Hematoporphyria peripheral neuropathy
Introduction
Introduction to hematoporphyrinic peripheral neuropathy Porphyria (porphyria), also known as blood chlorotic disease, is an abnormal pigment metabolism. During the process of heme biosynthesis, due to the genetic defects of certain enzymes related to porphyrin metabolism, the activity of the enzyme is reduced, and the porphyrin is reduced. And the porphyrin precursor accumulates in the body. According to different enzyme defects, the disease is clinically divided into several types, some of which can cause damage to the nervous system and are mainly characterized by peripheral nerve damage. basic knowledge Sickness ratio: 0.0001% Susceptible people: no specific population Mode of infection: non-infectious Complications: Hypertension Epilepsy
Cause
Causes of hematoporphyrinic peripheral neuropathy
Cause:
Porphyrin is the main substance for the synthesis of heme. The combination of heme and protein can not only synthesize hemoglobin, but also synthesize myoglobin, cytochrome and peroxidase, which are indispensable for in vivo metabolism. Porphyrin It is mainly synthesized in red bone marrow and liver. Although the synthetic sites are different, the synthesis steps are identical and each is independently regulated.
There are 8 enzymes in the process of hemoglobin synthesis. Different enzyme defects can lead to different clinical types of porphyria. At present, the gene localization of these enzymes is basically clear.
Pathogenesis
The synthesis of heme is mainly divided into two stages: pre-metabolism and late metabolism.
Pre-metabolism
In this period, glycine is synthesized from glycine, glycine and succinyl-CoA, and -amino-r-ketovaleric acid is synthesized by -amino-r-ketoglutarate synthetase. Acid, ALA), this process is carried out in mitochondria, and pyridoxal phosphate is used as a coenzyme. The produced ALA is transported into the cytoplasm of mitochondria in vitro. Two molecules of ALA are condensed under the catalysis of dehydratase. Molecular porphobilinogen (PBG).
2. Late metabolism
In this phase, PBG synthesizes heme, PBG via uroporphyrinogen I and porphyrinogen II synthetase, synthesizes uroporphyrinogen I, and activates uroporphyrinogen III synthetase, which will PBG It is condensed into uroporphyrinogen III, and urinary porphyrinogen III is produced by uroporphyrin III decarboxylase to form coproporphyrinogen III (CPGIII). CPGIII is then produced by coproporphyrinogen III oxidase. Protoporphyrinogen, protoporphyrin is formed by protoporphyrinogen oxidase to form protoporphyrin. Finally, protoporphyrin is hydrolyzed by iron chelatase to synthesize heme in mitochondria. Feedback function to adjust, that is, when hemoglobin is synthesized too much, it can inhibit the synthesis of ALA synthase, and slow down the synthesis of ALA. At this time, the porphyrin precursor is also reduced. Therefore, ALA synthase is the rate-limiting enzyme. Normally, the content is very small, the urinary porphyrin is excreted by urine, the coproporphyrin is excreted by urine and bile, and the protoporphyrin is excreted by feces. The protoporphyrin is connected by four pyrrole rings via the methylene bridge (-CH2-). , the sub-bridge is easy to be oxidized in the tissue to make the original The porphyrin becomes a porphyrin, and the protoporphyrin is colorless, and the porphyrin absorbs visible light and discolors, which is the cause of skin discoloration symptoms of porphyria. Patients who die rapidly, regardless of the central or peripheral nervous system, can be found without any abnormalities.
In patients with slower disease, the peripheral nerves may have different degrees of myelin degeneration, accompanied by dying-back axonal degeneration. Pathak and Asbury (1970) believe that the damage of motor fibers is more serious than that of sensory fibers. The axonal degeneration of the fiber often develops to the anterior root, while the sensory fibrosis is not extensive. The nerve fibers in the distal muscle of the severe patient completely disappear, but the large fibers from the muscle spindle are not damaged, and the motor neurons in the spinal cord and brain stem are not damaged. There may be retrograde changes with central Nissl dissolution. In patients with mental symptoms, the brain has no damage. In addition, the internal organs have mild chronic passive congestion, and the renal tubules may have flaky necrosis.
