Important
It is possible that the main title of the report Tyrosinemia, Hereditary is not the name you expected. Please check the synonyms listing to find the alternate name(s) and disorder subdivision(s) covered by this report.
Synonyms
Hepatorenal tyrosinemia
Hereditary tyrosinemia type 1
Fumarylacetoacetase deficiency
Congenital tyrosinosis
Disorder Subdivisions
Tyrosinemia type 1, acute form
Tyrosinemia type 1, chronic form
General Discussion
Tyrosinemia type I is a rare genetic metabolic disorder characterized by lack of the enzyme fumarylacetoacetate hydrolase (FAH), which is needed to break down the amino acid tyrosine. Failure to properly break down tyrosine leads to abnormal accumulation of tyrosine and its metabolites in the liver, potentially resulting in severe liver disease. Tyrosine may also accumulate in the kidneys and central nervous system.
Symptoms and physical findings associated with tyrosinemia type I include failure to gain weight and grow at the expected rate (failure to thrive), fever, diarrhea, vomiting, an abnormally enlarged liver (hepatomegaly), and yellowing of the skin and the whites of the eyes (jaundice). Tyrosinemia type I may progress to more serious complications such as severe liver disease. Tyrosinemia type one is inherited as an autosomal recessive trait.
Thursday, March 12, 2009
Tyrosinemia
Introduction
Background
Elevated blood tyrosine levels are associated with several clinical entities. The term tyrosinemia was first given to a clinical entity based on observations (eg, elevated blood tyrosine levels) that have proven to be common to various disorders, including transient tyrosinemia of the newborn (TTN), hereditary infantile tyrosinemia (tyrosinemia I), Richner-Hanhart syndrome (tyrosinemia II), and tyrosinemia III. In addition, a mysterious entity called tyrosinosis has been described once in the literature. This designation was chosen at a time when specific enzymatic diagnosis was unavailable, leaving a clinical description that has not been duplicated in the 50 years since its publication.
Transient tyrosinemia is believed to result from delayed enzyme maturation in the tyrosine catabolic pathway. This condition is essentially benign and spontaneously disappears with no sequelae. Transient tyrosinemia is not categorized as an inborn error of metabolism because it is not caused by a genetic mutation.
Hereditary infantile tyrosinemia, or tyrosinemia I, is a completely different disease. Patients have a peculiar (cabbagelike) odor, renal tubular dysfunction (Fanconi syndrome), and survival of less than 12 months of life if untreated. Fulminant onset of liver failure occurs in the first few months of life. Some patients have a later onset, usually before age 6 months, with a somewhat protracted course.
For many years, the diagnosis was based on the observation that plasma tyrosine and methionine levels were significantly elevated. Postmortem examination revealed that both the liver and the kidney had a highly unusual pattern of nodular cirrhosis, the histopathologic hallmark of the disease. In the early 1970s, researchers discovered that most severe liver diseases caused such findings regardless of etiology, and, in the late 1970s, the biochemical and enzymatic causes of the disease were reported.
Tyrosinemia II is a disease with a clinical presentation distinctly different from that described above. This presentation includes herpetiform corneal ulcers and hyperkeratotic lesions of the digits, palms, and soles, as well as mental retardation. The biochemical and enzymatic basis for the disease bears no relationship to that of tyrosinemia I, and tyrosinemia II is not discussed further in this article.
Tyrosinemia III is an extremely rare cause of intermittent ataxia, without hepatorenal involvement or skin lesions, and is also not discussed further in this article.
Pathophysiology
The biochemical basis for tyrosinemia I remained enigmatic until the late 1970s, when researchers described a compound called succinylacetone found in the urine of infants with the condition. Succinylacetone was ultimately determined to be the decarboxylation product of succinyl acetoacetate, a compound derived from the tyrosine catabolic intermediate fumarylacetoacetate. Investigators inferred that the enzymatic defect might reside in deficiency of fumarylacetoacetase, which mediates production of fumaric acid and acetoacetate. This inference was later proven correct; succinyl acetoacetate accumulated because of this defect. Decarboxylation produced succinylacetone, which was then excreted in the urine.
Although many aspects of the biochemical toxicity of this compound are known, the cellular basis for the multiorgan dysfunction found at the clinical level is unclear. In the kidney, succinylacetone has been demonstrated to be a mitochondrial toxin that inhibits substrate-level phosphorylation by means of the Krebs cycle. This compound also causes dysfunction of membrane transport in normal rat kidneys, altering membrane fluidity and possibly disrupting normal structure. It can cause renal tubular dysfunction in normal rat kidneys, mimicking human Fanconi syndrome, for which no other animal model is available. Beyond its effects on the kidney, succinylacetone is a potent inhibitor of δ-aminolevulinic acid dehydratase, the enzyme that mediates formation of porphobilinogen, the cyclic precursor of porphyrins in the heme biosynthetic sequence. Succinylacetone-related alterations in heme biosynthesis of normal rat liver and kidney have been demonstrated.
Recent data have suggested that fumarylacetoacetate itself induces mitotic abnormalities and instability in the genome.1 Research in murine animal models has indicated that this metabolite initiates apoptosis of hepatic and renal tubular cells. Taken together, these data form the basis for a unifying hypothesis regarding the development of hepatocellular carcinoma in children with hereditary tyrosinemia.
The effective therapeutic use of 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione (NTBC) in tyrosinemia does not normalize hepatic collagen metabolism, leaving the already fibrosed liver vulnerable to further structural damage. However, data regarding the hepatic response to NTBC are conflicting.
One group reported reversibility of cirrhotic nodules in a patient receiving NTBC treatment, whereas another group reported that the drug did little to suppress gene expression of other genes responsible for ongoing hepatic damage in a murine model. Longer-term experience with NTBC has provided more encouraging results, suggesting that children with the disease who receive NTBC prior to age 2 years of age have less than a 5% risk of developing hepatocarcinoma. In addition, corneal opacities due to deposition of tyrosine crystals in the tissues caused by long-term treatment with NTBC have been reported. Tyrosine levels rise because of the enzymatic block created in the p -hydroxyphenylpyruvic acid dioxygenase. A tendency for precipitation is noted because tyrosine is relatively insoluble compared with other amino acids. The potential long-term effects of precipitation in tissues other than the cornea remain unknown.
