Intestinal transit disorder

Introduction This disease is due to the defect of hereditary membrane transport, leading to an increase in the amount of amino acid excretion in the urine. The occurrence of this disease is the result of changes in the membrane carrier caused by autosomal recessive diseases. Normally glomerularly filtered amino acids are almost completely reabsorbed in the proximal tubules through a specific energy transport process. In the case of abnormal congenital amino acid metabolism, amino acids that are not well metabolized are elevated in plasma and appear in the urine, which is caused by an increase in ultrafiltration load and a defect in non-renal tubule transport. When the proximal renal tubular amino acid transport is deficient, the reabsorption disorder can occur, and amino aciduria and blood amino acid levels are reduced. When an amino acid reabsorption is impaired, reabsorption of other amino acids through the same transporter can also be reduced and result in a wider range of amino aciduria, such as cystineuria. When an amino acid is abnormally metabolized and accumulated in the body, excessive ultrafiltration can inhibit the reabsorption of other amino acids in the same transporter, such as abnormal alanine aminotransfer, hyperalaninemia, and a large amount of taurine in the urine. , isobutyric acid, alanine. When the tubular epithelial cells are leaking from the brush border or basement membrane, the reabsorbed amino acids from the cell back into the lumen cause extensive amino aciduria, such as Fanconi syndrome, lysine urine and so on. When a metabolite accumulates in tubular epithelial cells, it inhibits reabsorption rate, triggering amino aciduria, such as galactosemia and congenital fructose intolerance, and galactose phosphate or fructose phosphate can accumulate in renal tubular cells.

Cause

(1) Causes of the disease

This disease is due to the defect of hereditary membrane transport, leading to an increase in the amount of amino acid excretion in the urine. The occurrence of this disease is the result of changes in the membrane carrier caused by autosomal recessive diseases. Normally glomerularly filtered amino acids are almost completely reabsorbed in the proximal tubules through a specific energy transport process. In the case of abnormal congenital amino acid metabolism, amino acids that are not well metabolized are elevated in plasma and appear in the urine, which is caused by an increase in ultrafiltration load and a defect in non-renal tubule transport.

When the proximal renal tubular amino acid transport is deficient, the reabsorption disorder can occur, and amino aciduria and blood amino acid levels are reduced. When an amino acid reabsorption is impaired, reabsorption of other amino acids through the same transporter can also be reduced and result in a wider range of amino aciduria, such as cystineuria. When an amino acid is abnormally metabolized and accumulated in the body, excessive ultrafiltration can inhibit the reabsorption of other amino acids in the same transporter, such as abnormal -alanine aminotransfer, hyperalaninemia, and a large number of cattle in the urine. Sulfonic acid, isobutyric acid, -alanine. When the tubular epithelial cells are leaking from the brush border or basement membrane, the reabsorbed amino acids from the cell back into the lumen cause extensive amino aciduria, such as Fanconi syndrome, lysine urine and so on. When a metabolite accumulates in tubular epithelial cells, it inhibits reabsorption rate, triggering amino aciduria, such as galactosemia and congenital fructose intolerance, and galactose phosphate or fructose phosphate can accumulate in renal tubular cells.

(two) pathogenesis

The amino acid content of the normal human glomerular filtrate is approximately equal to that of plasma, and most of it is reabsorbed by the proximal tubule. The amino acids excreted in the urine are mainly glycine (70-200 mg/d), histidine (10-300 mg/d), taurine (85-320 mg/d), and methyl histidine (50-210 mg/d). Wait. This type of amino acid urine occurs when the renal tubule is dysfunctional for certain amino acid transport.

an examination

Related inspection

Gastrointestinal CT examination, fiberoptic colonoscopy, gastrointestinal imaging, bowel sounds

