PORPHYRIN DISORDERS
Porphyrins
are metabolic by-products, that have not followed the usual
synthesis from glycine and succinyl co-enzyme A to heme with
production of Porphobilinogen and aminolevulinic acid. Different
factors such as drugs , chemicals and hormones can increase
porphyrin synthesis.
The site of
disturbance is either in the liver (hepatic porphyria) or in the
bone marrow in the erythroid cells (erythropietic porphyria ).
Types of
porphyria
-
Hepatic
porphyria, this includes:
Porphyria
cutanea tarda
Acute
intermittent porphyria
Porphyria
variegata
-
Porphyria
due to bone marrow disturbance :
Erythropoietic
protoporphyria
Congenital
erythropoietic porphyria (Gunther‘s disease )
PORPHYRIA
CUTANEA TARDA
The clinical
manifestations are due to abnormal Porphyrins metabolism. Drugs such
as barbiturates, sulfonamides, chloramphenicol, chloroquine,
griseofulvin and toxins, fungicides (hexachlorobenzene), may cause
this type.
Different
types of porphyria can cause different skin , hair and nail
manifestations:
Clinical
Manifestations
Skin
manifestations
The skin is
fragile, tear easily and forming blisters due to dermo epidermal
separation.
Poikeloderma
like reaction in the form of pigmentation , atrophy and
telengectasia on sun exposed areas.
Hypopigmentation
and scarring after healing.
Hypertrichosis
is not a common manifestation of porphyria cutanea tarda.
Photosensitivity
The patients
are sensitive to sunlight even when they are indoors. Patients are
labile to have phototoxic reactions.
Associated
diseases
Liver
cirrhosis, hemochromatosis, carcinomas and Hodgkin‘s disease may
be associated with porphyria cutanea tarda.
Diagnosis
Urine shows
a pinkish coral red fluorescence under Wood‘s light .
Positive
bromosulphalin test.
Detection of
Porphyrins in urine and feces .
Three-step
procedure (devised by Castro): Disposable plastic column charged
with anion exchange resin, permits detection of various porphyrins
as well as their precursors.
Hereditary
Porphyria Cutanea Tarda
This is a
rare type, which is carried as a dominant gene and appears at early
age around 15 years of age.
Treatment
Phlebotomy:
500ml of blood every two weeks. Usually 3000-5000 ml of blood is
taken . Involution of skin lesions usually appear after the second
blood intake .
Chloroquine:
500mg twice weekly for the adult age are believed to have an
encouraging results.
Sodium
bicarbonate: used to
alkalinize urine may have a beneficial effect.
ACUTE
INTERMITTENT PORPHYRIA
(Porphyria
hepatica)
This type is
characterized by periodic attacks of abdominal colic,
gastrointestinal disturbances, paralysis and psychiatric
disturbances.
Clinical
Manifestations:
General
manifestations:
Abdominal
colic.
Peripheral
neuropathy.
Psychiatric
abnormality.
Skin
manifestations:
Skin
pigmentation.
Hirsutism.
Photosensitivity
is not a feature of this type .
PORPHYRIA
VARIAGATE
Skin
manifestations include those of porphyria cutanea tarda and acute
intermittent porphyria but occurring in earlier age groups.
ERYTHROPOIETIC
PORPHYRIA
Photosensitivity
causes polymorphous light eruption leading to pruritic, erythematous
papulo vesicular and urticarial rashes mainly on the sun-exposed
areas. Skin lesions heal leaving linear pitted scars .Other
manifestations are purpura , oedema and severe burning pain.
ERYTHROPOIETIC
PROTOPORPHYRIA
This type
appears early in childhood from 2-5 years of age and inherited as a
dominant trait. Photosensitization is a characteristic feature of
erythropoietic protoporphyria . In this type it is believed to be
due to the longer wavelengths of ultraviolet (UVL) which ranges
from 320-450nm. Ordinary window glass offers no protection from the
effect of sun on such patients.
Clinical
Manifestations
Skin lesions
are pruritic erythematous, plaque-like edema, wheals and even
vesicles or bullae on the sun exposed areas. The skin lesions may
heal with scarring with waxy thickening of the nose, cheeks, over
the proximal finger joints, circumoral atrophy and scarring.
Diagnosis
Characteristic
cutaneous lesions.
Photosensitivity.
Increased
proto-and coproporphyrins in feces.
Increased
porphyrins in red blood cells .
Fluorescent
microscopic examination of blood : Few drops of blood are diluted
1:5 with normal saline are placed on a microscopic slide and
examined by the oil immersion objective of a fluorescent microscope.
Erythrocytes
usually show characteristic fluorescence.
It should be
noted that in this type of porphyria , urine usually does not give
fluorescence under the Wood‘s light .
