Latent Cutaneous Porphyria, Type PCT, in a

Caucasian Woman

KURT NORREGAARD CHRISTENSEN, M.D.

TORBEN K. WITH, M.D.

Svendborg, Denmark

From the Departments of Medicine and Chemical Pathology, Svendborg County Hos- pital, 5700 Svendborg, Denmark. Requests for reprints should be addressed to Dr. Torben

K. With, Department of Chemical Pathology, Svendborg County Hospital, 5700 Svendborg, Denmark. Manuscript received October 27, 1970.

A case of latent cutaneous porphyria associated with a severe hemolytic anemia is reported. A complete family investigation showed no signs of heredity. The porphyrias may occur in as- sociation with malignant diseases, autoimmune conditions and other rare diseases. The relationship between skin photosensi- tivity and porphyrins does not seem to be a simple one.

Cutaneous porphyria occurs in three separate forms: congenital erythropoietic porphyria, erythropoietic protoporphyria and por- phyria cutanea tarda (PCT). The latter is subdivided into hered- itary and nonhereditary forms, all of them being of the hepatic type. The hereditary forms are believed to be transmitted as Mendelian dominants, as has been established particularly for South African (variegate) porphyria. This porphyria, which is characterized by fecal excretion of protoporphyrin and copro- porphyrin in high concentration, both in manifest and latent cases, has not yet been found in Denmark. We have seen sev- eral patients with so-called mixed porphyria, i.e., patients in whom symptoms of both cutaneous and acute intermittent por- phyria were present, either simultaneously or in succession, but these patients differ clearly from those with variegate porphyria by the absence of constant porphyrin excretion in the feces. In addition, these patients most often showed dominance of copro- porphyrin over protoporphyrin, or almost exclusively copropor- phyrin II I in their feces, and their relatives did not show in- creased fecal porphyrins.

The so-called nonhereditary form of PCT (PCT-NH) does not show simple Mendelian heredity but a more complicated and not as yet clear pattern of heredity as pointed out in recent re- views [l-3]. Although latent cases of hereditary cutaneous por- phyria, especially variegate porphyria, are frequent and well known, latent PCT-NH has, as far as we know, been described only twice: by Galambos [4] in an American Negro and by Zi- prkowsky et al. [5] in an Israeli subject. Galambos’ case was discovered because of red urine, Ziprkowsky’s case was found during investigation of a family.

Only a few investigators have carried out systematic family studies in PCT-NH. In addition to Ziprkowsky we have been able to find studies of this sort only by Holmes and Barnes [6] who found PCT in an alcoholic man and his sister; the cases of Barnes et al. [7], presenting recurring abdominal colic, are of the hereditary type (PCT-H).

Most investigators are inclined to regard a case of PCT as acquired or nonhereditary when there are no manifest cases of

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LATENT CUTANEOUS PORPHYRIA, TYPE PCT-CHRISTENSEN, WITH

porphyria in the family [8]. In our opinion the he-

redity of a case of porphyria cannot be regarded as elucidated without a study both of the patient

and as many relatives as possible, with so-called

“complete porphyrinologic investigation,” i.e., analyses of the urine for porphobilinogen (PBG),

delta-aminolevulinic acid (ALA) and porphyrins as

well as the feces for porphyrins [3,9]. Study of the

blood for porphyrins is necessary if urinary por- phyrins are normal, because the urine porphyrins are not increased in erythropoietic protoporphyria.

