Acta Med. Nagasaki 37:1-4

An Autopsy Case of Acute Intermittent Porphyria

Kunihiko Murase, M. D.,1 Kazuya Makiyama, M. D.,z Kohei Hara, M, D.,z

Masahiro Ito, M. D.,3) and Shigeru Nonaka, M. D.,4)

1) Department of Internal Medicine, Saint Francis Hospital 2) Second Department of Internal Medicine, Nagasaki University School of Medicine 3) Department of Pathlogy, Atomic Disease Institute, Nagasaki University School of Medidine 4) Department of Dermatology, Nagasaki University School of Medicine

A 35-year-old woman was admitted to our hospital because of abdominal pain and numbness of the lower extremities. Acute intermittent porphyria (AIP) was diagnosed because of porphyric bodies in the urine and faeces. Two years after first admission, she died from suffocation due to inhalation of sputum.

Autopsy revealed a precirrhotic liver with cholestasis, accompanied by deposits of brown pigments in the bile canaliculi. By fluorescence microscopy, a red autofluores-cence was observed in all parts of frozen sections of the liver under ultra-violet light. We conclude that liver dam-age in the patient with AIP may be induced by the hepato-toxic properties of porphyric bodies and exacerbated by the precipitation of porphyric bodies in the bile canaliculi and ducts.

Introduction

AIP is the result of an autosomal dominant inborn error in hepatic heme biosynthesis, and is the most common type of

porphyria (1, 2). Manifestations of AIP include acute symptoms such as abdominal pain and neuropsychiatric symptoms, but there is an absence of skin lesions. In AIP, the increase in hepatic aminolevulinate synthetase (ALAS) coupled with deficiency of uroporphyrinogen I synthetase

(UROS), are consistent with the excretory pattern (3, 4). As a result, porphyrins and their precursors are hyperproduced in the liver, and in spite of the salient clinical manifesta-tions, histological abnormalities are slight: fatty degen-eration, periportal fibrosis, round cell infiltration and brown

pigments in the hepatocytes (5, 6, 7, 8). An autopsy case of AIP showing interesting pathological findings is reported.

CASE REPORT

A 35-year-old woman was admitted to the St. Francis

Hospital because of abdominal pain and numbness of the lower extremities on April 28, 1988. For 20 years the

patient had habitually taken a headache medicine (Isopro-pylantipyrine). On January 3, 1987, she was admitted to a nearby hospital, where a diagnosis of hepatic porphyria was given.

Physical examination showed hypertension (170/100 mmHg). The abdomen was tender. The urine was red in color and negative for protein and occult blood. Hb was 9.9

g/dl, and the white blood cell count 5,500/mm3. The ALP and 7 -GTP levels were elevated (Table 1). Excretions of coproporphyrin, uroporphyrin, porphobilinogen (PBG), delta-aminolevulinic acid (ALA) in the urine; and copro-porphyrin, uroporphyrin, protoporphyrin in the faeces at the time of acute crisis were markedly elevated; but copro-, uro- and protoporphyrin in the faeces were normal at remission (Table 2).

The patient was admitted to our hospital eleven times, and 2 years after the first admission she died from suffo-cation.

Table 1. Laboratory Data on Admission

Urine

Protein

Sugar

Occult Blood

Stool

Occult Blood

Blood

RBC

Hb

WBC

PLT

Serology CRP

RA

HBsAg ESR

( — ) ( — ) ( — )

( — )

333 x 104/mm' 9.9 g/dl 5500/mm' 22.8 x 104/mm3

0.26 mg/di (—)

) 22 mm/hr

Biochemistry T. Bil GOT GPT ALP LAP -GTP

ChE LDH CPK Amy T. P BUN Cr Na

ClK Ca

0.7 mg/dl 27 IU/1 26 IU/1

310 IU/I 160 IU/I 421 IU/1 1.38 A PH 282 IU/1

15 IU/1 293 IU/1 6.6 g/dl

40.3 mg/di 1.3 mg/dl 140 mEq/1 4.3 mEq/1 105 mEq/1 8.5 mg/di

2

Table 2. Porphyrin and Precursors

K. Murase et al. A Case of Porphyria

Acute crisis Remission

Urine

Faecus

Blood

Coproporphyrin Uroporphyrin Porphobilinogen 6 -aiminolevulinic acid

Copro porphyrin

Uroporphyrin Protoporphyrin Co proporphyrin

Protoporphyrin

(LT 160 g/day) (2-20 g/day) (LT 2.0mg/day) (LT 5.0mg/day) (LT 640 g/day) (LT 80 g/day) (LT 1830 g/day) (LT 2.0 g/dl) (15-60 g/dl)

3000 3000 91.9

28.8

3442 1 067

5875 3 . 42

58.2

1 157

1 395

47. 1

10.2 l 45

44 201 0.67 31 .S

PATHOLOGICAL FINDINGS

An autopsy was performed 2 hour post mortem. The liver

weighed 1530 gm, and had a granular, red-brown surface.

The cut surface showed yellow nodules with thin septa (Fig. 1).