In patients with tyrosinemia who have undergone orthoptic liver transplantation, urinary excretion of succinylacetone dramatically decreases, although excretion generally persists at levels lower than those observed before transplantation. This persistence can be attributed to ongoing production of the compound by kidneys, which remain genetically affected by the enzyme defect. The generalized toxic effect on mitochondria, membranes, and heme biosynthesis can logically be assumed to be at the root of the pathologic observations of nodular cirrhosis.
Increased urinary excretion of δ-aminolevulinic acid can be attributed to inhibition of the heme biosynthetic pathway. A similar mechanism can account for the seizures commonly observed in patients; this mechanism is based on the demonstration of fumarylacetoacetase in the normal human brain. Genetic absence of the enzyme could then be assumed to induce cellular accumulation of succinylacetone and to facilitate its toxic effects on the neuron.
Frequency
United States
The estimated incidence is 1 case per 100,000 live births.
International
In some areas of North America, notably a region of Quebec province, the incidence is extraordinarily high, and the estimated incidence of carriers of a specific mutation is 1 in 14 adults.
Mortality/Morbidity
Affected infants often have a fulminant onset, with a rapid development of hepatic cirrhosis and failure.
The onset of hepatic failure places the infant at risk for a serious coagulopathy. Survivors of the neonatal episode are at significant risk of hepatocellular carcinoma.
In one series in which combined medical and surgical techniques were used, the mortality rate was reduced to less than 15%.
Sex
Tyrosinemia I is an autosomal recessive disorder; therefore, the sex distribution is equal.
The severity of onset and the subsequent course does not differ between the sexes.
Age
The disease is present from conception because it is caused by genetic mutation.
Most infants present within the first 2-3 months of life; far fewer infants present later with a chronic form, which frequently manifests initially as rickets and slowly developing hepatic cirrhosis.
Clinical
History
Failure to thrive may precede the appearance of more dramatic findings. Patients with such findings often have a history of diminished nutritional intake and anorexia.
The patient then develops vomiting and diarrhea, which rapidly progress to bloody stool, lethargy, and jaundice. At this stage, a distinctive cabbagelike odor may be appreciated.
At approximately age 1 year, infants with the chronic form may have failure to thrive and delayed walking, which may indicate rickets.
Because the disease is autosomal recessive, the family pedigree typically does not reveal previously affected individuals. However, a French-Canadian ancestry should raise suspicion because of the extraordinarily high incidence of heterozygotes in the adult population of this lineage.
Physical
Clinical suspicion should be extremely high in infants with failure to thrive and hepatomegaly in the first 3 months of life.
The acute onset may be dramatic, with hepatomegaly, jaundice, epistaxis, melena, purpuric lesions, marked edema, and the distinctive cabbagelike odor.
Because of the inhibitory effects of succinylacetone on the heme biosynthetic pathway, infants with the chronic form may develop polyneuropathy and painful abdominal crises, as seen in acute intermittent porphyria.
Survivors may have hepatic nodules and cirrhosis; the nodules may indicate hepatocellular carcinoma. Distant metastases can occur.
Causes
The sole explanation for tyrosinemia I is genetic mutation in homozygous form. Heterozygote individuals are entirely unaffected. The gene is mapped to band 15q23-q25, and approximately 30 distinct mutations have been reported, with no clear relationship between genotype and phenotype.
Background
Elevated blood tyrosine levels are associated with several clinical entities. The term tyrosinemia was first given to a clinical entity based on observations (eg, elevated blood tyrosine levels) that have proven to be common to various disorders, including transient tyrosinemia of the newborn (TTN), hereditary infantile tyrosinemia (tyrosinemia I), Richner-Hanhart syndrome (tyrosinemia II), and tyrosinemia III. In addition, a mysterious entity called tyrosinosis has been described once in the literature. This designation was chosen at a time when specific enzymatic diagnosis was unavailable, leaving a clinical description that has not been duplicated in the 50 years since its publication.
Transient tyrosinemia is believed to result from delayed enzyme maturation in the tyrosine catabolic pathway. This condition is essentially benign and spontaneously disappears with no sequelae. Transient tyrosinemia is not categorized as an inborn error of metabolism because it is not caused by a genetic mutation.
Hereditary infantile tyrosinemia, or tyrosinemia I, is a completely different disease. Patients have a peculiar (cabbagelike) odor, renal tubular dysfunction (Fanconi syndrome), and survival of less than 12 months of life if untreated. Fulminant onset of liver failure occurs in the first few months of life. Some patients have a later onset, usually before age 6 months, with a somewhat protracted course.
For many years, the diagnosis was based on the observation that plasma tyrosine and methionine levels were significantly elevated. Postmortem examination revealed that both the liver and the kidney had a highly unusual pattern of nodular cirrhosis, the histopathologic hallmark of the disease. In the early 1970s, researchers discovered that most severe liver diseases caused such findings regardless of etiology, and, in the late 1970s, the biochemical and enzymatic causes of the disease were reported.
Tyrosinemia II is a disease with a clinical presentation distinctly different from that described above. This presentation includes herpetiform corneal ulcers and hyperkeratotic lesions of the digits, palms, and soles, as well as mental retardation. The biochemical and enzymatic basis for the disease bears no relationship to that of tyrosinemia I, and tyrosinemia II is not discussed further in this article.
Tyrosinemia III is an extremely rare cause of intermittent ataxia, without hepatorenal involvement or skin lesions, and is also not discussed further in this article.
Pathophysiology
The biochemical basis for tyrosinemia I remained enigmatic until the late 1970s, when researchers described a compound called succinylacetone found in the urine of infants with the condition. Succinylacetone was ultimately determined to be the decarboxylation product of succinyl acetoacetate, a compound derived from the tyrosine catabolic intermediate fumarylacetoacetate. Investigators inferred that the enzymatic defect might reside in deficiency of fumarylacetoacetase, which mediates production of fumaric acid and acetoacetate. This inference was later proven correct; succinyl acetoacetate accumulated because of this defect. Decarboxylation produced succinylacetone, which was then excreted in the urine.
Although many aspects of the biochemical toxicity of this compound are known, the cellular basis for the multiorgan dysfunction found at the clinical level is unclear. In the kidney, succinylacetone has been demonstrated to be a mitochondrial toxin that inhibits substrate-level phosphorylation by means of the Krebs cycle. This compound also causes dysfunction of membrane transport in normal rat kidneys, altering membrane fluidity and possibly disrupting normal structure. It can cause renal tubular dysfunction in normal rat kidneys, mimicking human Fanconi syndrome, for which no other animal model is available. Beyond its effects on the kidney, succinylacetone is a potent inhibitor of δ-aminolevulinic acid dehydratase, the enzyme that mediates formation of porphobilinogen, the cyclic precursor of porphyrins in the heme biosynthetic sequence. Succinylacetone-related alterations in heme biosynthesis of normal rat liver and kidney have been demonstrated.