CASE REPORT

Our patient is a woman, born in 1903, in whom hemo- lytic anemia developed at the age of fifty-three; she was admitted to the medical department of the Svendborg Hospital in 1956. Her hemoglobin value was then 7.5 gm/L, red blood cell count 2.42 million/ cu mm, white blood cell count 4,3OO/cu mm. The erythrocyte sedimentation rate was 128 mm/hour. Re- ticulocytosis was present (5 per cent), Coombs’ direct test was negative. A marked hypogammaglobulinemia (5 per cent of the serum total protein of 7 gm/lOO ml) was present. A biopsy specimen of marrow was typi- cal of hemolytic anemia; liver function tests were nor- mal. Steroid therapy (prednisone) was instituted and continued for one year, during which complete remis- sion occurred. After discharge from the hospital the patient was examined regularly in the course of the following ten years; blood counts remained normal until 1966 when the anemia recurred. At that time her hemoglobin value was 8 gm/L, red blood cell count 2.36 million/cu mm, white blood cell count 24,OOO/cu mm, erythrocyte sedimentation rate 97 mm/hour, retic- ulocytosis 3 per cent. Prednisone therapy was instituted once more and was followed by complete remission. The prednisone dose was subsequently reduced. and two years later steroid therapy was discontinued. One year later hemolytic anemia recurred, and a third re- mission was induced by prednisone therapy. At that time the hemoglobin value was 12 gm, red blood cell count 3.08 million/cu mm, white blood cell count 2,800/ cu mm, reticulocytosis 2 per cent, direct Coombs’ test negative. plasma iron 0.15 pg/lOO ml and iron- binding capacity 0.713 mgj100 ml. Liver function was normal, but hypogammaglobulinemia was still present (7 per cent of a total protein of 6.5 gm/lOO ml), and the beta globulin level was elevated to 18 per cent of total protein. At that time (June 1968) her urine was selected for study during a systematic porphyrin inves- tigation program and surprisingly found to be rich in porphyrins. Normal excretion of PBG and ALA was found, and thin layer chromatography showed that her urinary porphyrin consisted of uroporphyrin and phyri- aporphyrin (heptacarboxylporphyrin) with traces of 6-, 5- and 4-carboxyl-porphyrin. an excretion pattern characteristic of PCT. Her fecal porphyrins were nor-

mal, and she had no clinical symptoms of porphyria, notably no photosensitivity or other skin complaints.

The studies on porphyrins and prophyrin precursors in her urine were repeated several times with similar results. Quantitative analysis showed ether-insoluble porphyrin (“uroporphyrin”) 115 to 280 pg/lOO ml and ether-soluble (“coproporphyrin”) between 36 and 40 pg/lOO ml. PBG ranged from 0.10 to 0.30 mg/iOO ml and ALA from 0.10 to 0.60 mg/lOO ml. Repeat exam- inations of fecal porphyrins still showed negative screening tests. Hemoglobin was 14 gm/lOO ml, red blood cell count 4.36 million/cu mm, white blood cell count 3,300 million/cu mm and reticulocytosis 1.6 per cent. Liver function tests were normal. Plasma iron was 0.130 mg/lOO ml and iron-binding capacity 0.266 pg/lOO ml. A liver biopsy was performed, but was un- fortunately not successful.

METHODS

The chemical methods were those previously pub- lished from our laboratory [iO,ll]. Later we improved our method for demonstration of the so-called phyri- aporphyrin (7-carboxyl-porphyrin) characteristic for PCT by thin layer chromatography with small plates (microscopic slides). The plates are run with acetone/ 0.5 N hydrochloric acid 7/3 v/v for fifteen minutes, sub- sequently dried in a hot air current and then run in the same mixture once more. This gives well marked sep- aration of 7-carboxyl porphyrin from uroporphyrin. For urine rich in porphyrins this can be achieved by direct application of the urine on the plate without pretreat- ment. If the porphyrin concentration is low it is neces- sary to extract the urine with amyl alcohol and subse- quently the amyl alcohol extract with 1 M hydrochlo- ric acid, or to adsorb the urine on talc and eluate with acetone/i M hydrochloric acid 9/l v/v. By chromatog- raphy the presence of uroporphyrin and phyriaporphyrins is demonstrated in the acetone hydrochloric acid eluate, or for urines low in porphyrins in an extract of 200 to 500 ml of urine with acetic acid amyl alcohol and a small volume of 1 M hydrochloric acid; all these analytical procedures can be completed withjn one hour.

PBG and ALA were determined by Mauzerall and Granick’s [12] method as modified by With [10,13].

The technic of the family investigation has been previously described [13].

FAMILY INVESTIGATION

A family investigation was planned and carried out with complete cooperation from all relatives. The fami- ly comprised sixteen members distributed over three generations. The first generation, including the patient, consisted of three sisters and two brothers, the sec- ond generation of two females and three males. Their children, the third generation, comprised two girls and four boys. The urine and feces of all these subjects were examined. In addition to the examination for PBG and ALA and screening for porphyrins in all the

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LATENT CUTANEOUS PORPHYRIA, TYPE PCT-CHRISTENSEN. WITH

relatives, the urine of six of them was studied by thin layer chromatography of concentrated extracts of 1 L of urine. In all the relatives the excretion of PBG and ALA was within the normal range, the screening test

for fecal porphyrins was negative, and chromatograph-

ic examination of the urine showed normal results, i.e.. no uroporphyrin or phyriaporphyrin.

