This thread is directed at those taking USMLE boards. I will try to put together some tough and tricky ones that determine who get's an average vs top score. No "run of the mill" stuff will be included (stuff that u will find in every mcq set ). Otherwise it will be a waste of my time and yours. All members can contribute to this thread. I will provide some neat hints under comments and extra edge section. Most of the matter will be in my own words but the matter will be drawn from Mark's Biochemistry, Harper and Wikipedia. Just an attempt to make the D-day the sweetest (-: Also visit this thread - http://forum.facmedicine.com/biochemistry/104-how-study-biochemistry.html#post34417
A 14-year-old Caucasian girl has been dieting to maximize her performance on the mile run with her track team. Although her lower weight initially improves her performance, she begins to fade in the last quarter-mile despite the exhortations of her trainer. She reports increasing muscle cramps and fatigue and undergoes stress testing that shows a progressive inefficiency of oxygen to energy conversion accompanied by increased blood lactate levels. Her sports medicine subspecialist attributes this to deficient fat stores and suggests a particular supplement. Which of the following would be most likely to benefit this patient? A. Glycine and tyrosine B. Thymidine C. Pantothenic acid D. Uridine E. Folate EXPLANATION: Pantothenic acid (vitamin B[SUB]5[/SUB]) is a component of coenzyme A (CoA) and acyl carrier protein (ACP). These proteins carry acyl groups with acetyl-CoA being important for fatty acid oxidation and many other metabolic reactions while ACP functions in fatty acid synthesis. Folic acid is made from glycine, serine, and choline and is important for methyl (one carbon) reactions such as the conversion of deoxyuridine monophosphate to thymidine (incorrect answers a, b and d, e). Stable forms of folate (folinic acid, synthetic leucovorin) can be used as part of a supplement mixture (thiamine, riboflavin, coenzyme Q, lipoic acid) for mitochondrial dysfunction. The reactive prosthetic group of both ACP and CoA is a phosphopantetheine sulfhydryl. In ACP, the phosphopantetheine group is attached to the 77-residue polypeptide chain via a serine hydroxyl. In CoA, the phosphopantetheine is linked to the 5' phosphate of adenosine that is phosphorylated in its 3' hydroxyl. The answer is C (-:
The Organic Acidurias A 5-month-old infant who has been experiencing lethargy, recurrent vomiting, respiratory distress, and muscular hypotonia is brought to the emergency room near comatose. Laboratory results indicate severe metabolic ketoacidosis associated with an extreme accumulation of methylmalonic acid in the blood and urine. Negative findings for pernicious anemia or other hematologic or neurologic symptoms of cobalamin deficiency indicate that the infant is suffering a defect in which of the following enzymes? A. malonyl-CoA decarboxylase B. methionine synthase C. methylmalonyl-CoA mutase D. methylmalonyl-CoA racemase E. propionyl-CoA carboxylase EXPLANATION: TCA cycle-mediated oxidation of propionyl-CoA, derived from the beta oxidation of fatty acids with an odd number of carbon atoms or from catabolism of several amino acids (e.g., valine and isoleucine), requires that it first be converted to succinyl-CoA. Methylmalonyl-CoA mutase is the terminal enzyme in this conversion process. The most common physical symptoms seen in patients with defective methylmalonyl-CoA mutase activity are failure to thrive, lethargy, vomiting, muscular hypotonia, and respiratory distress. Characteristic laboratory findings will be methylmalonic acidemia. Malonyl-CoA decarboxylase (choice A) is a mitochondrial enzyme involved in the catabolism of malonyl-CoA derived from the carboxylation of acetyl-CoA by propionyl-CoA carboxylase (the enzyme is not completely specific for propionyl-CoA). Deficiency in malonyl-CoA decarboxylase leads to developmental delay, hypotonia, seizures, metabolic acidosis, ketosis, and lactic acidemia. Clinical laboratory findings are characterized by malonic aciduria. Methionine synthase (choice B) is a vitamin B[SUB]12[/SUB] (cobalamin) requiring enzyme that converts homocysteine to methionine while simultaneously regenerating tetrahydrofolate (THF) from methyl-THF. Functional methionine synthase deficiency results from deficiencies in cobalamin and because of the role of the enzyme in THF regeneration, will lead to deficient thymidine nucleotide biosynthesis. Methylmalonyl-CoA racemase (choice D) is another enzyme in the conversion of propionyl-CoA to succinyl-CoA and no specific deficiencies in this enzyme have been