Recent data have suggested that fumarylacetoacetate itself induces mitotic abnormalities and instability in the genome.1 Research in murine animal models has indicated that this metabolite initiates apoptosis of hepatic and renal tubular cells. Taken together, these data form the basis for a unifying hypothesis regarding the development of hepatocellular carcinoma in children with hereditary tyrosinemia.
The effective therapeutic use of 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione (NTBC) in tyrosinemia does not normalize hepatic collagen metabolism, leaving the already fibrosed liver vulnerable to further structural damage. However, data regarding the hepatic response to NTBC are conflicting.
One group reported reversibility of cirrhotic nodules in a patient receiving NTBC treatment, whereas another group reported that the drug did little to suppress gene expression of other genes responsible for ongoing hepatic damage in a murine model. Longer-term experience with NTBC has provided more encouraging results, suggesting that children with the disease who receive NTBC prior to age 2 years of age have less than a 5% risk of developing hepatocarcinoma. In addition, corneal opacities due to deposition of tyrosine crystals in the tissues caused by long-term treatment with NTBC have been reported. Tyrosine levels rise because of the enzymatic block created in the p -hydroxyphenylpyruvic acid dioxygenase. A tendency for precipitation is noted because tyrosine is relatively insoluble compared with other amino acids. The potential long-term effects of precipitation in tissues other than the cornea remain unknown.
In patients with tyrosinemia who have undergone orthoptic liver transplantation, urinary excretion of succinylacetone dramatically decreases, although excretion generally persists at levels lower than those observed before transplantation. This persistence can be attributed to ongoing production of the compound by kidneys, which remain genetically affected by the enzyme defect. The generalized toxic effect on mitochondria, membranes, and heme biosynthesis can logically be assumed to be at the root of the pathologic observations of nodular cirrhosis.
Increased urinary excretion of δ-aminolevulinic acid can be attributed to inhibition of the heme biosynthetic pathway. A similar mechanism can account for the seizures commonly observed in patients; this mechanism is based on the demonstration of fumarylacetoacetase in the normal human brain. Genetic absence of the enzyme could then be assumed to induce cellular accumulation of succinylacetone and to facilitate its toxic effects on the neuron.
Frequency
United States
The estimated incidence is 1 case per 100,000 live births.
International
In some areas of North America, notably a region of Quebec province, the incidence is extraordinarily high, and the estimated incidence of carriers of a specific mutation is 1 in 14 adults.
Mortality/Morbidity
Affected infants often have a fulminant onset, with a rapid development of hepatic cirrhosis and failure.
The onset of hepatic failure places the infant at risk for a serious coagulopathy. Survivors of the neonatal episode are at significant risk of hepatocellular carcinoma.
In one series in which combined medical and surgical techniques were used, the mortality rate was reduced to less than 15%.
Sex
Tyrosinemia I is an autosomal recessive disorder; therefore, the sex distribution is equal.
The severity of onset and the subsequent course does not differ between the sexes.
Age
The disease is present from conception because it is caused by genetic mutation.
Most infants present within the first 2-3 months of life; far fewer infants present later with a chronic form, which frequently manifests initially as rickets and slowly developing hepatic cirrhosis.
Clinical
History
Failure to thrive may precede the appearance of more dramatic findings. Patients with such findings often have a history of diminished nutritional intake and anorexia.
The patient then develops vomiting and diarrhea, which rapidly progress to bloody stool, lethargy, and jaundice. At this stage, a distinctive cabbagelike odor may be appreciated.
At approximately age 1 year, infants with the chronic form may have failure to thrive and delayed walking, which may indicate rickets.
Because the disease is autosomal recessive, the family pedigree typically does not reveal previously affected individuals. However, a French-Canadian ancestry should raise suspicion because of the extraordinarily high incidence of heterozygotes in the adult population of this lineage.
Physical
Clinical suspicion should be extremely high in infants with failure to thrive and hepatomegaly in the first 3 months of life.
The acute onset may be dramatic, with hepatomegaly, jaundice, epistaxis, melena, purpuric lesions, marked edema, and the distinctive cabbagelike odor.
Because of the inhibitory effects of succinylacetone on the heme biosynthetic pathway, infants with the chronic form may develop polyneuropathy and painful abdominal crises, as seen in acute intermittent porphyria.
Survivors may have hepatic nodules and cirrhosis; the nodules may indicate hepatocellular carcinoma. Distant metastases can occur.
Causes
The sole explanation for tyrosinemia I is genetic mutation in homozygous form. Heterozygote individuals are entirely unaffected. The gene is mapped to band 15q23-q25, and approximately 30 distinct mutations have been reported, with no clear relationship between genotype and phenotype.
Hereditary Tyrosinemia Type I；HT-1
Preface:
Tyrosine is a non-essential amino acids the human body, the main sources include dietary intake and phenylalanine (phenylalanine) generated by metabolic intermediate product. When elevated plasma tyrosine may be referred to as high Tyrosinemia (hypertyrosinaemia; tyrosinaemia), its causes are likely to originate in the primary metabolic error, or by other causes of liver disease caused by cause. However because of high Tyrosinemia cause liver damage, but also much of the liver caused by continued high hair Tyrosinemia, the distinction between the two is not easy.
The basis of past studies indicate that high Tyrosinemia-related enzymes have at least three ways: tyrosine amino transferase (tyrosine aminotrasferase; TAT), ρ-hydroxy - phenyl - Coke grape acid oxidase (ρ - hydroxyphenylpyruvate dioxygenase; 4HPPD) and yanhusuo acetoacetic acid amide hydrolase (fumarylacetoacetate hydrolase; FAH), which, TAT will be the lack of eyes and skin caused by high Tyrosinemia, called Tyrosinemia type II ( Tyrosinaemia type II), also known as Richner-Hanhart syndrome (Richner-Hanhart syndrome), the main features of the soles of his feet to the palm of your hand horny albino disease (palmoplantar keratosis). 4HPPD will have much of a lack of abnormal metabolic products, including ρ-hydroxy - phenyl - coke gluconic acid, ρ-hydroxy - phenyl - Coke lactic acid and ρ-hydroxy - phenyl - acetate coke, which is also known as the tyrosine hypercalciuria. The lack of FAH can cause liver and kidney lesions, called Tyrosinemia type I (Tyrosinaemia type I), also known as tyrosine disease (tyrosinosis), can be divided into two types of acute and chronic, is the the focus of articles.
