) Acute Intermittent Porphyria (AIP)
Acute intermittent porphyria is inherited as an autosomal dominant, though it remains clinically silent in mostpatients who carry the trait. Clinical illness usually develops in women. Symptoms begin in the teens or 20s, butonset can begin after menopause in rare cases. The disorder is caused by partial deficiency of porphobilinogendeaminase activity, leading to increased excretion of aminolevulinic acid and porphobilinogen in the urine. Thediagnosis may be elusive if not specifically considered. The characteristic abdominal pain may be due toabnormalities in autonomic innervations in the gut. In contrast to other forms of porphyria, cutaneousphotosensitivity is absent in acute intermittent porphyria. Attacks are precipitated by numerous factors,including drugs and intercurrent infections. Hyponatremia may be seen, due in part to inappropriate release of
antidiuretic hormone, though gastrointestinal loss of sodium in some patients may be a contributing factor.
Clinical Findings
Symptoms and Signs
Patients show intermittent abdominal pain of varying severity, and in some instances it may so simulate acuteabdomen as to lead to exploratory laparotomy. Complete recovery between attacks is usual. Any part of thenervous system may be involved, with evidence for autonomic and peripheral neuropathy. Peripheralneuropathy may be symmetric or asymmetric and mild or profound; in the latter instance, it can even lead toquadriplegia with respiratory paralysis. Other central nervous system manifestations include seizures, psychosis,and abnormalities of the basal ganglia. Hyponatremia may further cause or exacerbate central nervous systemmanifestations.
Laboratory Findings
Often there is profound hyponatremia. The diagnosis can be confirmed by demonstrating an increased amountof porphobilinogen in the urine during an acute attack. Freshly voided urine is of normal color but may turndark upon standing in light and air.
Prevention
Avoidance of factors known to precipitate attacks of acute intermittent porphyria—especially drugs can reducemorbidity. Starvation diets also cause attacks and so must be avoided.
Treatment
Treatment with a high-carbohydrate diet diminishes the number of attacks in some patients and is a reasonableempiric gesture considering its benignity. Acute attacks may be life-threatening and require prompt diagnosis,withdrawal of the inciting agent (if possible), and treatment with analgesics and intravenous glucose andhematin. Electrolyte balance requires close attention. Liver transplantation may provide an option for patientswith disease poorly controlled by medical therapy.
3) Porphyria Cutanea Tarda
PCT, the most common of the Porphyrias, can be either sporadic (type 1) or familial (types 2 and 3) and canalso develop after exposure to halogenated aromatic hydrocarbons. Hepatic URO-decarboxylase is deficient inall types of PCT, and for clinical symptoms to manifest, this enzyme deficiency must be substantial (~20% ofnormal activity or less).
Clinical Features
Blistering skin lesions that appear most commonly on the backs of the hands are the major clinical feature.These rupture and crust over, leaving areas of atrophy and scarring. Lesions may also occur on the forearms,face, legs, and feet. Occasionally, the skin over sun-exposed areas becomes severely thickened, with scarringand calcification that resembles systemic sclerosis. Neurologic features are absent.
A number of susceptibility factors, can be recognized clinically and can affect management. These includehepatitis C, HIV, excess alcohol, elevated iron levels, and estrogens. Excess alcohol is a long-recognizedcontributor, as is estrogen use in women. Multiple susceptibility factors that appear to act synergistically can beidentified in the individual patient with PCT. Patients with PCT characteristically have chronic liver disease andsometimes cirrhosis and are at risk for hepatocellular carcinoma.
Diagnosis
Porphyrins are increased in the liver, plasma, urine, and stool. The urinary ALA level may be slightly increased,but the PBG level is normal. Urinary porphyrins consist mostly of uroporphyrin with lesser amounts ofcoproporphyrin. Plasma porphyrins are also increased.
Porphyria Cutanea Tarda: Treatment
Alcohol, estrogens, iron supplements, and, if possible, any drugs that may exacerbate the disease should bediscontinued, but this step does not always lead to improvement. A complete response can almost always beachieved by the standard therapy, repeated phlebotomy, to reduce hepatic iron. A unit (450 mL) of blood can beremoved every 1–2 weeks. The aim is to gradually reduce excess hepatic iron until the serum ferritin reachesthe lower limits of normal. Because iron overload is not marked in most cases, remission may occur after onlyfive or six phlebotomies; however, PCT patients with hemochromatosis may require more treatments to bringtheir iron levels down to the normal range.
An alternative when phlebotomy is contraindicated or poorly tolerated is a low-dose regimen of chloroquine orhydroxychloroquine, both of which complex with the excess porphyrins and promote their excretion. Hepaticimaging can diagnose or exclude complicating hepatocellular carcinoma. Treatment of PCT in patients withend-stage renal disease is facilitated by administration of erythropoietin.