identified. Propionyl-CoA carboxylase (choice E) is the first enzyme in the conversion of propionyl-CoA to succinyl-CoA. Deficiency in propionyl-CoA carboxylase is a major cause of ketotic hyperglycemia syndrome. Accumulation of propionic acid is evident in the blood of afflicted individuals. Ans C Comments – Inborn errors of metabolism have one thing in common – Failure to thrive. So the stem of the questioon will be invariably the same for the most part. An infant is brought in few months after being born with …vomitting, irritability, lethargy…blah…blah. The key for exam takers to getting which one (of the multitude of inborn errors of metabolism ) it isin 40 seconds lies in the key metabolic discrepancy, which leads to an elevation of certain substance typically in blood and being found in increased amounts in the excretory products typically urine ( where it is also easy to detect ). Now the pediatrician doesen’t have the biochemical info to start with. He has to rely on some key feature in the clinical presentation such as musty odour of urine for PKU or time of onset ex – fructose intolerance typically starts around the time of weaning ( until which time the child was doing well ). Anthropometry and delay in developmental milestones are non-specific. Other metabolic parameters derangements such as low blood sugar, electrolye imbalances etc. are also typically a common denominator to most of these disorders. Acidosis is also non-specific unless the culprit acid is someone other than lactic acid ex – methylmalonic aciduria in this case pointing to a def. of methylmalonyl-CoA mutase. [FONT=&]Traditionally the inherited metabolic diseases were categorized as disorders of carbohydrate metabolism, amino acid metabolism, organic acid metabolism, or lysosomal storage diseases. In recent decades, hundreds of new inherited disorders of metabolism have been discovered and the categories have proliferated. Following are some of the major classes of congenital metabolic diseases, with prominent examples of each class. Many others do not fall into these categories. ICD-10 codes are provided where available.[/FONT] [FONT=&]Disorders of carbohydrate metabolism [/FONT] [FONT=&]E.g., glycogen storage disease[/FONT] [FONT=&]Disorders of amino acid metabolism [/FONT] [FONT=&]E.g., phenylketonuria, maple syrup urine disease, glutaric acidemia type 1[/FONT] [FONT=&]Urea Cycle Disorder or Urea Cycle Defects [/FONT] [FONT=&]E.g., Carbamoyl phosphate synthetase I deficiency[/FONT] [FONT=&]Disorders of organic acid metabolism (organic acidurias) [/FONT] [FONT=&]E.g., alcaptonuria[/FONT] [FONT=&]Disorders of fatty acid oxidation and mitochondrial metabolism [/FONT] [FONT=&]E.g., Medium-chain acyl-coenzyme A dehydrogenase deficiency (often shortened to MCADD.)[/FONT] [FONT=&]Disorders of porphyrin metabolism [/FONT] [FONT=&]E.g., acute intermittent porphyria[/FONT] [FONT=&]Disorders of purine or pyrimidine metabolism [/FONT] [FONT=&]E.g., Lesch-Nyhan syndrome[/FONT] [FONT=&]Disorders of steroid metabolism [/FONT] [FONT=&]E.g., lipoid congenital adrenal hyperplasia, congenital adrenal hyperplasia[/FONT] [FONT=&]Disorders of mitochondrial function [/FONT] [FONT=&]E.g., Kearns-Sayre syndrome[/FONT] [FONT=&]Disorders of peroxisomal function [/FONT] [FONT=&]E.g., Zellweger syndrome[/FONT] [FONT=&]Lysosomal storage disorders [/FONT] [FONT=&]E.g., Gaucher's disease[/FONT] [FONT=&]E.g., Niemann Pick disease[/FONT] [FONT=&]- this differential is from Wiki[/FONT] On step 1 u will be tested on atleast 60% of the inborn errors of metabolism. Everybody who gets the ones on Carb ( glycogen storage , fructose intolerance etc. ) and Lysosomal storage diseases are assured of an average score and these are covered well in DIT, Kaplan, Najeeb, Pass program, First Aid (nice charts) etc. and so most who take the exams get these. The ones who get the : organic acidurias, tyrosinemias etc. right are the ones who stand head and shoulders above the rest ( becos it is not spoon fed by the major coaching programs and needs individual effort ). [FONT=&]The big 4 organic acidurias that are commonly tested r (and u will definitely see one of these on ur exam) : [/FONT] [FONT=&]1) propionic acidemia, 2) methylmalonic acidemia, 3) maple syrup urine disease and 4) isovaleric acidemia [/FONT](-:
The Organic Acidurias - In detail [FONT=&] I will tackle each one of the big 4 [/FONT] [FONT=&]Firstly some background – what produces these organic acids ?[/FONT] [FONT=&] Ans – They are the by products of: [/FONT] [FONT=&]1) ODD CHAIN FATTY ACID METABOLISM and [/FONT] [FONT=&]2) Amino Acid Metabolism ex. Branched chain i.e Isoleucine, Leucine and Valine ( I Love Velmont Maple syrup ) whose deragement accounts for the famous Maple syrup Urine diseases and[/FONT] a product of alpha-ketobutyric acid, which in turn is a product of digestion of threonine and methionine. Now both these groups are converted into Propionyl CoA (which happens to be the last man standing in case of odd chain FA metab) and subsequently cconverted into Succciny CoA ( part of TCA Cycle ). So I seem them as Martyrs – Even when they r going down ( being degraded ) they r doing so in a “Blaze of Glory” i.e by giving us some extra energy ( more ATP via Kreb cycle ). Whether we respect their martydom and use that energy appropriately for our own good and for the good of others or otherwise is upto us. click to enlarge image [FONT=&]If u wish, u can think of this as being similar to the clotting cascade, with an extrinsic arm ( Odd Chain Fatty Acid ), an intrinsic arm ( Branched chain amino acids ), Propionyl CoA being akin to activated factor X and the rest, like they say - Is History. [/FONT] [FONT=&]The reaction in simple words ( “Readers Digest Style” )[/FONT] [FONT=&]Propionyl-CoA carboxylase[/FONT][FONT=&] catalyses the carboxylation reaction of propionyl CoA in the mitochondrial matrix. The enzyme is biotin dependent. The product of the reaction is (S)-methylmalonyl CoA. (S)-Methylmalonyl-CoA is not directly utilizable by animals; it is acted on by a racemase to give (R)-methylmalonyl-CoA. The latter is converted by methylmalonyl-CoA mutase (one of a very few Vitamin B[SUB]12[/SUB] dependent enzymes) to give succinyl-CoA. The latter is converted to oxaloacetate and then malate in the Krebs cycle. Export of malate into the cytosol leads to formation of oxaloacetate, phosphoenol pyruvate, and other gluconeogenic intermediates.[/FONT] [FONT=&]ATP + propanoyl-CoA + HCO[SUB]3[/SUB][SUP]-[/SUP] <=> ADP + phosphate + (S)-methylmalonyl-CoA[/FONT] [FONT=&]Recap [/FONT][FONT=&]– [/FONT][FONT=&]Sources of [/FONT]Propionyl-CoA [FONT=&]It is formed as a product of beta-oxidation of odd-chain fatty acids.[/FONT] [FONT=&]It is also a product of metabolism of isoleucine and valine.[/FONT] [FONT=&]It is a product of alpha-ketobutyric acid, which in turn is a product of digestion of threonine and methionine.[/FONT] [FONT=&][/FONT] [FONT=&]Symptoms in general of Organic Acidemias[/FONT] [FONT=&]Organic acidemias are usually diagnosed in infancy, characterized by urinary excretion of abnormal amounts or types of organic acids. The diagnosis is usually made by detecting an abnormal pattern of organic acids in a urine sample by gas chromatography-mass spectrometry. In some conditions, the urine is always abnormal, in others the characteristic substances are only present intermittently. Many of the organic acidemias are detectable by newborn screening with tandem mass spectrometry.[/FONT] [FONT=&]These disorders vary in their prognosis, from manageable to fatal, and usually affect more than one organ system, especially the central nervous system.[/FONT] [FONT=&]Neurological damage and developmental delay are common factors in diagnosis, with associated symptoms ranging from poor feeding to slow growth, lethargy, vomiting, dehydration, malnutrition, hypoglycemia, hypotonia, metabolic acidosis, ketoacidosis, hyperammonemia, and if left untreated, death.[/FONT] [FONT=&]Treatment in General[/FONT] Treatment or management of organic acidemias vary. There are no effective treatments for all of the conditions, though treatment for some may include a limited protein/high carbohydrate diet, intravenous fluids, amino acid substitution, vitamin supplementation, carnitine and induced anabolism. [FONT=&]First up[/FONT]- Propionic acidemia (PA) [FONT=&]Propionic acidemia[/FONT][FONT=&], also known as propionic aciduria, propionyl-CoA carboxylase deficiency and ketotic glycinemia,is a rare autosomal recessivemetabolic disorder, classified as a branched-chain organic acidemia.[/FONT] [FONT=&]The disorder presents in the early neonatal period with progressive encephalopathy. Death can occur quickly, due to secondary hyperammonemia, infection, cardiomyopathy, or basal ganglial stroke.[/FONT] [FONT=&]Pathophysiology[/FONT] [FONT=&]In healthy individuals, the enzyme propionyl CoA carboxylase (PCC) converts propionyl CoA to methylmalonyl CoA, en-route to Succinyl CoA. Individuals with PA cannot perform this conversion because the enzyme propionyl CoA carboxylase is nonfunctional (due to - Mutations in both copies of the PCCA or PCCB genes). The essential amino acids isoleucine, valine, threonine, and methionine and odd-chain fatty acids are simply converted to propionyl CoA, before the process stops, leading to a buildup of propionyl CoA. Instead of being converted to methylmalonyl CoA, propionyl CoA is then converted into propionic acid, which builds up in the bloodstream. Also ketones and other toxic compounds accumulate in the blood, causing the signs and symptoms of propionic acidemia. Propinyl CoA also hampers Acetyl CoA carboxylase thus impairing fatty acid synthesis in the brain and liver.