Premature babies are often temporary Tyrosinemia (Trainsient neonatal tyrosinaemia), occasionally longer in full-term newborns can also be seen. This is probably the outstanding 4HPPD neonatal or temporary lack of sophisticated, high volume of phenylalanine and tyrosine intake, or caused by a lack of vitamin C. Such defects as babies grow, 4HPPD increasingly sophisticated and improved, taking vitamin C can also be passed and quickly corrected.
Etiology:
Hereditary Tyrosinemia type I is mainly due to caused by the lack of FAH. Tyrosine metabolism in the whole into fumarate (fumarate) and acetoacetic acid (acetoacetate) a total of five by the enzyme-catalyzed reaction steps:
A. formed by transglutaminase ρ-hydroxyphenyl pyruvic acid (ρ-hydroxyphenylpyruvate).
B. three carbon containing branched-chain oxidation and simultaneously transfer and decarboxylation and the formation of uric acid (homogentisate).
C. will be oxidized into uric acid and maleic acid amide alone acetoacetic acid (maleylacetoacetate).
D. will be maleic acid acetoacetic acid amide single line into the role of heterogeneous yanhusuo acetoacetic acid amide (fumarylacetoacetate).
E. will yanhusuo acetoacetic acid amide hydrolase into yanhusuo acid and acetoacetic acid.
FAH participated in the fifth reaction. When the lack of FAH, the entire tyrosine metabolism will be hindered, making yanhusuo acetoacetic acid amide will be substantial accumulation of single-amide maleic acid acetoacetic acid may also be affected by the cumulative in the body, resulting in liver and kidney damage. These metabolites will be to restore (reduce) and go carboxylation (decarboxylate) into amber acetone (succinylacetone; SA), and gathered in the patient's plasma and urine. Therefore, the examination of patients in vivo SA concentration, the diagnosis can be used as high an important basis for Tyrosinemia. In addition, because of metabolism of the suspension may also be caused by ρ-hydroxyphenyl pyruvic acid and its derivatives accumulated in the body.
Genetic model:
Currently known human FAH gene is located in the first 15 pairs of chromosomes on the long arm (15q23-q25), belong to autosomal recessive genetic. Liver cells of patients with DNA sequence sequencing analysis showed that 34 gene mutation point and the lack of FAH.
Classification (type):
1. Acute high Tyrosinemia:
This situation will have a baby for rapid and fulminant course, if it is not treated in time, patients will be dead quickly. Attack is usually at 1-6 months old when the sick are often loss of appetite, vomiting, diarrhea, abdominal distension and symptoms of low blood sugar, etc., and may cause growth retardation, anxiety, fever and hepatomegaly phenomenon, at the same time there will be melena, hematemesis, hematuria, and the performance of congestion, such as hemolysis, and then lead to renal tubular dysfunction (renal tubular dysfunction). Happen because of liver disease, the sick began to emerge rickets (rickets), symptoms such as hepatosplenomegaly. Some patients have neurological diseases and low-tension phenomenon. These neurological diseases may be accompanied by more serious complications, such as sometimes similar to acute intermittent porphyria pyrrole alveolar (acute intermittent porphyria) of symptoms, nerve lesions caused by muscle weakness disease and high blood pressure. As the disease intensifies, jaundice, edema, abdominal effusion, lethargy, coma, liver failure and even death of such a phenomenon will happen.
2. Chronic Tyrosinemia:
The majority of chronic high Tyrosinemia in One of the children after the age of only developed symptoms. Growth retardation, gastrointestinal symptoms, sexual cirrhosis, multiple renal defects and rickets are clinical performance. Early in the disease may only be elevated tyrosine, while the later will show methionine (methionine) increased. Usually before the age of 10 at death, autopsies often visible liver tumor.
Diagnosis:
1. Antenatal check-up:
(1) such as the parents are known to cause high Tyrosinemia point mutations may be the amniotic fluid cells smoking pregnant women to carry out the analysis of point mutations.
(2) can also detect the concentration of SA in amniotic fluid to see if too high.
(3) pregnant women to take the chorionic or amniotic fluid cells, to cultivate proliferation. To be charged after a certain number of cells, measuring the activity of FAH cells to see if there is a lack of FAH phenomenon.
2. Blood tests:
Tyrosinemia is currently the most high credibility test are quantitative blood and urine of SA and its pre-chemokine concentration. Although the sensitivity of this approach, but there is still a small number of patients with low concentrations of SA at this time, it is necessary to detect the FAH activity in cultured cells as a secondary diagnosis. By the impact of genetic variability, a healthy individual cultured cells may also appear low activity FAH phenomenon. Similarly, the patient's liver samples may also be because cell culture gene back when (reversed) case, which was highly active in the illusion of FAH. Therefore, FAH enzyme activity as a diagnostic test only when the reference, not only as a diagnostic credentials.
In addition to the concentration of SA can be used as high Tyrosinemia diagnostic tools, some biochemical aspects of detection may also apply to patients in general. For example: the concentration of serum tyrosine will increase, but the concentration of methionine was not significantly improved. Urine ρ-hydroxy - phenyl - coke gluconic acid, ρ-hydroxy - phenyl - Coke lactic acid and ρ-hydroxy - phenyl - acetate concentration of coke will improve. When renal tubular damage, the Labor Department will show Fanconi Syndrome (Fanconi syndrome), which means in the urine has high levels of amino acids, glucose and phosphate. When the liver cell damage, and affect the generation of protein will also be some variety of chemical and biological performance, can be used as a basis for diagnosis. For example: vitamin K-dependent coagulation factors in acute illness is very high concentrations, while the chronic patients the concentration of the body is not normal. Vis-à-vis other liver enzyme activity, the patients in vivo γ-Glutamyltransferase activity will improve. α-fetoprotein concentrations in vivo in acute patients has increased significantly, but in chronic patients showed normal concentrations.
