Alcohol-Related Liver Disease

Heme biosynthesis

Malnutrition: What you need to know
The Phoenicians and the Syrians who dwell in Palestine confess themselves that they have learnt it from the Egyptians, and the Syrians about the river Thermodon and the river Parthenios, and the Macronians, who are their neighbors, say that they have learnt it lately from the Colchians. The nurse is contributing to the plan of care for a patient who is having an intravenous pyelogram IVP done to diagnose possible bladder cancer. Thank you for your feedback. Administer half of the prescribed dose. The nurse is reinforcing teaching provided to a patient about antibiotics prescribed for a UTI. D Prerenal injury causes include decreased blood pressure from dehydration, blood loss, shock, trauma to or blockage in the arteries to the kidneys, and NSAIDs and cyclooxygenase-2 inhibitors, which impair the autoregulatory responses of the kidney by blocking prostaglandin, which is necessary for renal perfusion. Surgeries, radiation, and tumors can also cause disease in the hypothalamus.

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Iron and heme metabolism

This margin of error is acceptable, considering the ease with which creatinine clearance is measured. Unlike precise GFR measurements involving constant infusions of inulin, creatinine is already at a steady-state concentration in the blood, and so measuring creatinine clearance is much less cumbersome. However, creatinine estimates of GFR have their limitations. All of the estimating equations depend on a prediction of the hour creatinine excretion rate, which is a function of muscle mass which is quite variable.

One of the equations, the Cockcroft and Gault equation see below does not correct for race. With a higher muscle mass, serum creatinine will be higher for any given rate of clearance.

A common mistake made when just looking at serum creatinine is the failure to account for muscle mass. Hence, an older woman with a serum creatinine of 1. Creatinine-based equations should be used with caution in cachectic patients and patients with cirrhosis. They often have very low muscle mass and a much lower creatinine excretion rate than predicted by the equations below, such that a cirrhotic patient with a serum creatinine of 0.

One method of determining GFR from creatinine is to collect urine usually for 24 h to determine the amount of creatinine that was removed from the blood over a given time interval. If the blood concentration is 0. Creatinine clearance C Cr is calculated from the creatinine concentration in the collected urine sample U Cr , urine flow rate V dt , and the plasma concentration P Cr. This is commonly represented mathematically as. A person has a plasma creatinine concentration of 0.

The common procedure involves undertaking a hour urine collection, from empty-bladder one morning to the contents of the bladder the following morning, with a comparative blood test then taken. The urinary flow rate is still calculated per minute, hence:. While most adults have a BSA that approaches 1.

Twenty-four-hour urine collection to assess creatinine clearance is no longer widely performed, due to difficulty in assuring complete specimen collection. To assess the adequacy of a complete collection, one always calculates the amount of creatinine excreted over a hour period.

This amount varies with muscle mass, and is higher in young people vs. An unexpectedly low or high hour creatinine excretion rate voids the test. Nevertheless, in cases where estimates of creatinine clearance from serum creatinine are unreliable, creatinine clearance remains a useful test. These cases include "estimation of GFR in individuals with variation in dietary intake vegetarian diet, creatine supplements or muscle mass amputation, malnutrition, muscle wasting , since these factors are not specifically taken into account in prediction equations.

A number of formulae have been devised to estimate GFR or C cr values on the basis of serum creatinine levels. One interesting feature of the Cockcroft and Gault equation is that it shows how dependent the estimation of CCr is based on age.

The age term is — age. Since these formulae do not adjust for body mass, they relative to the Cockcroft-Gault formula underestimate eGFR for heavy people and overestimate it for underweight people.

Researchers pooled data from multiple studies to develop and validate this new equation. Sixteen additional studies, which included participants, were used for external validation. As separate equations for different populations: This formula was developed by Levey et al.

This formula was developed by Rule et al. In children, the Schwartz formula is used. The method of selection of the constant k has been questioned as being dependent upon the gold-standard of renal function used i.

One problem with any creatinine-based equation for GFR is that the methods used to assay creatinine in the blood differ widely in their susceptibility to non-specific chromogens, which cause the creatinine value to be overestimated.

In particular, the MDRD equation was derived using serum creatinine measurements that had this problem. The NKDEP program in the United States has attempted to solve this problem by trying to get all laboratories to calibrate their measures of creatinine to a "gold standard", which in this case is isotope dilution mass spectrometry IDMS.

In late not all labs in the U. Problems with creatinine varying muscle mass, recent meat ingestion much less dependent on the diet than urea , etc. One of these is cystatin C , a ubiquitous protein secreted by most cells in the body it is an inhibitor of cysteine protease. Cystatin C is freely filtered at the glomerulus. After filtration, Cystatin C is reabsorbed and catabolized by the tubular epithelial cells, with only small amounts excreted in the urine.