[/FONT] [FONT=&]In many cases, PA can damage the brain, heart, and liver, cause seizures, and delays to normal development like walking and talking. During times of illness the affected person may need to be hospitalized to prevent breakdown of proteins within the body. Each meal presents a challenge to those with PA. If not constantly monitored, the effects would be devastating. Dietary needs must be closely managed by a metabolic geneticist or metabolic dietician.[/FONT] [FONT=&]HINT :[/FONT][FONT=&]Propionic acidemia is characterized almost immediately in newborns[/FONT][FONT=&]. Symptoms include poor feeding, vomiting, dehydration, acidosis, low muscle tone (hypotonia), seizures, and lethargy. The effects of propionic acidemia quickly become life-threatening.[/FONT] [FONT=&]Second[/FONT][FONT=&] - [/FONT][FONT=&]Methylmalonic acidemia[/FONT] [FONT=&]Comes in 2 flavors[/FONT] [FONT=&]1) due to the def. of Vit B12 ( generally seen in adults and in those populations who are strict vegs or are malnourished ). This form shows a relatively slow progression.[/FONT] [FONT=&]Pathological mechanism – Methylmalonyl replaces malonyl group in fatty acid synthesis (leading to the formation of a new branched chain Fatty acid) and it’s incorporation into myelin destroys the normal membrane structure. Also, the Propionyl CoA that backs up downstream, inhibits Acetyl CoA carboxylase, leading to the impairment in fatty acid synthesis in the liver, brain etc.[/FONT] [FONT=&]2) due to def. of Methylmalonyl CoA mutase (an Aut. Recessive disorder) – which catalyses the ultimate step in the conversion of propionyl CoA to SuccinylCoA. In this case the acidemia is more severe (direct damage) and this in conjunction with secondary hyperammonemia (from the backed up amino acids), and impaired fatty acid metabolism (as mentioned above) leads to progressive encephalopathy and an overt expression/ presentation in early neonatal period or in the early months of life. [/FONT] [FONT=&]Clue will be the mention of elevated methylmalonic acid in blood and urine +/- elevted propionic acid levels ( but lower compared to propionic acidemia/aciduria).[/FONT] [FONT=&]Third [/FONT][FONT=&]– Maple Syrup Urine disease [/FONT] [FONT=&]B4 discussing Maple Syrup, I will briefly touch upon Amino acid catabolism. I will try and make it as simple as possible. Let’s see what all does our amino acid have in addition to a carbon skeleton ( which can be salvaged for energy – either via conversion to proprionyl CoA or Acetyl CoA ) – it has an amino group ( which is stripped off in the 1[SUP]st[/SUP] step i.e transamination by the transaminases ) , then it’s carboxyl group is lost ( in oxidative decarboxylation – a process catalysed by α – ketoacid dehydrogenase ) and lastly the dehdrogenase step (using FAD as the coenzyme). This is common to all amino acids and after this their paths diverge.[/FONT] Maple syrup urine disease (MSUD), also called branched-chain ketoaciduria, is an autosomal recessive metabolic disorder affecting branched-chain amino acids. [FONT=&]MSUD is caused by a deficiency of the branched-chain alpha-keto acid dehydrogenase complex (BCKDC), leading to a buildup of the branched-chain amino acids (leucine, isoleucine, and valine) and their toxic by-products (ketoacids – becos the transamination step is still intact ) in the blood and urine. [/FONT] [FONT=&]Diagnosis[/FONT] [FONT=&]The disease is named for the presence of sweet-smelling urine, with an odor similar to that of maple syrup or burnt sugar. The smell is also present and sometimes stronger in the ear wax of an affected individual. Prior to the easy availability of plasma amino acid measurement, diagnosis was commonly made based on suggestive symptoms and odor. Affected individuals are now often identified with characteristic elevations on plasma amino acids who do not have the characteristic odor. The compound responsible for the odor is sotolon (sometimes spelled sotolone). [/FONT] [FONT=&]Biochemical complication and Symptoms[/FONT] [FONT=&]Accumulation of branched chain amino acids causes an impairment in the transport and function of other amino acids [/FONT]Ã [FONT=&] protein biosynthesis is reduced. Also BCA competitively inhibit glutamate dehydrogenase.