Treatment:
1.NTBC treatment (NTBC treament):
NTBC (2 - (2-nitro-4-trifluoro-methylbenzoyl) -1,3-cyclo-hexanedione) are good 4HPPD inhibitor, can block ρ-hydroxyphenyl pyruvic acid into uric acid and reduce the emergence of SA , is the latest for the treatment of high Tyrosinemia method. According to the report show: sick every day at oral 0.6 mg / kg NTBC, apart from a ρ-hydroxyphenyl pyruvic acid and tyrosine concentrations will increase, other biochemical abnormalities will become normal, and clinical symptoms will be dramatically improved. NTBC can also be used for treatment of this and similar neurological pyrrole rhodopsin alveolar symptoms. Because of the concentration of tyrosine due to the use of NTBC to increase, therefore, diet control are necessary.
Long-term use of the NTBC study has been discussed, especially with NTBC the incidence of liver cancer among relevance, the current can not be determined. The sooner the use of NTBC, the serious anomaly appears more difficult. So far, NTBC No side effects were reported.
2. Liver transplant (Liver Transplantation):
Handling stolen goods in liver transplant to treat the first type of high Tyrosinemia about 10 years of development time, because this type of patients will have severe liver damage, so when the recipient can have the provider of the liver the normal performance of the enzyme missing the phenomenon of patients will be improved, blood and urine in abnormal metabolites will disappear. Access to liver transplant patients can be normal after the diet, does not require special control of tyrosine and phenylalanine intake. In spite of this, the patient urine concentrations of SA and there will still be increased, presumably because of the problem caused by the kidneys. Liver transplant kidneys after long-term prognosis remains unclear.
3. Diet (Dietary treament):
Diet control are the first for the treatment of high Tyrosinemia method, the concept is to limit the tyrosine and phenylalanine intake so low that only the body can grow normally required. This food must come from a special formula, mainly the use of protein hydrolysates or without tyrosine and phenylalanine of the amino acid mixture, then add very small amounts of natural protein to supplement the appropriate tyrosine and phenylalanine. When a patient separately on tyrosine and phenylalanine intake daily to maintain at 15-20 mg / kg, the in vivo concentration of SA would be difficult to be detected. With diet control, due to renal tubular dysfunction resulting symptoms almost completely revert back to normal. However, liver diseases and malignant tumors can not take this to have access to treatment and prevention, so when the liver tumor severely damaged or elections, such as needed by other methods such as the liver transplant to improve conditions.
4. Supportive treatment (Supportive treament):
For patients with acute disease, the supportive treatment is necessary. Patients often lack the potassium ions and phosphate, therefore, necessary to add the right amount of timely. In addition, coagulation factors, calcium, albumin, phosphate, electrolytes and acid-base balance are required under close monitoring and correction. When patients in the acute attack, the tyrosine and phenylalanine intake must be reduced to at least as far as possible. Increase in vitamin D can be used to treat rickets; patients if there is infection, infection control and immediately required to be addressed.
Tyrosine is a non-essential amino acids the human body, the main sources include dietary intake and phenylalanine (phenylalanine) generated by metabolic intermediate product. When elevated plasma tyrosine may be referred to as high Tyrosinemia (hypertyrosinaemia; tyrosinaemia), its causes are likely to originate in the primary metabolic error, or by other causes of liver disease caused by cause. However because of high Tyrosinemia cause liver damage, but also much of the liver caused by continued high hair Tyrosinemia, the distinction between the two is not easy.
The basis of past studies indicate that high Tyrosinemia-related enzymes have at least three ways: tyrosine amino transferase (tyrosine aminotrasferase; TAT), ρ-hydroxy - phenyl - Coke grape acid oxidase (ρ - hydroxyphenylpyruvate dioxygenase; 4HPPD) and yanhusuo acetoacetic acid amide hydrolase (fumarylacetoacetate hydrolase; FAH), which, TAT will be the lack of eyes and skin caused by high Tyrosinemia, called Tyrosinemia type II ( Tyrosinaemia type II), also known as Richner-Hanhart syndrome (Richner-Hanhart syndrome), the main features of the soles of his feet to the palm of your hand horny albino disease (palmoplantar keratosis). 4HPPD will have much of a lack of abnormal metabolic products, including ρ-hydroxy - phenyl - coke gluconic acid, ρ-hydroxy - phenyl - Coke lactic acid and ρ-hydroxy - phenyl - acetate coke, which is also known as the tyrosine hypercalciuria. The lack of FAH can cause liver and kidney lesions, called Tyrosinemia type I (Tyrosinaemia type I), also known as tyrosine disease (tyrosinosis), can be divided into two types of acute and chronic, is the the focus of articles.
Premature babies are often temporary Tyrosinemia (Trainsient neonatal tyrosinaemia), occasionally longer in full-term newborns can also be seen. This is probably the outstanding 4HPPD neonatal or temporary lack of sophisticated, high volume of phenylalanine and tyrosine intake, or caused by a lack of vitamin C. Such defects as babies grow, 4HPPD increasingly sophisticated and improved, taking vitamin C can also be passed and quickly corrected.
Etiology:
Hereditary Tyrosinemia type I is mainly due to caused by the lack of FAH. Tyrosine metabolism in the whole into fumarate (fumarate) and acetoacetic acid (acetoacetate) a total of five by the enzyme-catalyzed reaction steps:
A. formed by transglutaminase ρ-hydroxyphenyl pyruvic acid (ρ-hydroxyphenylpyruvate).
B. three carbon containing branched-chain oxidation and simultaneously transfer and decarboxylation and the formation of uric acid (homogentisate).
C. will be oxidized into uric acid and maleic acid amide alone acetoacetic acid (maleylacetoacetate).
D. will be maleic acid acetoacetic acid amide single line into the role of heterogeneous yanhusuo acetoacetic acid amide (fumarylacetoacetate).
E. will yanhusuo acetoacetic acid amide hydrolase into yanhusuo acid and acetoacetic acid.
FAH participated in the fifth reaction. When the lack of FAH, the entire tyrosine metabolism will be hindered, making yanhusuo acetoacetic acid amide will be substantial accumulation of single-amide maleic acid acetoacetic acid may also be affected by the cumulative in the body, resulting in liver and kidney damage. These metabolites will be to restore (reduce) and go carboxylation (decarboxylate) into amber acetone (succinylacetone; SA), and gathered in the patient's plasma and urine. Therefore, the examination of patients in vivo SA concentration, the diagnosis can be used as high an important basis for Tyrosinemia. In addition, because of metabolism of the suspension may also be caused by ρ-hydroxyphenyl pyruvic acid and its derivatives accumulated in the body.