CONGENITAL
ERYTHROPOIETIC PORPHYRIA
This type is
a hereditary disease, transmitted by an autosomal recessive gene.
Clinical
Manifestations
Skin
manifestations
Skin
manifestations appear early in infancy on the sun-exposed areas that
are due to photosensitivity. Painful bullous lesions, which heal by
destructive and disfiguring scarring and causing destruction of the
cartilage of the nose, ears, and nails.
Cicatricial
alopecia
Hypertrichosis:
with hair on the cheeks, profuse eyebrows, and long eyelashes
(“monkey face“).
Urine shows
high amount of copro and uropophyrines.
Diagnosis
Congenital
erythropietic porphyria has the following characteristics that are
diagnostic even in early infancy:
Red urine in
early infancy .
Photosensitivity
Hemolytic
anemia
Splenomegaly
Erythrodontia
of both deciduous and permanent teeth.
Coral red
fluorescence of the teeth when exposed to Wood‘s light.
PHENYLKETONURIA
This disease
affects children with blond hair, blue eyes and fair skin due to
lack of the enzyme phenylalanine hydroxylase, which is essential for
degradation of phenylalanine to tyrosine.
Clinical
Features:
Photosensitivity.
Eczema like
reaction.
Secondary
infections are common.
Scleroderma-like
skin lesions.
Induration
of thighs and buttocks are common manifestations in affected infants
and children.
General
manifestations.
Mental
deficiency.
Epileptic
seizers.
Laboratory
findings.
Presence of
phenyl pyruvic acid in urine. This can be easily detected by adding
to urine few drops of ferric chloride solution that will give deep
green color.
Treatment
Special diet
for infants and young children containing low phenylalanine and this
should be given immediately after birth.
ALKAPTONURIA
AND OCHRONOSIS
This is a
hereditary disease transmitted as an autosomal recessive gene, due
to enzymatic defect in the metabolism of tyrosine and phenylalanin.
Clinical
Manifestations.
Dark urine,
which becomes later black due to increased homogentisic acid
secretion in urine.
Deposition
of brown-black pigment in the connective tissue.
In older age
groups the manifestations are:
Pigmentation
of the sclera, which is an early sign.
Deposition
of pigment in the cartilage of the ears, nose and tendons of the
extremities which may show blue, mottled brown macules.
Internal
organs mainly great vessels, valves and larynx, genitalia may be
also involved .
Arthropathy
affecting the spinal joints , hips ,knees and shoulders.
ABNORMAL
LIPID METABOLISM
XANTHOMATOSIS
Xanthomatosis
is accumulation of lipids in association of foam cells in the
tissues.
Different
clinical types.
Xanthelasma
palpebrarum: this is
the most common type of xanthomas affecting any age. Middle age women
are the commonest to have this problem especially those who have
biliary diseases. The lesions are yellowish plaques on the eyelids,
which may coalesce to form large plaques.
Plane
xanthomas:
yellowish, raised papules, symmetrically distributed mainly on the
eyelids sides of the neck and palms.
Eruptive
xanthomas: yellow
papules appear on the extensor surfaces of the limbs, joints and
buttocks surrounded by a rim of erythema and may be tender. Eruptive
xanthoma is associated by increased serum triglycerides .
Fig.354.
Xanthomatoses
|
Fig.355.
Xanthomatoses
Fig.355d.
Xanthomatosis
Fig.355e. Xanthomatosis
|
Tendinous
xanthomas: nodular
yellowish lesions appear on the tendons on the extensor surface due
to cholesterol infiltration.
Tuberous
xanthomas:
symmetrical nodular lesions, appear over the extensor surface of the
joints and accompanied by increased serum triglycerides and
cholesterol.
MANIFESTATIONS
OF HYPERLIPOPROTEINEMIA
-
Primary
Hyperlipoproteinemia
Familial
hyperlipoproteinemioa
Different
types:
Type I
hyperlipoproteinemia
Type II
hyperlipoproteinemia
Type III
hyperlipoproteinemia
Type IV
hyperlipoproteinemia
Type V
hyperlipoproteinemia
-
Secondary
Hyperlipoproteinemia
Secondary to
systemic diseases
Xanthomatous
biliary cirrhosis
Hematopoeitic
diseases
Xanthoma
diabeticorum
Lipoid
nephrosis
Myxedema
Pancreatitis
Generalized
xanthelasma
Histiocyhtosis
X
Litterer
-Siwe disease
Hand
-Schuller-Christian disease.
Eosinophilic
granuloma.
Juvenile
xanthogranuloma.
Refsum‘s
Syndrome
This
syndrome is a genetic disorder of lipid metabolism.
Neurological
and cutaneous features characterize this syndrome.
The
underlying abnormality is a deficiency in phytanic acid, displacing
unsaturated fatty acids as linolenic acid from tissue lipids.