[/FONT] [FONT=&]From early infancy (may seem health at birth), symptoms of the condition include poor feeding, vomiting, dehydration, lethargy, hypotonia, seizures, hypoglycaemia, ketoacidosis, opisthotonus, pancreatitis, coma and death within one year of birth.[/FONT] [FONT=&]Management[/FONT] [FONT=&]Keeping MSUD under control requires careful monitoring of blood chemistry and involves both a special diet and frequent testing.[/FONT] [FONT=&]A diet with minimal levels of the amino acids leucine, isoleucine, and valine must be maintained in order to prevent neurological damage. As these three amino acids are required for proper metabolic function in all people, specialized protein preparations containing substitutes and adjusted levels of the amino acids have been synthesized and tested, allowing MSUD patients to meet normal nutritional requirements without causing harm.[/FONT] [FONT=&]Usually, patients are also monitored by a dietitian. Their diet must be adhered to strictly and permanently. However, with proper management, those afflicted are able to live healthy, normal lives and not suffer the severe neurological damage associated with the disease.[/FONT] [FONT=&]Note – U may be tested on the mech of exess amino acids in urine and they will throw in an absorption problem at the level of the tubules. As u know now it is excess amino acids that are spilling into the urine becos the absorption mechanism is overwhelmed. Primary absorption problem is seen with Hartnup disease [/FONT]also known as "pellagra-like dermatosis" in which non-polar amino acids (particularly tryptophan) are not absorbed and in Cystinuria. Generalised aminoacid uria is seen in Fanconi syndrome. [FONT=&]Lastly - [/FONT][FONT=&]Isovaleric Acidemia ( the least tested among the four )[/FONT] [FONT=&]Isovaleric acidemia, also called isovaleric aciduria is due to isovaleric acid CoA dehydrogenase deficiency(involved in the 3[SUP]rd[/SUP] step of the common pathway mentioned above), is a rare autosomal recessive metabolic disorder which disrupts or prevents normal metabolism of the branched-chain amino acid leucine.[/FONT] [FONT=&]A characteristic feature of isovaleric acidemia is a distinctive odor of ‘sweaty feet’ or ‘cheesy odor’ in breath and body fluids. This odor is caused by the buildup of a compound called isovaleric acid in affected individuals. [/FONT][FONT=&]Prognosis[/FONT] [FONT=&]In about half of cases, the signs and symptoms of this disorder become apparent within a few days after birth and include poor feeding, vomiting, seizures, and lack of energy that can progress to coma. These medical problems are typically severe and can be life-threatening. [/FONT] [FONT=&]In the other half of cases, the signs and symptoms of the disorder appear during childhood and may come and go over time. They are often triggered by an infection or by eating an increased amount of protein-rich foods. [/FONT] [FONT=&]Treatment[/FONT][FONT=&] consists of dietary protein restriction, particularly leucine. During acute episodes, glycine is sometimes given, which conjugates with isovalerate forming isovalerylglycine, or carnitine which has a similar effect.[/FONT] [FONT=&]Elevated hydroxyisovalerate is a clinical marker of biotin deficiency. Without biotin, leucine and isoleucine cannot be fully metabolized. This leads to the formation of hydroxyisovalerate instead of the normal useful byproducts of leucine and isoleucine catabolism. Elevated hydroxyisovalerate can be caused by genetic conditions or dietary deficiency of biotin, and many patients with organic acidemias related to incomplete leucine catabolism can benefit from supplemental biotin.Biotin deficiency on its own can have severe physiological and cognitive consequences that closely resemble symptoms of organic acidemias.[/FONT] Now how do they trick w.r.t. isovaleric acidemia ? Well, they will ask which amino acid metabolism is affected and most people will ans Valine. Remember that the ans is LEUCINE otherwise u will LOSE this question wink) If u guys like my post, show ur appreciation by simply pushing the thanks button. Don't need to post thank you messages as that will break the flow of the thread. If I am wrong somewhere, or if u wish to add something please post below and enrich this thread. (-:
The Porphyrias [FONT=&] These are from my personal notes on the subjects. U willnot see more than 2 questions on this in Step 1, but if u r aiming for max scores then it's imp. It's very exhaustive, so do it when u hav the time and energy. Porphyria (means purple )[/FONT] - porphyria is a group of inherited disorders, involving the abnormalities in the production of heme pigments - porphyrias are charecterised by 3 major findings a) photodermatitis b) neuropsychiatric c) visceral coomplaints ( abdominal pain or cramping ) Types 1) Acute_Intermittent_Porphyria 2) Congenital_Erythropoetic_Porphyria 3) Porphyria_Cutanea_Tarda 4) Hereditary_Coprophyria 5) Variegate_Porphyria 6) Congenital_Erythropoetic_Porphyria Inheritance The enzymes for heme synthesis are in short supply and so the full capacity of the maternal and paternal genes are required to produce optimal levels of enzymes”¦amy loss of gene activity will result in inadequate enzymes and hence Autosomal Dominant”¦..except Congenotal Erythropoetic Porphyria ( Autosomal recessive ) [FONT=&]Classification of Porphyrias[/FONT] Hereditary a) Erythropoetic porphyria ( problems in heme synthesis ) ex ”“ Congenital Erythropoetic porphyria b) Hepatic ( problems in Cyt P450 synthesis ) ex - Acute Intermittent porphyria, Porphyria cutanea tarda, hereditary coproporphyria, Variegate porphyria c) Mixed ”“ ex ”“ protoporphyria Acquired ex ”“ Pb poisoning Some types of porphyria begin in early childhood ex ”“ Cong. Erythropoetc Porphyria, some at puberty ex ”“ Acute Intermittent porphyria & others begin in adulthood ex ”“ porphyria cutanea tarda ( mostly men > 35 yrs age ) Porphyria cutanea tarda, also happens to be the most common porphyria. A classic attack of acute porphyria generally begins with - colicky abdominal pain Followed by - vomitng and constipation, personality changes ( delirium, hallucinations etc. ), peripheral paresthesias ( numbness and tingling ), weakness, paralysis, & low B.P, shock, electrolyte imbalances ( all of which can be life threatening ) - urine may become red brown following an attack - exposure to sun can cause reddening skin, pain, sensations of heat, blistering and edema of skin. These lesions heal slowly, often with scarring & pigment changes & can be disfiguring. The acute porphyrias ( classically acute intermittent porphyria ) imitate many other diseases from acute appendicitis to acute Schizophrenia. Between attacks patients have mild symptoms, including ”“ psychoneurosis. Mechanisms behind the symptomatology/ pathogenesis ∆ amino levulinnic acid & porphobillinogen ( both neurotoxins ) - produce cerebral dysfunction and damage ( confusion and psychiatric disease ) - autonomic neropathy ( constipation, urinary retention, tachycardia and hypertension ) - peripheral neuropathy ( pain in the back and legs or paresthesias ) - severe and sometimes chronic abdominal pain Uroporphyrinogen & Protoporphyrinogen ( when exposed to light generate free radicals & cause the classic blistering and scarring of skin ) - worst wavelength is 400 μm ( “Soret Band” ) responsible for orange-red fluorescence, which is not screened out by window glass or standard sunscreens - these patients need to use opaque stuff on the skin - β carotene which absorbs the problem photons is the mainstay of therapy. For some reason uroporphrinogen also causes lanugo hair”¦look especially over cheeks and temples Now let’s take a look at the individual porphyrias 1) Acute Intermittent Porphyria - Autosomal dominant - Uroporphyrinogen 1 synthase def. aka PGB deaminase df. - Symptoms are those related to accumulation of the neurotoxins (∆ amino levulinnic acid & porphobillinogen)”¦no cutaneous symptoms because the porphyrins don’t accumulate. An acute attack starts with abdominal pain ( severe ) +/- psychiatric symptoms +/- tachycardia +/- labile hypetension CNS symptoms ”“ autonomic ( abdominal pain, sweating, vascular spasms, labile hypertension, sinus tachycardia ) Peripheral neuropathy Grave signs - resp. paralysis ( unable to speak, breathe or swallow ), complete flaccid paralysis which develops over a few days, hallucinations, seizures, coma, bulbar paralysis, hypothalami dysfunction or cerebellar or basal gangla involvement Note: A severe hyponatremia can develop from SIADH, G I loss & possibly renal loss. Lab findings ”“ [FONT=&] The Watson-Schwartz reaction is used as a simple screening test for the presence of elevated urinary PBG levels. [/FONT] [FONT=&] REAGENT - 2 grams of 4-dimethylaminobenzaldehyde made up to 100 ml with 6N HCl. [/FONT] [FONT=&] PROCEDURE [/FONT] [FONT=&] Mix 1 ml of freshly-voided urine with 1 ml of reagent. Shake and allow to stand. A pink or red colour implies the presence of either PBG or urobilinogen. Now add 2 ml of chloroform, shake well and allow to settle. Two layers result. PBG, if present, will remain in the top or aqueous layer, imparting a pink colour to it. [/FONT] [FONT=&]It is essential that the pink colour is confined to only one layer: if large amounts of either PBG or urobilinogen are present, both layers will remain coloured. In this case, use