Sun screen lotions and beta carotene are recommended to prevent skin damage caused by sun light.
4) Hereditary Coproporphyria
HCP is an autosomal dominant hepatic porphyria that results from the half-normal activity of COPRO-oxidase.The disease presents with acute attacks, as in AIP. Cutaneous photosensitivity also may occur, but much lesscommonly than in VP. HCP patients may have acute attacks and cutaneous photosensitivity together orseparately. HCP is less common than AIP and VP.
Clinical Features
HCP is influenced by the same factors that cause attacks in AIP. The disease is latent before puberty, andsymptoms, which are virtually identical to those of AIP, are more common in women. HCP is generally lesssevere than AIP. Blistering skin lesions are identical to PCT and VP.
Diagnosis
COPRO III is markedly increased in the urine and feces in symptomatic disease and often persists, especially infeces, when there are no symptoms. Urinary ALA and PBG levels are increased (but less than in AIP) duringacute attacks but may revert to normal more quickly than in AIP when symptoms resolve. Plasma porphyrinsare usually normal or only slightly increased, but they may be higher in cases with skin lesions. The diagnosisof HCP is readily confirmed by increased fecal porphyrins consisting almost entirely of COPRO III, whichdistinguishes it from other porphyrias. An increase in the fecal COPRO III/COPRO I ratio is useful fordetecting latent cases.
Although the diagnosis can be confirmed by measuring COPRO-oxidase activity, the assays for thismitochondrial enzyme are not widely available and require cells other than erythrocytes.
Hereditary Coproporphyria: Treatment
Neurologic symptoms are treated as in AIP .Phlebotomy and chloroquines are ineffective when cutaneouslesions are present.
5) Variegate Porphyria
VP is an autosomal dominant hepatic porphyria that results from the deficient activity of PROTO-oxidase, theseventh enzyme in the heme pathway, and can present with neurologic symptoms, photosensitivity, or both. VPis particularly common in South Africa, where 3 of every 1000 whites have the disorder.
Clinical Features
VP can present with skin photosensitivity, acute neurovisceral crises, or both. Acute attacks are identical tothose in AIP and are precipitated by the same factors as AIP. Blistering skin manifestations are similar to thosein PCT but are more difficult to treat and usually are of longer duration. Homozygous VP is associated withphotosensitivity, neurologic symptoms, and developmental disturbances, including growth retardation, ininfancy or childhood.
Diagnosis
Urinary ALA and PBG levels are increased during acute attacks but may return to normal more quickly than inAIP. Increases in fecal protoporphyrin and COPRO III and in urinary COPRO III are more persistent. Plasmaporphyrin levels also are increased, particularly when there are cutaneous lesions. VP can be distinguishedrapidly from all other porphyrias by examining the fluorescence emission spectrum of porphyrins in plasma atneutral pH since VP has a unique fluorescence peak at neutral pH.
Assays of PROTO-oxidase activity in cultured fibroblasts or lymphocytes are not widely available.
Variegate Porphyria: Treatment
Acute attacks are treated as in AIP, and hemin should be started early in most cases. Other than avoiding sunexposure, there are few effective measures for treating the skin lesions. Beta-Carotene, phlebotomy, andchloroquine are not helpful.
B) The Erythropoietic Porphyrias
In the erythropoietic porphyrias, excess porphyrins from bone marrow erythrocyte precursors are transportedvia the plasma to the skin and lead to cutaneous photosensitivity.
1) X-Linked Sideroblastic Anemia
XLSA results from the deficient activity of the erythroid form of ALA-synthase and is associated withineffective erythropoiesis, weakness, and pallor.
Clinical Features
Typically, males with XLSA develop refractory hemolytic anemia, pallor, and weakness during infancy. Theyhave secondary hypersplenism, become iron overloaded, and can develop hemosiderosis. The severity dependson the level of residual erythroid ALA-synthase activity and on the responsiveness of the specific mutation toPyridoxal 5´-phosphate supplementation.
Diagnosis
Peripheral blood smear reveals a hypochromic, microcytic anemia with striking anisocytosis, poikilocytosis,and polychromasia; the leukocytes and platelets appear normal. Hemoglobin content is reduced, and the meancorpuscular volume and mean corpuscular hemoglobin concentration are decreased.
Bone marrow examination reveals hypercellularity with a left shift ,megaloblastic erythropoiesis with anabnormal maturation. A variety of Prussian blue–staining sideroblasts are observed.
Levels of urinary porphyrin precursors and of both urinary and fecal porphyrins are normal. The level oferythroid ALA-synthase is decreased in bone marrow, but this enzyme is difficult to measure in the presence ofthe normal ALA-synthase housekeeping enzyme. Definitive diagnosis requires the demonstration of mutationsin the erythroid ALAS gene.