Prevention
Hematoporphyrinic peripheral neuropathy prevention
The most important thing to prevent porphyria attacks is the principle of individualization, including the following:
1. Family members should be screened to establish preventive measures and identify potential patients.
2. Toxic drugs should be avoided.
3. Fasting should be avoided, even for a short period of hunger (such as postoperative or intermittent disease), diet therapy for obese patients in the clinical remission period of porphyria should gradually reduce weight.
4. Heme treatment can prevent frequent recurrence, but there is no standard treatment plan; now the study advocates hemoglobin treatment once or twice a week.
5. For patients who often have pre-menstrual attacks, gonadotropin-releasing hormone analogues and low-dose estrogen replacement therapy can be prevented, but remains to be studied. Oral contraceptives are sometimes effective, but progesterone has a risk of exacerbating porphyria.
Complication
Hematoporphyrinic peripheral neuropathy complications Complications, hypertension, epilepsy
Chronic blisters are found in skin lesions exposed to light. Scar formation is a hallmark of PCT; tachycardia, hypertension, sweating, and irritability are common; tremors, epilepsy, and psychiatric symptoms can occur. Tachycardia, high blood pressure, sweating, and irritability are common. This may be due to the release of excessive blood into the autonomic nervous system and catecholamines. When peripheral nerves are involved, about half of the patients have sensory loss or pain, affecting single limbs. Or multi-limb, more rapid muscle atrophy within 1 week and develop into flaccid paralysis.
Symptom
Symptoms of hematoporphyrinic peripheral neuropathy Common symptoms Photoallergic abdominal pain, bloating, nausea, constipation, intestinal cramps, diarrhea, tremor, urinary incontinence
There are many classification methods for porphyria, which are classified according to the location of porphyrin metabolic disorders: 1 erythropoietic porphyria occurring in the bone marrow. 2 Hepatic hematoporphyria disease that occurs in the liver. 3 Protoporphyrin disease occurring in the liver or bone marrow.
Some scholars are also divided into neuroporphyria, neurocutaneous porphyria and porphyria based on clinical manifestations. The main clinical manifestations of three porphyria diseases that are prone to neurological damage are described below.
1. acute intermittent porphyria (AIP)
Is autosomal dominant inheritance, hepatic porphyria, more than post-pubertal onset, clinical manifestations of paroxysmal abdominal cramps with nausea, vomiting and constipation, but also intestinal fistula, heart rate is accelerated (usually 100 ~ 160 Times / min), blood pressure rises autonomic dysfunction, and a quarter of patients may have seizures.
Abdominal pain is the most common, its severity can be misdiagnosed as acute abdomen, other abdominal symptoms include nausea, vomiting, constipation and diarrhea, paralytic ileus can cause abdominal distension, abdominal symptoms are due to the role of visceral nerves, the same bladder can also be affected It can be seen that there is urinary retention, urinary incontinence, dysuria and frequent urination. Because there is no inflammation, abdominal tenderness and rebound tenderness are not obvious, and the body temperature is normal or slightly higher. Therefore, the symptoms are not as obvious as the symptoms.
Tachycardia, high blood pressure, sweating, irritability are common, which may be caused by excessive release of autonomic nervous system and catecholamine into the blood, common motor neuropathy, severe paralysis, respiratory insufficiency, and rare death. Due to the lesions of the hypothalamus, inappropriate secretion of ADH can lead to water retention and hyponatremia, which can cause epilepsy. Hypertension can persist, which may be related to kidney damage. Chronic liver abnormalities are common and there is unexplained hepatocellular carcinoma. The rate is rising.
When peripheral nerves are involved, about half of the patients have feelings of sensation or pain, affecting single or multiple limbs, and more often, within 1 week, muscle atrophy develops and develops into flaccid paralysis. The latter focuses on the proximal and lower limbs, and a few patients have limbs. Loss of distal sensation, sputum reflexes weakened or disappeared, and the condition may improve within a few days, but severe muscle weakness can last for months or years, especially when delaying diagnosis and treatment.
The brain is often affected by the VII, X is the most common, the V, XI, XII pairs can also be affected, mainly for the formation of sound, swallowing disorders and hemifacial spasm, in addition, tremors and epilepsy, other central nervous system symptoms Including mental disorders, such as irritability, hallucinations, and symptoms such as depression and mania.