Cystatin C levels are therefore measured not in the urine, but in the bloodstream. Equations have been developed linking estimated GFR to serum cystatin C levels. Most recently, some proposed equations have combined sex, age and race adjusted cystatin C and creatinine. The most accurate is sex, age and race adjusted cystatin C, followed by sex, age and race adjusted creatinine and then cystatine C alone in slightly different with adjusted creatinine.

After age 40, GFR decreases progressively with age, by 0. A decreased renal function can be caused by many types of kidney disease. Upon presentation of decreased renal function, it is recommended to perform a history and physical examination , as well as performing a renal ultrasound and a urinalysis.

The most important items in a physical examination are signs of vasculitis , lupus erythematosus , diabetes , endocarditis and hypertension. A urinalysis is helpful even when not showing any pathology, as this finding suggests an extrarenal etiology. Hematuria may be caused by glomerular disease or by a disease along the urinary tract.

The most relevant assessments in a renal ultrasound are renal sizes, echogenicity and any signs of hydronephrosis. Renal enlargement usually indicates diabetic nephropathy, focal segmental glomerular sclerosis or myeloma. Renal atrophy suggests longstanding chronic renal disease. Risk factors for kidney disease include diabetes, high blood pressure, family history, older age, ethnic group and smoking.

But significant decline of the GFR from a previous test result can be an early indicator of kidney disease requiring medical intervention. The sooner kidney dysfunction is diagnosed and treated the greater odds of preserving remaining nephrons, and preventing the need for dialysis. The severity of chronic kidney disease CKD is described by six stages; the most severe three are defined by the MDRD-eGFR value, and first three also depend on whether there is other evidence of kidney disease e.

Not all clinicians agree with the above classification, suggesting that it may mislabel patients with mildly reduced kidney function, especially the elderly, as having a disease. From Wikipedia, the free encyclopedia. The New England Journal of Medicine. Annals of Internal Medicine. Journal of Nuclear Medicine Technology. Oxford Textbook of Clinical Nephrology Fourth ed. Clinical Physiology and Functional Imaging. American Journal of Kidney Diseases. Ferrochelatase then inserts the iron, which completes heme synthesis.

While the ferrochelatase reaction looks rather trivial and indeed can proceed with appreciable rate spontaneously, the enzyme is important: Heme retains the vinyl groups that were introduced at the stage of protoporphyrinogen IX.

Addition of the sulfhydryl groups of cysteine side chains across these vinyl groups can produce covalent bonds between heme and some of its apoproteins.

Such covalent attachment occurs for example in cytochrome C oxidase, but it does not happen in hemoglobin. Hereditary deficiencies are known for each of the enzymes in the synthetic pathway. Clinical symptoms are due to both lack of heme and to the accumulation of biosynthetic intermediates. A lack of heme therefore disinhibits this enzyme and amplifies the accumulation of intermediates upstream of the enzyme defect in question.

Backed-up synthetic intermediates often undergo spontaneous conversion to aberrant products. Inhibition of heme synthesis can also result from causes other than enzyme defects. The most common cause is iron depletion; another one is deficiency of vitamin B 6 , which can result from malnutrition or, in inflammatory intestinal diseases, from malabsorption.

Vitamin B 6 pyridoxin is the precursor of pyridoxal phosphate, the coenzyme in aminolevulinate synthase. Lead intoxication causes inhibition of porphobilinogen synthase see slide Regardless of the underlying cause, the inhibition of heme synthesis will result in red blood cells that are smaller and contain less hemoglobin than normal ones.

This condition is named microcytic, hypochromic anemia. The accumulation of porphyrin precursors in various enzyme defects in porphyrin synthesis can cause photosensitization of the skin. The clinical picture can vary a bit, depending on the specific intermediate. As an example, we will consider the disease porphyria cutanea tarda translated: Here, the deficient enzyme is uroporphyrinogen III decarboxylase see slide The accumulating uroporphyrinogen distributes throughout the body and becomes oxidized non-enzymatically to the non-physiological product uroporphyrin III.

In the skin, uroporphyrin III can absorb photons and then react with molecular oxygen to produce reactive oxygen species; the latter inflict the skin tissue damage that is illustrated in the slide. An important aspect of treatment is the protection of skin from direct sunlight. The absorbed wavelength range or absorption spectrum differs between the various porphyrins.

Uroporphyrin III has an absorption peak at nm, which is at the blue end of the visible spectrum; this peak is readily detectable in blood serum samples left.

The sun light is more intense in the visible range than in the UV range. Sun screen lotion, which is designed to absorb UV light but not visible light, will not prevent photosensitization by uroporphyrin III. Sporadic PCT is often associated with disturbances of iron homeostasis. In homozygous form, this gene defect causes hemochromatosis , a disease that is characterized by severe iron overload.

HFE knockout mice show increased intestinal expression and activity of iron uptake transporters. Iron overload of the liver can also occur in chronic infections and in other chronic inflammatory diseases see section Blood letting—which depletes iron—is reportedly beneficial in PCT, regardless of the cause of the iron overload. The genetic defect in acute intermittent porphyria concerns the enzyme porphobilinogen deaminase. Porphobilinogen is excreted with the urine and, through spontaneous oxidation, forms a characteristic red pigment.