In a variety of amino acid transport deficiency diseases, such as cystineuria, dibasic amino aciduria, Hartnup disease, iminoglycineuria, dicarboxy amino aciduria, manifested as structurally similar amino acid transport abnormalities, suggesting membrane A gene-specific membrane receptor or vector is present on it. The fact that these transport defect diseases affect only one amino acid transport indicates the presence of a substrate-specific transport system that affects the operating system in the kidney and/or intestine and does not affect other tissues. This type of homozygous type I lacks cystine, lysine, arginine and ornithine-mediated small intestinal transit, and its heterozygotes have a normal amino acid urinary excretion type. Type II homozygotes lack intestinal lysine-mediated transport, but preserve the ability to transport cystine, and their heterozygotes have a modest increase in urine excretion of the four amino acids. Type III homozygotes retain these four amino acid-mediated intestine transport capacities, and their heterozygotes have only a slight increase in urinary lysine and cystine flux.

1. Cysturia: an autosomal recessive disorder. Its pathogenesis is the transport of cystine in the proximal renal tubular brush border membrane and gastrointestinal tract, and the loss of lysine, arginine and ornithine sites in the same transport system, resulting in the histidine A large amount of loss; later found that the tubular disulfide formed by cysteine-homocysteine also has a reabsorption disorder. The concentration of cystine and other three amino acids in the blood of patients with cystine urine did not increase, and the clearance rate of the amino acids in the kidney was significantly increased, and the clearance rate of cystine was more than 30 times larger than normal. After feeding lysine and ornithine to patients with cystinuria, the blood concentration does not increase, and a large amount of these amino acids appear in the feces. The use of jejunal mucosa biopsy specimens for active transport studies also confirmed transport defects. In patients with cystine urine, the average monthly urinary excretion of cystine is 3036.8 mmol (normal maximum value is about 74.88 mmol/1 g creatinine), which is obviously supersaturated, and its solubility is low. It can only dissolve l2481664 in urine of pH 5-7. Methyl / L, it is easy to precipitate crystals, when the urine is concentrated, the increase in crystal formation is easy to form stones, causing renal colic, urinary tract obstruction or infection.

2. Hartnup disease: is caused by proximal renal tubular epithelial cells and jejunal mucosa for neutral monoamino and monocarboxy amino acid transport disorders. The amino acids of transport barrier are alanine, serine, threonine, valine, leucine, isoleucine, phenylalanine, tyrosine, tryptophan, histidine, glutamic acid and Tianmen Aspartic acid and the like. The most important of these is the defect in tryptophan transport. Tryptophan is largely lost in urine and feces, resulting in insufficient formation of nicotinamide, causing pellagrain-like skin damage and neurological symptoms. In addition, guanidine and tryptamine produced by tryptophan-like degradation in the intestine, phenethylamine produced by phenylalanine, tyramine produced by tyrosine and other amines significantly exceed the detoxification ability of the liver. Entering the blood circulation causes central nervous system symptoms, manifested as paroxysmal cerebellar ataxia and mental symptoms. There are two types of this disease: type I with small bowel dysfunction; type II with barrier-free.

The clinical manifestations of various amino acid urine have their commonality and personality. The common clinical manifestations of various amino acid urine are growth and development disorders, short stature and varying degrees of mental retardation. The characteristic performance is often different due to the different types of amino acid urine.

1. Cysturia: The disease usually develops after birth, but it is manifested in the 20 to 30 years old and can be diagnosed. The main clinical manifestations are:

(1) Specific renal amino acid urine: There are a large amount of cystine and three kinds of dibasic amino acids (lysine, arginine and ornithine) in the urine, and the excretion of urinary cystine is larger (average daily discharge Up to 730mg) can be seen in concentrated urine sediment crystals, three subtypes of homozygous urinary cystine, lysine, arginine and ornithine are positive, type II and III patients The heterozygous urinary cystine and lysine are also positive.

