HPU can be can be described as a stress-induced double deficiency of pyridoxal-5-phosfate and zinc. In most of the cases a deficiency of manganese is found as well. It belongs to the porphyrin diseases.
This is a heterogeneous group of congenital or acquired defects in the metabolism of haem caused by abnormalities of enzymes involved in the biosynthesis.
Porphyrin disease are sometimes classified in terms of clinical presentation, as acute or non-acute. HPU belongs to the non-acute porphyries. Normally in non-acute porphyries porphobilinogen deaminase is raised. Up till now this has not been investigated in HPU.
In all porphyrin disease, HPL is found in the urine of the patients as well.
HPL can be derived from (1) monovinyl- or mono-ethyl porphyrins, (2) bilirubin by chemical oxidoreduction or (3) intestinal bacteria (Irvine and Wilson (1976).
What are really porphyrin disorders? They are congenital enzyme deficiencies in the production of haem. Toxic porphyrins are deposited in body tissues. The acquired forms starts after crash diet (illness), infections, exposure to chemicals/toxins, the use of drugs (especially anti-depression, anti-anxiety of anti-psychotic drugs). The patients are mainly female.
Symptoms of porphyria such as abdominal discomfort (belly pains, constipation, nausea), leg cramps, weakness of the muscles in the arm, anxiety and agitation, skin complaints that increase during exposure to the sun are found in HPU to. Other symptoms like a slightly rapid heartbeat and convulsions, are however, found much less frequent in HPU-patients.
Studying thousands of patients with krytopyrroluria, porphyria and HPU we found the following structure in complaints.
Symptoms caused by a decrease of the haem production
In the case of HPU less haem is produced than normally. Only in severe cases this causes complaints. Haem is the building block of haemoglobin, myoglobulin and cytochrome C. So in these severe cases anaemia, tiredness, muscular weakness and functional liver problems are present. In the haem formed in most of the cases more zinc is linked than normal. So part of the haemoglobin is zinc-haemoglobin.
Symptoms caused by deficiencies of Pyridoxal-5-phosphate and zinc
Much more complaints are however caused by the deficiencies of pyridoxal-5-phosphate, zinc and manganese. To these complaints belong also muscle weakness, joint complaints (hypermobility), problems carbohydrate intolerance, allergy due by a bad protein digestion, problems around menstrual cycle, pregnancy and childbirth (miscarriage) (instability of the pelvis), hypoglycaemia or diabetes.
Symptoms caused by down regulation
Other symptoms are caused by down regulation. These symptoms are tiredness, hyperactivity/drive, thyroid dysfunction, headache/migraine, gluten sensitivity, low blood pressure, infertility, overweight, heart and vascular disease, pituitary hypofunction and so on.
Alcohol and certain drugs show an increase of porphyria complaints, while vitamin B6 and zinc show an improvement.
One of the most severe cases of kryptopyrroluria was described in literature (Pfeiffer, 1987):
"Since she was 11, Sara’s life had been a nightmare of mental and bodily suffering. Her history included insomnia, episodic loss of reality, attempted suicide by hanging, partial seizures, nausea, vomiting and loss of periods. Here knees were so painful and her mind so disperceptive that she walked slowly with her feet wide apart like a peasant following a hand plough drawn by tired oxen. Her brain wave and standard blood tests were within normal limited. At times her lift side of the body went into spasms with foot clawed and fist doubled up. Both arm and leg had a wild flying motion. Restraints were needed at these times. Psychotherapy was ineffective and most tranquillisers accentuated the muscle symptoms.
She was diagnosed as B6 and zinc deficient and treatment started.
HPU-complaints in youngsters
HPU-complaints normally increase with age. In children only specified complaints can be seen. The following signs can be an indications for HPU:
The HPL combines with pyridoxal-5-phosphate to form a stable base, which is excreted in the urine complexes with zinc or other minerals like manganese. Pyridoxal-5-phosphate plays an important role in the formation of niacinamide (sometimes called vitamin B3) from tryptophan, and also picolinic acid from tryptophan. Zinc is required for the conversion of pyridoxine to pyridoxal-5-phosphate. Picolinic acid plays a role in the uptake of minerals like zinc, chromium, manganese and magnesium. Here an important downward spiral starts.
Humans with (pseudo) pellagra, porphyria (MacSweeney, 1975) and HPU, which exhibit similar characteristics, all have high serum copper levels.
The loss of vitamin B6 by the complexing of HPL with pyridoxal-5-phosphate and zinc would explain partially the increased vitamin B6 requirement found in pellagra patients. Vitamin B6 is required in the conversion of tryptophan into niacin, and a deficiency of vitamin B6 would interfere with the maintenance of the niacin levels in the body.
Zinc added to the diet accelerates healing of wounds because zinc has an effect on collagen synthesis and other aspect of collagen metabolism (Prasad and Oberleas, 1976). Copper on its hand is involved in the structural integrity of bone collagen. These factors assume importance in the skin changes of the pellagra, schizophrenia and HPU patients.
Tension, anxiety and depression in adult HPU patients are caused by the secondary deficiency of vitamin B3 (niacinamide). Of thirty patients with severe HPU which besides pyridoxal-5-phosphate and zinc also got niacinamide ten were free of these complaints within a month. Another eight patients recovered in two months. In healthy people 1.5% of tryptophan is converted to niacinamide. One milligram vitamin B3 is made out of 60 mg tryptophan. In HPU patients this conversion is much lower. It is known that women pregnant in there last three months have a much higher conversion rate.
Because copper activates MAO and DAO enzymes the histamine level normally is very low in HPU-children. This low levels gives rise to new complaints. Although the children looks healthy they are often overstimulated, hyperactive, depressive and have a high threshold for pain. Because of their insomnia they turn night into day.
Irving, D.G. and D.L. Wilson (1976) Porphyrins in Human Diseases. Karger, Basel.
Kamsteeg, J. Kryptopyrroluria: vrouwenkwaaltjes zijn echt niet altijd psychisch, KEAC, Weert 61 pp.
MacSweeney, D.A. (1975) Lancet 2:510.
Pfeiffer, C.C. (1987) Mental Illness and Schizophrenia. Thorsons Pub. Group, Wellingborough.
Prasad, A.S. and D. Oberleas (1976) Trace Elements in Human Health and Disease. Vol. I. Academic Press, New York.