COMMENTS

In view of the results of this family investigation the

present case was classified as latent nonhereditary

PCT (PCT-NH). As already mentioned this disease

cannot be regarded as nonhereditary in the strict

sense of this word but shows a complicated, not yet

elucidated, pattern of heredity [1,2]. Even in Turk-

ish hexachlorobenzene porphyria an unquestion-

ably hereditary tendency has been demonstrated [14]. This toxic porphyria differs markedly, how-

ever, from PCT, e.g., by being primarily a disease

of children.

The connection between PCT-NH and chronic

alcoholism has long been known [1,2]. The asso- ciation of PCT with a variety of hematologic, ma-

lignant and systemic diseases has been pointed

out by several investigators and has recently been

discussed in the monographs of Perrot [l] and

Gajdos and Gajdos-Tdrok [2]. The most important

of these diseases are scleroderma, dermatomyosi-

tis, generalized lupus erythematosus, Hodgkin’s

disease, reticulosis, Waldenstrom’s macro-

globulinemia and various malignant tumors. Fur-

ther, Berman [15,16] has demonstrated an in-

creased incidence of PCT among diabetic subjects.

Cases of cutaneous porphyria associated with

hemolytic anemias of autoimmune genesis have also been described [17,18]. Gajdos et al. [19]

described a child who between the second and

twelfth year suffered from porphyria accompanied

by recurrent infections, lymphocytosis, thrombo-

penic purpura and a severe hemolytic anemia.

Steiner et al. [20] described a case of PCT com-

plicated by autoimmunization, including hemolytic anemia, leukopenia, hypogammaglobulinemia and

severely impaired liver function. The relation-

ship of PCT to autoimmune diseases is, however,

far from clear. It may be a rare coincidence of

complicated patterns of heredity, or porphyria may

act as a “trigger” of autoimmune react-ions or

vice versa [21]. The role of disturbances in iron

metabolism has also been discussed [22] and is not clear.

The predominant feature of our case was a se- vere hemolytic anemia, presumably of the auto-

immune type, which recurred as soon as steroid

therapy was stopped. The abnormal porphyrin ex-

cretion was discovered accidentally when the pa-

tient was in good condition and liver function was

not impaired, but a pronounced hypogamma-

globulinemia was present. The porphyrin excretion

showed the typical pattern of PCT, and there was

normal excretion of porphyrin precursors. There

was no abuse of alcohol and no toxic agent could be demonstrated. The plasma iron level was low.

Skin manifestations were completely absent in

our case, despite the markedly increased excre-

tion and pathologic pattern of porphyrins. Since

the heroic self-experiment of Meyer-Betz in 1913

[23], it has been generally assumed that light

sensitivity in PCT is a simple consequence of the

presence of porphyrins. However, comparison of

clinical reports with detailed chemical studies on

porphyrins and their metabolites lead to the im-

pression that the cause of the photosensitivity is

less simple [2]. Investigation of porphyric pigs

has shown absence of photosensitivity even in

animals with a very high level of porphyrin in the

serum [24]. Chemical considerations alone make

it probable that the photosensitivity is not due

solely to the porphyrins proper but also, and per-

haps mainly, to certain metabolites with extra-

ordinarily high paramagnetism. Such metabolites

can be formed in the skin during exposure to sun-

light. This was pointed out by von Dobeneck [25],

who discovered the extraordinarily high para-

magnetism and electron spin-resonance of the

polymers of some dipyrroles, the so-called pro-

pents-dyopents. Possibly photosensitivity in por-

phyria is primarily due to the formation of such

pyrrole compounds in the skin.

ADDENDUM

Since this paper was submitted for publication,

Doss et al. [26] presented, during the Second In- ternational Conference on Porphyrin Metabolism

and the Porphyrias, Cape Town, December 1970,

six cases of chronic hepatic porphyria without

cutaneous symptoms and with the porphyrin ex-

cretion pattern characteristic for PCT (sympto-

matic porphyria), i.e., predominance of uro- and

phyriaporphyrin as in our case. The cases were uncovered during a study of liver biopsy speci-

mens for porphyrins, and the patients suffered

from cirrhosis, fatty liver or chronic aggressive

hepatitis. A systematic study of urine from pa-

tients with chronic liver disease utilizing the simple

screening methods outlined by us [9], including

thin layer chromatography [lo], would therefore presumably disclose several cases of PCT.

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LATENT CUTANEOUS PORPHYRIA, TYPE PCT-CHRISTENSEN, WITH

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