Clinical
Manifestations
Skin
manifestations
are
mainly dryness of the skin, which simulate icthyosis vulgaris.
General
manifestations begin
early in childhood similar to retinitis pigmentosa with different
neurological (polyneuropathy), ataxia, cardiac and bone
manifestations.
Various
neurological changes
occur, including deafness, cerebellar degeneration, polyneuropathy,
and retinitis pigmentosa and cardiac abnormalities.
Refsum‘s
syndrome can be diagnosed by lipid analysis of the blood or the
skin. Normally no or very little phytanic acid is found in the blood
(0-33 mumol/l).
Treatment
Treatment by
a phytanic acid-free diet, in which green vegetables and dairy
products are excluded, has been used. Plasma exchange in conjunction
with diet.
ABNORMAL
AMINO - ACIDS METABOLISM
These
changes are recessively transmitted error of metabolism of amino
acids leading to different skin manifestations. The skin
manifestations depend on the specific amino-acid metabolism
abnormality.
ALKAPTINURIA
This
syndrome is due to deficiency in homogentisic acid oxidase leading
to accumulation of homogentisic acid that can be detected in urine.
Clinical
Features
In early
life: dark urine and
sweat.
Arthropathy
of spines and knees due to chondreal cartilage thickening.
In older age
groups the skin of
forehead, ears, cheeks and around the eyes is pigmented.
Pigmentation
of the sclera.
HOMOCYSTINURIA
This disease
is due to disorder in methionin metabolism due to an absence of
hepatic cystathione synthetase causing abnormality in collagen
formation.
Clinical
Features
The clinical
manifestations appear early, in the first year of life.
Thin,
yellowish skin and atrophic scars.
Fine sparse
hair, which brittles easily due to disulfide bond reduction.
Intravascular
clotting leading to livedo reticularis.
Treatment
Diet low in
methionin.
Supplement
by pyridoxine and cysteine may give good improvement.
HARTNUP
DISEASE
This error
of metabolism of tryptophane leads to nicotinic acid deficiency.
The changes
occur early in infancy due to unabsorbed tryptophene, which is
broken into the gut to indoles that is absorbed, metabolized and
excreted in urine as indican.
Clinical
Features
Skin
manifestations are
like pellagra in the form of dry, scaly and sharply demarcated rash on
the sun-exposed areas.
Photosensitivity.
Neurological
manifestations:
ataxia and mental retardation.
Diagnosis
By the
clinical picture.
Pellagra
like eruption.
Neurological
manifestations, ataxia and mental disturbances.
Urine
examination shows increase in indican and monocarboxylic amino acid.
Treatment
Nicotinamide.
Treatment of
skin manifestations by emollients and keratolytics as topical
salicylic acid in an ointment base alone or in combination with
steroids (Locasalene).
Sunscreens
and avoiding too much exposure to sunlight.
LYSOSOMAL
STORAGE DISEASE
These
metabolic disorders are due to a defect in specific enzymes leading
to accumulation of intermediary metabolic products in lysosomal
organelles.
These
syndromes include Hurler‘s syndrome, Chediak-Higash syndrome and
others.
LITTERER-SIWE
DISEASE
This disease
appears early in infancy in the first months of life.
Clinical
Features
Skin
manifestations
The skin
manifestations are brown, scaly papules on the seborrheic areas on
the scalp, behind the ears, naso-labial folds and mid chest.
Systemic
manifestations include purpura, systemic histiocytosis and
malignancy.
Most infants
die in the first two years from infections mainly due to pneumonia.
Treatment
Treatment is
not always curative.
Antibiotics
for pulmonary infections.
Corticosteroids.
Cytosine and
blood transfusion can be tried.
ANDERSON‘S
FABRY DISEASE
(Lipoangiokeratoma)
This is a
rare X linked recessive trait storage disorder leading to
accumulation of ceramide trihexose in the tissues mainly in the
endothelium of smooth muscles and blood vessels.
Clinical
Manifestations
This
syndrome has complex skin and systemic manifestations.
Skin
manifestations begin to appear in the adult age in the form of dark
blue or black lesions mainly on the back, abdomen, buttocks,
umbilicus and mouth.
Systemic
manifestations appear early in childhood in the form of weakness,
malaise, cramps. In adult age, there is vague symptoms as fever
after exercise with decreased sweating, neurological and
psychological episodes and severe pain of the feet and hands.
Serious and
even fatal complications in older age groups are due to cardiac,
renal and cerebrospinal accidents.
MORQUIO AND
HURLER SYNDROMES
Both of
these syndromes are genetic diseases due to error of metabolism of
mucopolysaccharides leading to greatly thickening of the skin due to
deposit of mucopolysaccharides in tissues limiting joint movements.
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