(2) Urinary tract cystine stones: As a large amount of cystine exceeds the saturation in the urine, the solubility in hard urine decreases, forming stones. Cystine stones account for 1% to 2% of kidney stones. Yellow-brown, hard, varying in size, the larger can be staghorn shape, often multiple, not completely X-ray, with a thin shadow, due to the inclusion of disulfide, it is less than the density of calcium stones. The stone is positively reacted with sodium nitroprusside cyanide and can be used as a screening diagnostic test. Urinary calculi are often an important clue for patients to get a diagnosis. Commonly caused symptoms are renal colic, hematuria, urinary tract obstruction, and secondary urinary tract infections, which can cause renal insufficiency in the advanced stage.

If the amount of urinary cystine excretion is small and its concentration is below saturation, it is called acalculous cystinuria. Studies suggest that in the family of patients with cystinuria, there may also be several patients with no cystic urinary mildness.

(3) Short body, mental retardation: may be related to the loss of a large number of amino acids (especially lysine).

(4) pyrrolidine and acridine urine: due to the absorption of these amino acids by the jejunum, a large amount of lysine and ornithine are degraded in the intestine to produce cadaverine and putrescine, which are reduced to pyrrolidine and acridine from the urine after absorption. discharge.

(5) Others: a small number of patients can be combined with hyperuricemia, hypocalcemia, hemophilia, muscular atrophy, pancreatitis, retinitis pigmentosa and so on.

2. Two-base amino acid urinary disease: This disease is an autosomal recessive genetic disease, which is the result of mutation of the gene encoding the transport protein, since this protein is only used to transport lysine, arginine and ornithine. And cystine reabsorbs normally.

Clinical manifestations: Type I is generally asymptomatic, and a few homozygotes may have mental retardation; type II dibasic amino acid urine is heavier than type I, and plasma dibasic amino acid concentration is lowered. In recent years, hepatocytes may be found to have dysfunction in this type of patient due to Lack of substrate lysine, arginine and ornithine circulation disorder, can not completely detoxify, so patients with protein intolerance, manifested as hyperammonemia, vomiting, diarrhea, growth and mental retardation and splenomegaly Even hepatic encephalopathy, diagnosed by family history and urinary amino acid analysis.

3. Homocysteinuria: This disease is a rare autosomal recessive disorder. Only the renal tubules have a barrier to cystine transport, and there is no corresponding transport disorder in the jejunum. The patient's urine only a slight increase in cystine excretion. Dibasic amino acid displacement is normal, generally no urinary calculi.

4. Hartnup disease: clinical manifestations are paroxysmal, symptoms often appear in childhood, adolescence, and then relieve themselves. The main manifestations of this disease are:

(1) Pella-like skin rash: the exposed parts of the skin are red, dry and scaly, or chapped, blistering and oozing, sensitive to light, increased after sun exposure, and good response to nicotinamide treatment.

(2) paroxysmal cerebellar ataxia: mostly occurs in the severe period of the disease, manifested as gait instability, limb tremor, may have involuntary dance-like movements, poor eye aggregation, nystagmus, often diplopia, severe There may be seizures or fainting, occasional mental symptoms and emotional instability, hallucinations, delirium or dementia. The attack usually does not exceed 1 week, and it relieves itself without leaving sequelae. The intelligence is generally normal or mildly damaged and the body is short.

(3) Specific amino acid urine: mainly threonine, serine, histidine, alanine, hydroxyproline discharge is normal, so it can be distinguished from all amino acid urine. Glycine, proline and hydroxyproline are normally excreted and can be distinguished from iminoglycine urine. Diuretic two-base amino acid excretion is also normal, which can be distinguished from cystine urine.

(4) Intestinal transport disorder: due to the decomposition of amino acids in the intestine, especially tryptophan, a large amount of purine metabolites are produced by the decomposition of bacteria. Indole sulfate (urine blue mother), mercapto-3-acetic acid can appear in the urine.

(5) Fecal examination: In addition to tryptophan in the feces, there are a large number of branched chain amino acids, phenylalanine, and other amino acids. The disease has little effect on the growth and development of children, and the height is only slightly affected, and the mental development is basically normal.