X-Linked Sideroblastic Anemia: Treatment
The severe anemia may respond to pyridoxine supplementation. This cofactor is essential for ALA-synthaseactivity, and mutations in the pyridoxine binding site of the enzyme have been found in several responsivepatients. Cofactor supplementation may make it possible to eliminate or reduce the frequency of transfusion.Unresponsive patients may be transfusion-dependent and require chelation therapy.
2) Congenital Erythropoietic Porphyria
CEP, also known as Günther disease, is an autosomal recessive disorder. It is due to the markedly deficient, butnot absent, activity of URO-synthase and the resultant accumulation of uroporphyrin I and coproporphyrin Iisomers. CEP is associated with hemolytic anemia and cutaneous lesions.
Clinical Features
Severe cutaneous photosensitivity begins in early infancy. The skin over light-exposed areas is friable, andbullae and vesicles are prone to rupture and infection. Skin thickening, hypo- and hyperpigmentation, andhypertrichosis of the face and extremities are characteristic. Secondary infection of the cutaneous lesions canlead to disfigurement of the face and hands. Porphyrins are deposited in teeth and in bones. As a result, the teethare reddish-brown and fluoresce on exposure to long-wave ultraviolet light. (Erythrodontia)-See figure Hemolysis is probably due to the marked increase in erythrocyte porphyrins and leads to splenomegaly. Adultswith a milder form of the disease also have been described.
Diagnosis
Uroporphyrin and coproporphyrin (mostly type I isomers) accumulate in the bone marrow, erythrocytes,plasma, urine, and feces. The predominant porphyrin in feces is coproporphyrin I. The diagnosis of CEP can beconfirmed by demonstration of markedly deficient URO-synthase activity and/or the identification of specificmutations in the UROS gene. The disease can be detected in utero by measuring porphyrins in amniotic fluidand URO-synthase activity in cultured amniotic cells or chorionic villi, or by the detection of the family’sspecific gene mutations.
Figure-2 showing Erythtrodontia in Congenital Erythropoietic porphyria
Severe cases often require transfusions for anemia. Chronic transfusions of sufficient blood to suppresserythropoiesis are effective in reducing porphyrin production but results in iron overload. Splenectomy mayreduce hemolysis and decrease transfusion requirements. Protection from sunlight and from minor skin traumais important. Beta Carotene may be of some value. Complicating bacterial infections should be treatedpromptly. Recently, bone marrow and cord blood transplantation has proven effective in several transfusion-dependent children, providing the rationale for stem-cell gene therapy.
3) Erythropoietic Protoporphyria
EPP is an inherited disorder resulting from the partial deficiency of ferrochelatase activity, the last enzyme inthe heme biosynthetic pathway. EPP is the most common erythropoietic porphyria in children and, after PCT,the second most common porphyria in adults. EPP patients have ferrochelatase activities as low as 15–25% inlymphocytes and cultured fibroblasts. Protoporphyrin accumulates in bone marrow reticulocytes and thenappears in plasma, taken up in the liver, and excreted in bile and feces.
Clinical Features
Skin photosensitivity, which differs from that in other porphyrias, usually begins in childhood and consists ofpain, redness, and itching occurring within minutes of sunlight exposure .Photosensitivity is associated withsubstantial elevations in erythrocyte protoporphyrin and occurs only in patients with genotypes that result inFerrochelatase activities below ~35% of normal. Redness, swelling, burning, and itching can develop shortlyafter sun exposure Symptoms may seem out of proportion to the visible skin lesions.
Although EPP is an erythropoietic porphyria, up to 20% of EPP patients may have minor abnormalities of liverfunction, and in about 5% of these patients the accumulation of protoporphyrins causes chronic liver diseasethat can progress to liver failure and death.
Diagnosis
A substantial increase in erythrocyte protoporphyrin, which is predominantly free and not complexed with zinc,is the hallmark of this disease. Protoporphyrin levels are also variably increased in bone marrow, plasma, bile,and feces.
Erythropoietic Protoporphyria: Treatment
Avoiding sunlight exposure and wearing clothing designed to provide protection for conditions with chronicphotosensitivity are essential. Oral Beta-carotene improves tolerance to sunlight in many patients. Thebeneficial effects of -carotene may involve quenching of singlet oxygen or free radicals.
Treatment of hepatic complications, which may be accompanied by motor neuropathy, is difficult.Cholestyramine and other porphyrin absorbents such as activated charcoal may interrupt the enterohepaticcirculation of protoporphyrin and promote its fecal excretion, leading to some improvement. Splenectomy maybe helpful when the disease is accompanied by hemolysis and significant splenomegaly. Plasmapheresis andintravenous hemin are sometimes beneficial.
Liver transplantation has been carried out in some EPP patients with severe liver complications and is oftensuccessful in the short term. Bone marrow transplantation is considered after the liver
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