Genetic model:
Currently known human FAH gene is located in the first 15 pairs of chromosomes on the long arm (15q23-q25), belong to autosomal recessive genetic. Liver cells of patients with DNA sequence sequencing analysis showed that 34 gene mutation point and the lack of FAH.
Classification (type):
1. Acute high Tyrosinemia:
This situation will have a baby for rapid and fulminant course, if it is not treated in time, patients will be dead quickly. Attack is usually at 1-6 months old when the sick are often loss of appetite, vomiting, diarrhea, abdominal distension and symptoms of low blood sugar, etc., and may cause growth retardation, anxiety, fever and hepatomegaly phenomenon, at the same time there will be melena, hematemesis, hematuria, and the performance of congestion, such as hemolysis, and then lead to renal tubular dysfunction (renal tubular dysfunction). Happen because of liver disease, the sick began to emerge rickets (rickets), symptoms such as hepatosplenomegaly. Some patients have neurological diseases and low-tension phenomenon. These neurological diseases may be accompanied by more serious complications, such as sometimes similar to acute intermittent porphyria pyrrole alveolar (acute intermittent porphyria) of symptoms, nerve lesions caused by muscle weakness disease and high blood pressure. As the disease intensifies, jaundice, edema, abdominal effusion, lethargy, coma, liver failure and even death of such a phenomenon will happen.
2. Chronic Tyrosinemia:
The majority of chronic high Tyrosinemia in One of the children after the age of only developed symptoms. Growth retardation, gastrointestinal symptoms, sexual cirrhosis, multiple renal defects and rickets are clinical performance. Early in the disease may only be elevated tyrosine, while the later will show methionine (methionine) increased. Usually before the age of 10 at death, autopsies often visible liver tumor.
Diagnosis:
1. Antenatal check-up:
(1) such as the parents are known to cause high Tyrosinemia point mutations may be the amniotic fluid cells smoking pregnant women to carry out the analysis of point mutations.
(2) can also detect the concentration of SA in amniotic fluid to see if too high.
(3) pregnant women to take the chorionic or amniotic fluid cells, to cultivate proliferation. To be charged after a certain number of cells, measuring the activity of FAH cells to see if there is a lack of FAH phenomenon.
2. Blood tests:
Tyrosinemia is currently the most high credibility test are quantitative blood and urine of SA and its pre-chemokine concentration. Although the sensitivity of this approach, but there is still a small number of patients with low concentrations of SA at this time, it is necessary to detect the FAH activity in cultured cells as a secondary diagnosis. By the impact of genetic variability, a healthy individual cultured cells may also appear low activity FAH phenomenon. Similarly, the patient's liver samples may also be because cell culture gene back when (reversed) case, which was highly active in the illusion of FAH. Therefore, FAH enzyme activity as a diagnostic test only when the reference, not only as a diagnostic credentials.
In addition to the concentration of SA can be used as high Tyrosinemia diagnostic tools, some biochemical aspects of detection may also apply to patients in general. For example: the concentration of serum tyrosine will increase, but the concentration of methionine was not significantly improved. Urine ρ-hydroxy - phenyl - coke gluconic acid, ρ-hydroxy - phenyl - Coke lactic acid and ρ-hydroxy - phenyl - acetate concentration of coke will improve. When renal tubular damage, the Labor Department will show Fanconi Syndrome (Fanconi syndrome), which means in the urine has high levels of amino acids, glucose and phosphate. When the liver cell damage, and affect the generation of protein will also be some variety of chemical and biological performance, can be used as a basis for diagnosis. For example: vitamin K-dependent coagulation factors in acute illness is very high concentrations, while the chronic patients the concentration of the body is not normal. Vis-à-vis other liver enzyme activity, the patients in vivo γ-Glutamyltransferase activity will improve. α-fetoprotein concentrations in vivo in acute patients has increased significantly, but in chronic patients showed normal concentrations.
Treatment:
1.NTBC treatment (NTBC treament):
NTBC (2 - (2-nitro-4-trifluoro-methylbenzoyl) -1,3-cyclo-hexanedione) are good 4HPPD inhibitor, can block ρ-hydroxyphenyl pyruvic acid into uric acid and reduce the emergence of SA , is the latest for the treatment of high Tyrosinemia method. According to the report show: sick every day at oral 0.6 mg / kg NTBC, apart from a ρ-hydroxyphenyl pyruvic acid and tyrosine concentrations will increase, other biochemical abnormalities will become normal, and clinical symptoms will be dramatically improved. NTBC can also be used for treatment of this and similar neurological pyrrole rhodopsin alveolar symptoms. Because of the concentration of tyrosine due to the use of NTBC to increase, therefore, diet control are necessary.
Long-term use of the NTBC study has been discussed, especially with NTBC the incidence of liver cancer among relevance, the current can not be determined. The sooner the use of NTBC, the serious anomaly appears more difficult. So far, NTBC No side effects were reported.
2. Liver transplant (Liver Transplantation):
Handling stolen goods in liver transplant to treat the first type of high Tyrosinemia about 10 years of development time, because this type of patients will have severe liver damage, so when the recipient can have the provider of the liver the normal performance of the enzyme missing the phenomenon of patients will be improved, blood and urine in abnormal metabolites will disappear. Access to liver transplant patients can be normal after the diet, does not require special control of tyrosine and phenylalanine intake. In spite of this, the patient urine concentrations of SA and there will still be increased, presumably because of the problem caused by the kidneys. Liver transplant kidneys after long-term prognosis remains unclear.
3. Diet (Dietary treament):
Diet control are the first for the treatment of high Tyrosinemia method, the concept is to limit the tyrosine and phenylalanine intake so low that only the body can grow normally required. This food must come from a special formula, mainly the use of protein hydrolysates or without tyrosine and phenylalanine of the amino acid mixture, then add very small amounts of natural protein to supplement the appropriate tyrosine and phenylalanine. When a patient separately on tyrosine and phenylalanine intake daily to maintain at 15-20 mg / kg, the in vivo concentration of SA would be difficult to be detected. With diet control, due to renal tubular dysfunction resulting symptoms almost completely revert back to normal. However, liver diseases and malignant tumors can not take this to have access to treatment and prevention, so when the liver tumor severely damaged or elections, such as needed by other methods such as the liver transplant to improve conditions.