5. Aminoglycineuria: The disease is an autosomal recessive disorder, including proline, hydroxyproline and glycine, which is due to the co-transport system of the above three amino acids or glycine by renal tubular epithelial cells. Or caused by a disorder in the selective transport system of imino acids. Patients are generally asymptomatic, with occasional mental retardation, convulsions, and increased protein in the cerebrospinal fluid. The disease can be divided into 4 types: type I has jejunal transport disorder, and type II, III, and IV have no jejunal transport disorder. The disease has a good prognosis. Neonatal glycine urine often reflects the total amino aciduria during the normal developmental period of 6 months after birth, and persistent glycine urine appears in the infants' Fanni's syndrome. Pure glycine urine is mostly benign and generally asymptomatic.

6. Dicarboxyl amino acid urine: This disease is an autosomal recessive disorder caused by renal and tubular small intestine glutamate and aspartate transport disorders. Clinically divided into two types: type I with jejunal absorption disorder, manifested as fasting hypoglycemia and ketoacidosis (may be related to amino acid deficiency associated with gluconeogenesis), growth and mental development disorders in children, congenital thyroid function Low, episodes of hypoglycemia, decreased CO2 binding, increased blood valine, and a large amount of glutamate and aspartic acid in the urine. Type II see jejunal absorption disorder, clinically very rare, generally asymptomatic, only urinary carboxy amino acid urine excretion increased.

7. Methionine malabsorption syndrome: This disease is rare, caused by renal and intestinal epithelial cells on the transport of sulfur-containing amino acids. The clinical manifestations were mainly white hair, edema, mental retardation, paroxysmal hyperventilation, convulsions, and celery-like odor in the urine (caused by methionine urine and its degradation product -hydroxybutyrate). There is also a large amount of phenylpyruvate and tyrosine in the urine.

8. -Amino Acid Urine: -amino acid urinary excretion in the urine, taurine, -alanine, and -isobutyric acid appear in the whole amino acid urine. Taurine can also occur in urine when normal people eat too much meat and seafood. The clinical manifestations of this disease are epileptic seizures and coma, and -alanine--ketoglutarate transaminase activity is reduced.

A preliminary diagnosis of various amino acid urines can be made based on clinical manifestations, family history, and urinary amino acid screening (qualitative). Quantitative analysis of urine chromatography is also helpful for diagnosis and typing.

1. The basis for the diagnosis of cystineuria is as follows:

(1) History of family hereditary diseases.

(2) Symptoms and signs of kidney stones such as colic, hematuria, urinary tract obstruction and/or urinary tract infection.

(3) Cyst stone stones repeatedly occur in the urinary tract, and hexagonal flat crystals can be seen by microscopic examination of urine sediment.

(4) KUB plain film sees multiple bilateral urinary tract, thin shadows, and different sizes of stones.

(5) urine nitrohydrocyanate test positive, can determine the diagnosis (take a small amount of stone powder in a test tube, add 1 drop of concentrated ammonia, add 1 drop of 5% sodium cyanide, after 5 minutes, add 3 drops 5% sodium nitroprusside, such as cherry red immediately, indicating positive, indicating the presence of cystine). There were cystine and two-base amino acids in the urine (normal highest values were cystine 74.88 mmol/g creatinine, lysine, arginine, and ornithine were 8892, 918.4, 1665.4 mol/g creatinine).

2. Hartnup disease can diagnose the disease according to the following characteristics:

(1) There are typical clinical symptoms, lack of smokeless acid.

(2) There is psoriasis-like skin damage.

(3) Increased specific amino acid content in urine.

(4) In addition to tryptophan in the feces, there are a large number of branched proline, phenylalanine and other amino acids.

Differential diagnosis

The differential diagnosis of this disease is mainly related to the identification of various types of renal amino acid urine, which are mainly distinguished by specific amino acids in urine. In addition, it should be distinguished from other causes of amino acid urine. For example, cystineuria is mainly differentiated from cystine disease or cystine storage disease, homocysteine urine, and cysteine disease is systemic metabolism. Sexual disease, cystine is deposited in various tissues.

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