Histologic examination of the liver showed chronic active hepatitis (precirrhosis); portal lymphocytic infil-

tration, fibrosis; destruction of the limiting plates; choles-

Fig. 1. The cut surface of the liver shows yellow nodules with thin septa

Fig. 2. Liver: The specimen shows portal lymphocytic infil-tration, fibrosis and destruction of limiting plates (precirrhosis)

with deposits of brown pigment in the bile canaliculi (HE X 40)

tasis; and deposits of brown pigments in the bile canaliculi

(Fig. 2). No siderosis was detected in the deposits. By

fluorescence microscopy, red auto-fluorescence was ob-

served in all parts of the formalin fixed frozen section, and

intense red autofluorescence was observed at the deposits,

under ultraviolet light (Fig. 3). There was nerve cell chro-

matolysis at the plexuses of Auerbach in the small intestine

and colon (Fig. 4).

Fig. 3. Liver: (formalin fixed frozen section). Red autofluores-

cence was observed under ultraviolet light (Fluorescence Micros-

copy x 40)

Fig. 4. Colon: The specimen shows nerve cell chromatolysis at the plexuses of Auerbach in the small intestine (HE X 100)

K. Murase et al.: A Case of Porphyria

Discussion

There is general agreement that the three forms of hepatic

porphyria-AIP, variegate porphyria and hereditary copro-

porphyria-are distinct disease entities (7, 8, 9). In AIP, skin

lesions due to photosensitivity do not occur and fecal

protoporphyrin and coproporphyrin concentrations are nor-

mal at remission. Skin symptoms occur in one half of patients with variegate porphyria, and in one third of those

with coproporphyria (8). In variegated porphyria the most

characteristic biochemical abnormality is a marked increase

in the concentration of porphyrin in the faeces, with the

levels of protoporphyrin exceeding those of copropor-

phyrin. In coproporphyria, the characteristic abnorrnalities

are the excretion of large amounts of coproporphyrin and

normal amounts of PBG and ALA, except during an acute attack (5, 6).

The pathological changes of the liver are similar in AIP,

porphyria cutanea tarda (PCT) and erythropoietic protopor-

phyria (EPP), but the damage in patients with AIP is the

mildest of the three diseases (6). Some authors have de-

scribed the histological findings in AIP as being fatty

change, periportal fibrosis, round cell infiltration and

brown pigments in the hepatocytes (5, 6, 7, 8). Grayish-

blue maculae at macroscopic examination and acicular inclusions at microscopic examination appear to be specific

for PCT (10). Histopathologic examination of the liver in

EPP has revealed cholestasis with accumulations of brown

pigment in the forrn of bile plugs in the canaliculi; periph-

eral fibrosis, and micronodular cirrhosis (1 1, 12, 13). The

pathogenesis of the liver disease in EPP is not clearly

understood, but it has been proposed that the cholestatic

liver damage in EPP may be induced by the hepatotoxic

properties of protoporphyrin and exacerbated by the pre-

cipitation of protoporphyrin in the bile canaliculi (13). In

our patient, the liver revealed precirrhosis with cholestasis,

accompanied by deposits of brown pigment in the bile canaliculi. The long-terrn consequence of persisting heme

biosynthesis disorder and porphyrin overproduction might

be accumulative liver injury.

Gastro-intestinal disturbances are conspicuous in the

clinical syndrome of AIP. The mode of involvement of the

gastro-intestinal tract is not yet entirely clear. Severe ab-

dominal cramping pains, constipation, and abdominal dis-

tention are frequently encountered, but the altered physiology responsible for these findings is seldom inves-

tigated. Previous reports suggest that the motility of an

isolated segment of the gastro-intestinal tract may be af-

fected (14, 15). Berlin and Cotton reported that there has

been observed a dilatation of the small intestine and

moderate dilatation of the colon demonstrable by roentge-

nogram of the abdomen, and that the disturbance of gastro-

intestinal function is probably due to the toxic effect of the

porphyrins upon the autonomic nerves (14). The change in

the peripheral nerves is well known (16, 17, 18). In our

3

case, nerve cell chromatolysis at the plexuses of Auerbach

in the small intestine and colon was noted. This finding

may support the theory that abdominal pain results from

autonomic neuropathy, which produces imbalance in the innervation of the gastro-intestinal tract with resultant areas

of spasm and dilatation.

Therapy of AIP includes prophylaxis, treatment of symptoms and complications, and attempts to reverse the

fundamental disease process. For the last measure three

approaches have been initiated: a high-carbohydrate diet

(19, 20), intravenous administration of hematin (21, 22),

and oral cimetidine (23). Carbohydrate intake inhibits the

induction of hepatic ALAS in experimental porphyria (20),

and in human AIP (19). Intravenous hematin adminis-tration, which suppresses hepatic ALAS activity in the rat

(22), was found to be beneficial for AIP attacks (21), but

commercial hematin is not available. Horie et al. reported

that cimetidine is a potent inhibitor of cytochrome P-450

mediated drugs, and appears to increase the hepatic heme

content, which controls feedback regulation of ALAS. In

our patient, glucose (lO0-250 grams per day) was admin-

istered intravenously, and proved to be effective.

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