4. Supportive treatment (Supportive treament):
For patients with acute disease, the supportive treatment is necessary. Patients often lack the potassium ions and phosphate, therefore, necessary to add the right amount of timely. In addition, coagulation factors, calcium, albumin, phosphate, electrolytes and acid-base balance are required under close monitoring and correction. When patients in the acute attack, the tyrosine and phenylalanine intake must be reduced to at least as far as possible. Increase in vitamin D can be used to treat rickets; patients if there is infection, infection control and immediately required to be addressed.
Hereditary tyrosinemia
Tyrosine (Tyrosine) are a non-essential amino acids the human body, mainly from the dietary intake and phenylalanine (phenylalanine) metabolism. Caused by elevated plasma tyrosine may come from a number of diseases, including: the transient neonatal Tyrosinemia (Transient tyrosinemia of the newborn, TTN), hereditary Tyrosinemia Type I ( Hereditary tyrosinemia I), Tyrosinemia type II (tyrosinemia II; also known as Richner-Hanhart syndrome), Tyrosinemia type III (tyrosinemia III). Neonatal Tyrosinemia is temporary because of tyrosine metabolism caused by the enzyme is not yet mature enough, most of them occurred in premature infants, who will be with sophisticated enzymes has been improved, there will be no sequels. Tyrosinemia Type I and II clinical completely different type of patients have liver and kidney area of the main lesion; of patients with type II have toes, palms, soles of the feet over horny situation, will there is intellectual problem.
Tyrosinemia type I is mainly due to yanhusuo acetoacetic acid amide hydrolase enzymes (fumarylacetoacetate hydrolyase, FAH) caused by the lack of. FAH makes the lack of tyrosine metabolism have been hampered, leading to acetoacetic acid amide fumarate (fumarylacetoacetate) accumulation, can not be converted into fumarate (fumarate) and acetoacetic acid (acetoacetate). Substantial accumulation of acetoacetic acid amide fumarate into succinate acyl acetone (succinylacetone; SA), exist in the patient's plasma and urine. SA caused by the accumulation of liver injury; will inhibit omega-aminolevulinic acid (omega-ALA) hydrolase role, with the sort of acute porphyria (acute intermittent porphyria) of neurological symptoms.
Genetic model
Currently known human FAH gene is located in the first 15 pairs of chromosomes on the long arm (15q23-q25), belong to autosomal recessive genetic. Liver cells of patients with DNA sequence sequencing analysis showed that 34 gene mutation point and the lack of FAH. Tyrosinemia in the Americas and Europe to the incidence rate of one hundred thousandth 1/120000. Quebec, Canada and Norway, Finland, the incidence of higher, Quebec, the highest incidence of 1/1846, Norway and Finland for 1/60000.
Symptoms
Acute Tyrosinemia:
This situation will have a baby for rapid and fulminant course, if it is not treated in time, patients will be dead quickly. Usually a few weeks after birth to 6 months time attack, patients often have poor appetite, vomiting, diarrhea, abdominal distension and low blood sugar symptoms such as jaundice and ascites, who have a similar taste of cabbage; and may cause growth retardation, anxiety, fever and hepatomegaly phenomenon, at the same time there will be melena, hematemesis, hematuria, and the performance of congestion, such as hemolysis, and then lead to renal tubular dysfunction (renal tubular dysfunction), secondary rickets (rickets), liver symptoms such as splenomegaly. Some patients have neurological diseases and low-tension phenomenon. These neurological diseases may be accompanied by more serious complications, such as sometimes similar to acute intermittent? Pyronaridine alveolar rhodopsin (acute intermittent porphyria) of symptoms, nerve lesions caused by muscle weakness disease and high blood pressure. As the disease intensifies, jaundice, edema, abdominal effusion, lethargy, coma, liver failure and even death of such a phenomenon will happen.
Chronic Tyrosinemia:
Tyrosinemia with acute symptoms, similar symptoms and incidence of late, the majority of patients after one year of age at onset. Rickets, liver and kidney barrier, high blood pressure, nervous system barriers to clinical symptoms, usually around the age of 10 may be found in the liver.
Diagnosis
Prenatal care:
Such as known prior to the one-child or both parents Tyrosinemia point mutations may be the amniotic fluid cells smoking pregnant women to carry out the analysis of point mutations. SA can also be detected in amniotic fluid concentrations are too high look.
Pregnant women to take the chorionic or amniotic fluid cells, to cultivate proliferation. To be charged after a certain number of cells, measuring the activity of FAH cells to see if there is a lack of FAH phenomenon.
Blood tests:
At present the most credible test Tyrosinemia quantitative blood and urine are in SA and its pre-chemokine concentration. Although the sensitivity of this approach, but there is still a small number of patients with low concentrations of SA at this time, it is necessary to detect the FAH activity in cultured cells as a secondary diagnosis. By the impact of genetic variability, a healthy individual cultured cells may also appear low activity FAH phenomenon. Similarly, patients with liver samples may also be because cell culture gene back when (reversed) case, which was highly active in the illusion of FAH. Therefore, FAH enzyme activity as a diagnostic test only when the reference, not only as a diagnostic credentials.
Treatment
Food Control:
The use of low-protein diet and with no phenylalanine and tyrosine special formula to restrict these two amino acid intake to provide enough physical capacity required for normal growth. With diet control, due to renal tubular dysfunction resulting symptoms can be fully answered almost normal. However, liver diseases and malignant tumors can not take this to have access to treatment and prevention, so when the liver severely damaged or have a tumor, the need to rely on other methods such as liver transplant, such as to improve the condition.
Liver transplant:
When the transplanted liver function, the patient's enzyme deficiency phenomenon would be improved, long-term effects than simply to better diet control. After liver transplantation can be a normal diet, no need for special restrictions. However, patients with urine testing is still out of SA, think are caused by the kidneys. After liver transplantation for renal prognosis of the long period of time remains unclear.
NTBC treatment:
2 - (2-nitro-4-trifluoromethylbenzoyl) -1,3-cyclohexanedione (NTBC) can block ρ-hydroxyphenyl pyruvic acid (ρ-hydroxyphenylpyruvate) and transformed into uric acid (homogentisate), to reduce the emergence of SA. Studies have shown NTBC can improve on clinical symptoms and biochemical abnormalities. Because of the concentration of tyrosine due to the use of NTBC to increase, therefore, diet control are necessary.