The dysregulation mainly affects heme synthesis in the liver. As the name of the disease suggests, it is not always manifest but only intermittently. Heme is the prosthetic group of cytochrome P enzymes, which are important in drug metabolism and are induced in the liver by various drugs see slide It appears that ALA synthase is induced along with the cytochrome P enzymes, and AIP attacks are often triggered or aggravated by the application of such drugs.

Specific drugs that induce cytochrome P and ALA synthase include barbituric acid derivatives and carbamazepine, which were, and occasionally still are, used in the treatment of psychiatric symptoms. Fatal outcomes have occurred when AIP patients were misdiagnosed and treated with barbituric acid derivatives. Red blood cells have a regular lifespan of days although it can be considerably shorter in some diseases. At the end of this lifespan, they are captured and ingested by phagocytes in the spleen and the liver.

When the globin protein is proteolytically degraded, heme is released. Heme itself undergoes degradation mostly in the liver. Ring cleavage by heme oxygenase produces biliverdin, which is in turn reduced to bilirubin. Some bilirubin is excreted into the bile as such; however, the greater share is first conjugated with glucuronic acid by UDP-glucuronosyltransferase, form 1A1, and excreted thereafter.

The major transport protein responsible for excretion of the diglucuronide is an ABC transporter ABCC2 , the same one that also secretes bile acids see slide In the anaerobic environment that prevails inside the colon, the released bilirubin subsequently undergoes reduction, again by bacterial enzymes, to variously colored pigments that produce the stool color.

Another reduction product, urobilinogen, is taken up and excreted with the urine, causing the yellow color of the latter. Some fairly simple clues can narrow down the cause of jaundice in a given patient. If excretion of bilirubin is blocked, the pigments derived from it will be absent, and the stool will have a grayish color.

Hemolysis consists in the accelerated decay of red blood cells; it may result from biochemical causes such as glucosephosphate dehydrogenase deficiency see section 9. In hemolysis, the serum level of unconjugated bilirubin will be more strongly increased than that of the diglucuronide. On the other hand, when the flow of the bile is backed up, the conjugated bilirubin will spill back into the serum and will be increased.

Liver diseases can affect synthesis, conjugation and biliary secretion of bilirubin in various degrees, and either form of bilirubin can be more strongly increased than the other. Neonatal jaundice is a normal event that is caused by a transiently low level of UDP-glucuronosyltransferase 1A1. If the serum level of bilirubin gets too high, however, it may accumulate in the brain and cause neurological problems see next slide. To prevent this, newborns can be treated with phototherapy see slide As in many other gene defects, there are variants with total or partial disruption of enzyme activity.

When residual enzyme activity is present, it is possible to increase it with drugs such as phenobarbital that transcriptionally induce it. As in neonatal jaundice, phototherapy is also used in Crigler-Najjar syndrome, but its efficiency decreases with time, since the growth of the body reduces its surface to volume ratio, and therefore a diminishing fraction of the bilirubin in the body can be reached by illumination.

The disease is best treated with liver transplants, as the transplanted liver will not be affected by the underlying gene defect and be able to conjugate and excrete bilirubin. This slide shows a brain section from a patient with severe bilirubin encephalopathy. The yellow color in the deeper structures of the forebrain, the so-called basal ganglia , is due to bilirubin accumulation.

Through an unknown biochemical mechanism, bilirubin causes damage to the basal ganglia, which results in motor dysfunction and other neurological symptoms. In phototherapy, bilirubin absorbs photons and subsequently undergoes cis-trans isomerization across the two remaining double bonds between the pyrrole rings of the bilirubin molecule, as well as ring formation [ ].

This slide shows some of the photochemical reaction products. The 4Z,15Z isomer of bilirubin top left is the one that is produced directly by biliverdin reductase, and which is eliminated very slowly in the unconjugated form. The other isomers are eliminated more rapidly; the fastest rate of elimination is observed with lumirubin cyclobilirubin. While the absorption maximum of bilirubin is in the blue wavelength band, green light reportedly produces lumirubin more efficiently, and it also induces less cytotoxic byproducts in cell culture models [ ].

It seems, however, that blue lamps are still more widely used in practice, and the literature does not make mention of significant side effects of blue light, even in the long-term treatment of Crigler-Najjar patients [ ]. The inhibition of heme oxygenase with Sn-mesoporphyrin has been used successfully in clinical studies to treat neonatal jaundice.

The study summarized in this slide examined the effectiveness of Sn-mesoporphyrin in the treatment of newborns with glucosephosphate dehydrogenase deficiency see slide 9.

In this condition, the lifespan of red blood cells is diminished, which increases the rate of heme degradation; newborns therefore are at an increased risk of severe jaundice. Remarkably, a single injection of the drug was sufficient to reduce the peak levels of bilirubin to a greater extent than the reference treatment phototherapy.

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