a pipette to suck off the upper, aqueous layer, deposit this into a fresh tube, add more chloroform and allow to separate once more. [/FONT] [FONT=&] INTERPRETATION OF THE TEST [/FONT] [FONT=&]Urobilinogen will extract into the lower layer, which contains the chloroform. Thus, if the colour is confined to the lower layer, the urine contains urobilinogen: this is of no significance in terms of porphyria. [/FONT] [FONT=&]Porphobilinogen will extract into the upper, aqueous layer. If this layer is red or pink, PBG is probably elevated which suggests an acute porphyria. [/FONT] [FONT=&]The Watson-Schwartz reaction is negative in quiescent VP. Any positive result in VP therefore confirms an acute attack. In AIP, the test may remain positive in remission. Absolute confirmation of the presence of an acute attack can only be gained by performing accurate ALA and PBG quantitation in the laboratory and comparing them with previous values for the same patient. Therefore it is suggested that any patient known to have porphyria and who shows a positive Watson-Schwartz reaction, and has compatible clinical features, must be considered to be suffering from the acute attack. [/FONT] [FONT=&]This test is at best a rough guide to a patient's clinical state: in particular, the intensity of the response is very dependent on the degree of concentration or dilution of the urine. [/FONT] [FONT=&] Ref - Porphyria SA[/FONT] The screening test can be followed by a quantitative test by measuring the amount of PBG in a 24-hour specimen or even a spot sample of urine. A very high urine PBG, when determined by a reliable method such as the Mauzerall-Granick method, is diagnostic for the presence of an acute Porphyria. There are several considerations to keep in mind regarding PBG measurements: · Urine PBG usually remains high between attacks of AIP, especially if the attacks are frequent. Thus, although a high PBG does indicate that the patient has an acute Porphyria, it does not prove that the patient is having an attack at the time. · Urine PBG may gradually become normal if there have been no attacks of AIP for a long time. · Urine PBG can become normal within 1-2 days after heme therapy. · In patients with HCP or VP, urine PBG can become normal more quickly after attacks than in patients with AIP. Urine porphyrins usually stay increased in these patients even when the PBG falls to normal. · Urine PBG is normal in most individuals who have inherited AIP but have never had symptoms. Therefore, it is not reliable for testing relatives. Urine porphyrins are usually increased in acute porphyrias, but measuring them is less useful than measuring PBG. Increases in urine porphyrins are common in other medical conditions. Therefore, finding an increase in urine porphyrins may not mean that the patient has Porphyria. Ref - AIP, HCP, VP & ADP | The American Porphyria Foundation The screening test should be followed by a quantitative test on the urine sample”¦gives a better idea about the condition being acute and falling levels suggest the attack is resolving. The porphyrins should also be measured in blood, urine and feces which will be markedly raised in the other porphyrias with problems more downstream along the pathway. Rx - Identify and avoid precipitating factors - High carb diet ( > 400 g / day ) - Phenothiazines for abdominal pain - Proparanol for hypertension and tachycardia - Hematin ( if no coagulopathy ) Since nerve regeneration is the rate-limiting factor to improvement of established neuropathy, hematin will have no effect on recovery”¦.but if given earlier in the course of an attack, it will limit the extend of neurological injury. 2) Congenital Erythropoetic Porphyria - Autosomal recessive - Uroporphyrinogen III cosynthase def. Photosensitivity in this very rare autosomal recessive disorder may begin in infancy. Clinical manifestations include skin and ”˜erythron’. Skin ”“ cutaneous lesions such as vesicles & bullae form on light exposed skin which after time of ulceration & erosion cause scarring. The scarring can cause severe defoemities particularly of the face and fingers Other complications include ”“ hypertrichosis, alopecia, conjunctivitis, keratitis. Teeth are red and fluorescent. Erythron ”“ Crystals in RBC cause hemolysis and the most severe forms have given rise to stories of vampires and werwolves ( becos a blood meal would suppress the heme synthesis pathway ). Lab ”“ Urine has port wine color, ↑ uroprphyrin Blood ”“ hemolytic anemia, Bone marrow ”“ normoblastic hyperplasia ( red fluorescence 400 nm ) Feces - ↑ uroprphyrin, ↑ Coproprphyrin Rx - Prophylaxis for skin lesions, Antibiotics for infected skin lesions - Splenectomy to reduce hemolysis & prevent excessive porphyrin production - transfusion will ↓ erythropesis & ↓ porphyrin production - hematin i.v administration has been effective in a few patients as also bone marrow transplantation - β carotene may be tried but not as effective as in protoporphyria. 