Long-term use of the NTBC study has been discussed, especially with NTBC the incidence of liver cancer among relevance, the current can not be determined. The sooner the use of NTBC, the serious anomaly appears more difficult. So far, NTBC No side effects were reported.
Supportive treatment:
For patients with acute disease, the supportive treatment is necessary. Patients often lack the potassium ions and phosphate, therefore, necessary to add the right amount of timely. In addition, coagulation factors, calcium, albumin, phosphate, electrolytes and acid-base balance are required under close monitoring and correction. When patients in the acute attack, the tyrosine and phenylalanine intake must be reduced to at least as far as possible. Increase in vitamin D can be used to treat rickets; patients if there is infection, infection control and immediately required to be addressed.
Tyrosinemia type I is mainly due to yanhusuo acetoacetic acid amide hydrolase enzymes (fumarylacetoacetate hydrolyase, FAH) caused by the lack of. FAH makes the lack of tyrosine metabolism have been hampered, leading to acetoacetic acid amide fumarate (fumarylacetoacetate) accumulation, can not be converted into fumarate (fumarate) and acetoacetic acid (acetoacetate). Substantial accumulation of acetoacetic acid amide fumarate into succinate acyl acetone (succinylacetone; SA), exist in the patient's plasma and urine. SA caused by the accumulation of liver injury; will inhibit omega-aminolevulinic acid (omega-ALA) hydrolase role, with the sort of acute porphyria (acute intermittent porphyria) of neurological symptoms.
Genetic model
Currently known human FAH gene is located in the first 15 pairs of chromosomes on the long arm (15q23-q25), belong to autosomal recessive genetic. Liver cells of patients with DNA sequence sequencing analysis showed that 34 gene mutation point and the lack of FAH. Tyrosinemia in the Americas and Europe to the incidence rate of one hundred thousandth 1/120000. Quebec, Canada and Norway, Finland, the incidence of higher, Quebec, the highest incidence of 1/1846, Norway and Finland for 1/60000.
Symptoms
Acute Tyrosinemia:
This situation will have a baby for rapid and fulminant course, if it is not treated in time, patients will be dead quickly. Usually a few weeks after birth to 6 months time attack, patients often have poor appetite, vomiting, diarrhea, abdominal distension and low blood sugar symptoms such as jaundice and ascites, who have a similar taste of cabbage; and may cause growth retardation, anxiety, fever and hepatomegaly phenomenon, at the same time there will be melena, hematemesis, hematuria, and the performance of congestion, such as hemolysis, and then lead to renal tubular dysfunction (renal tubular dysfunction), secondary rickets (rickets), liver symptoms such as splenomegaly. Some patients have neurological diseases and low-tension phenomenon. These neurological diseases may be accompanied by more serious complications, such as sometimes similar to acute intermittent? Pyronaridine alveolar rhodopsin (acute intermittent porphyria) of symptoms, nerve lesions caused by muscle weakness disease and high blood pressure. As the disease intensifies, jaundice, edema, abdominal effusion, lethargy, coma, liver failure and even death of such a phenomenon will happen.
Chronic Tyrosinemia:
Tyrosinemia with acute symptoms, similar symptoms and incidence of late, the majority of patients after one year of age at onset. Rickets, liver and kidney barrier, high blood pressure, nervous system barriers to clinical symptoms, usually around the age of 10 may be found in the liver.
Diagnosis
Prenatal care:
Such as known prior to the one-child or both parents Tyrosinemia point mutations may be the amniotic fluid cells smoking pregnant women to carry out the analysis of point mutations. SA can also be detected in amniotic fluid concentrations are too high look.
Pregnant women to take the chorionic or amniotic fluid cells, to cultivate proliferation. To be charged after a certain number of cells, measuring the activity of FAH cells to see if there is a lack of FAH phenomenon.
Blood tests:
At present the most credible test Tyrosinemia quantitative blood and urine are in SA and its pre-chemokine concentration. Although the sensitivity of this approach, but there is still a small number of patients with low concentrations of SA at this time, it is necessary to detect the FAH activity in cultured cells as a secondary diagnosis. By the impact of genetic variability, a healthy individual cultured cells may also appear low activity FAH phenomenon. Similarly, patients with liver samples may also be because cell culture gene back when (reversed) case, which was highly active in the illusion of FAH. Therefore, FAH enzyme activity as a diagnostic test only when the reference, not only as a diagnostic credentials.
Treatment
Food Control:
The use of low-protein diet and with no phenylalanine and tyrosine special formula to restrict these two amino acid intake to provide enough physical capacity required for normal growth. With diet control, due to renal tubular dysfunction resulting symptoms can be fully answered almost normal. However, liver diseases and malignant tumors can not take this to have access to treatment and prevention, so when the liver severely damaged or have a tumor, the need to rely on other methods such as liver transplant, such as to improve the condition.
Liver transplant:
When the transplanted liver function, the patient's enzyme deficiency phenomenon would be improved, long-term effects than simply to better diet control. After liver transplantation can be a normal diet, no need for special restrictions. However, patients with urine testing is still out of SA, think are caused by the kidneys. After liver transplantation for renal prognosis of the long period of time remains unclear.
NTBC treatment:
2 - (2-nitro-4-trifluoromethylbenzoyl) -1,3-cyclohexanedione (NTBC) can block ρ-hydroxyphenyl pyruvic acid (ρ-hydroxyphenylpyruvate) and transformed into uric acid (homogentisate), to reduce the emergence of SA. Studies have shown NTBC can improve on clinical symptoms and biochemical abnormalities. Because of the concentration of tyrosine due to the use of NTBC to increase, therefore, diet control are necessary.
Long-term use of the NTBC study has been discussed, especially with NTBC the incidence of liver cancer among relevance, the current can not be determined. The sooner the use of NTBC, the serious anomaly appears more difficult. So far, NTBC No side effects were reported.
Supportive treatment:
For patients with acute disease, the supportive treatment is necessary. Patients often lack the potassium ions and phosphate, therefore, necessary to add the right amount of timely. In addition, coagulation factors, calcium, albumin, phosphate, electrolytes and acid-base balance are required under close monitoring and correction. When patients in the acute attack, the tyrosine and phenylalanine intake must be reduced to at least as far as possible. Increase in vitamin D can be used to treat rickets; patients if there is infection, infection control and immediately required to be addressed.
Subscribe to:
Posts (Atom)