The above symptoms can be aggravated by taking phenobarbital, sulfonamides, aminopyrine, estrogen, succinamide, etc., because these drugs cause increased demand for hepatic hemoglobin, promote the synthesis of hepatic cytochrome P450, and thus ALA synthase Increased, the urine excreted a large number of porphyrin precursors PBG and ALA.
2. Variant porphyria (variant porphyria)
Is an autosomal dominant hepatic porphyria, found in puberty.
Clinical manifestations of skin pigmentation and photoallergic, paroxysmal abdominal cramps and multiple peripheral neuropathy, similar to acute intermittent porphyria, increased urinary ALA and PBG excretion during acute exacerbation, fecal porphyrin in urine and feces Protoporphyrin also showed an increase.
3. Fecal porphyria (coproporphyria)
Also known as hereditary fecal porphyria, is an autosomal dominant inheritance, which is hepatic porphyria.
Can occur at any age, showing abdominal cramps, peripheral nerves and psychiatric symptoms, sometimes the skin is sensitive to light, but mild, Kuhnel et al reported 53 cases of hereditary fecal porphyria, abdominal pain, peripheral neuropathy, mental symptoms, heart The frequency of vascular disease and skin symptoms was 89%, 33%, 28%, 25% and 14%, respectively.
Some patients are clinically asymptomatic, but a large amount of fecal porphyrin can be excreted in urine and feces, and ALA and PBG in urine are significantly increased during the attack.
Examine
Examination of hematoporphyrinic peripheral neuropathy
1.24h urinary porphyrin, total fecal porphyrin and total plasma porphyrin determination, urinary porphyrin precursor ALA and PBG detection is also helpful for diagnosis.
2. The erythrocyte PBG deaminase activity of most AIP patients is about 50% of normal people, which is helpful for the diagnosis of patients with elevated plasma or urine PBG.
When the PBG deaminase activity in the family declines, it is useful to measure the erythrocyte PBG deaminase for screening the family. Unlike patients with new symptoms, the asymptomatic family members with low PBG deaminase activity are Its urine PBG does not rise.
When screening family members, both erythrocyte PBG deaminase and urinary PBG should be measured, because none of the carriers can completely detect all carriers of the disease. For families with AIP genetic mutations, DNA detection is the most Sensitive and most specific methods, but only if the genetic mutations are well defined.
3. Other blood tests
Including serum iron, liver function, kidney function, routine examination of erythrocyte sedimentation rate; rheumatism series, immunoglobulin electrophoresis and other serological tests related to autoimmunity.
4. Detection of serum heavy metals (lead, mercury, arsenic, antimony, etc.).
5 EMG and neurophysiological examination.
6. Organize biopsies (including skin, sural nerves, muscles and kidneys) as necessary to identify other sensory peripheral neuropathies.
Diagnosis
Diagnosis and identification of hematoporphyrinic peripheral neuropathy
The disease has no specific clinical manifestations, and the diagnosis is difficult. The color of the urine is darkened after being exposed to sunlight. The brown or wine red color indicates the possibility of the disease. The diagnosis depends on 24h urinary porphyrin, total fecal porphyrin and plasma. Determination of the total amount of porphyrin, urinary porphyrin precursor ALA and PBG detection also contribute to the diagnosis.
The peripheral neuropathy of acute intermittent porphyria is similar to that of Guillain-Barre syndrome. It is easily misdiagnosed. The former has abdominal pain, low back pain in the kidney area, mental abnormalities, obvious arrhythmia, and normal or only slightly elevated cerebrospinal fluid protein. Lead poisoning and porphyria can have limb paralysis, abdominal pain, arrhythmia, hypertension and encephalopathy, and lead poisoning may also have porphyrin metabolism disorders, which are confusing, but urinary fecal porphyrin and ALA during lead poisoning The amount of elimination is significantly increased, while the urinary urinary porphyrin and porphyrin bilirubin are only slightly elevated, which is different from porphyria disease. The increase of blood lead level in lead poisoning can be identified by both. The acute abdominal porphyria abdominal pain is easily misdiagnosed as acute abdomen and surgical exploration; mental symptoms are easily misdiagnosed as schizophrenia or encephalitis; skin changes are easily misdiagnosed as frostbite, clinical should pay attention to identification.