3) Porphyria cutanea tarda ( most common ) - Autosomal dominant - Uroporphyrinogen III Decarboxylase def. - Common in men ( usually after age 35 years ) - 2 forms a) familial b) acquired ( alcohol consumption, Fe overload, estrogen use ”“ particularly when combined with alcohol ) - NO neurological manifestations Clinical manifestation - Minor trauma to sun-exposed skin causes vesicles or bullae to develop, the vesicles or bullae are followed by erosions and scarring - Acute photosensitivity reactions are not common - In time milia, areas of pigmentation, depigmentation, hirsutism & sclerodermal changes occur. - Patients with untreated disease for a significant period of time may develop cirrhosis & hepato-cellular carcinoma. Lab findings - Serum Fe is often increased. - Liver biopsy ”“ hepatocellular damage with fatty infiltration & hemosiderosis - Urine ”“ Uroporphyrin ↑↑↑ , Coproporphyrin ↑ Rx - Repeated phlebotomy to deplete body iron stores ( removal of a total of 5 ”“ 10 liters is usually required to obtain clinical remission ) - If the patient is unable to tolerate phlebotomy, then chloroquine 125 ”“ 250 mg x 3 times / week. What wiki has to say about the Rx - Since PCT is a chronic condition, a comprehensive management of the disease is the most effective means of treatment. Primarily, it is key that patients diagnosed with PCT avoid alcohol consumption, iron supplements, excess exposure to sunlight (especially in the summer), as well as estrogen and chlorinated cyclic hydrocarbons, all of which can potentially exacerbate the disorder. Additionally, the management of excess iron (due to the commonality of hemochromatosis in PCT patients) can be achieved through phlebotomy, whereby blood is systematically drained from the patient. Low doses of antimalarials can be used. They remove excess porphyrins from the liver by increasing the excretion rate. Remission can be seen within 6”“12 months. Originally, higher doses were used to treat the condition but are no longer recommended because of liver toxicity.Finally, due to the strong association between PCT and Hepatitis C, the treatment of Hepatitis C (if present) is vital to the effective treatment of PCT. Chloroquine, hydroxychloroquine, and venesection are typically employed in the management strategy. 4) Hereditary Coproporphyria - Autosomal dominant - Coproporphyrinogen oxidase ↓ Clinical Manifestation - The clinical manifestation is very similar to AIP ( but milder ) - Skin is sensitive but extensive damage is rare. Rx - Infusion of hematin is used to control this disorder - Mx is similar to AIP 5) Variegate Porphyria - Autosomal dominant - Protoporphyrinogen oxidase ↓ - Has cut manifestations similar to Porphyria cutanea tarda and during the acute phase it will mimic the neuro symptoms of AIP The distinction between AIP, HCP and VP is not required since the Mx is the same. Lab findings ”“ during acute attacks ALA & PBG is increased. -- when asymptomatic or with cutaneous lesions only an ↑ in uroporphyrin & coproporphyrin may be noted & confused with PCT ( the increase in fecal protoporphyrin seen in both acute and asymptomatic periods in VP, allow the differentiation between the 2 disorders ) Rx ”“ Mx is the same as AIP - Rx of cut manifestations may be difficult and β ”“ carotene therapy is not that effective. 6) Erythropoetic Protoporphyria - Autosomal dominant - Ferrochelatase def. - Prognosis favorable ”“ normal life span Clinical Manifestations - Primarily a photosensitivity syndrome : in childhood cutaneous symptoms of the skin such as burning or itching after light exposure occurs. Burning is often accompanied by erythema and edema. Light thru a window pane may evoke the symptoms. Chronic symptoms may occur causing scarring and thickening of the skin in light exposed areas with symptoms being more severe in summer. - Liver disease ”“ a minority get liver damage, sometimes even liver cirrhosis from porphyrin crystals which accumulate in hepatic parenchyma. Gall stones are very common. - Neuropathy ”“ eventually there can be enough ↑ in porphobilinogen to result in a neuropathy Rx - β carotene ( takes 1 ”“ 3 mo after initiation of Rx to show improvement ) 7) Aquired Porphyrias and pseudoporphyrias - Most imp. Pb poisoning, which simulates AIP ( abdominal pain, insanity etc. ) - Pb ion mainly inhibits ∆ ALA dehydratase, ferrocheletase
