CLINICO-PATHOLOGICAL CONFERENCE
A case of generalized Hailey-Hailey disease
with fatal liver injury
Masayuki Amagai, Masakazu Kobayashi, Kanji Wakabayashi,1 Megumi Hakuno, Akinori Hashiguchi,2Takeji Nishikawa and Jun-ichi Hata2
Departments of Dermatology, 1Internal Medicine and 2Pathology, School of Medicine, Keio University, Tokyo
Japan(Received for Publication on July 5, 2000)

Abstract. We report a case of a 59-year-old man with a severe generalized form of Hailey-Hailey
disease that was complicated by fatal liver injury. Erosive lesions were ®rst noted in the axillary andperianal regions at 15 year of age, and Hailey-Hailey disease was diagnosed based on the clinical features and histologic ®ndings in skin biopsy specimens. The patient was treated with at ®rst topicalsteroids and later a low dose of a corticosteroid, but the skin lesions gradually became generalized.
At 45 years of age liver dysfunction was detected after azathioprine and vinblastine treatment for
the generalized skin lesions. The liver injury gradually progressed and ®nally the patient died. The
gene responsible for Hailey-Hailey disease was recently identi®ed as ATP2C1, and it encodes a Ca2B transport ATPase with broad expression, including in skin and liver. This ®nding suggests that mutation of the ATP2C1 gene may give rise to an extracutaneous phenotype, such as the liver dysfunction
observed in severe cases, including our own. Further accumulation of cases is necessary to determine
whether this is true. (Keio J Med 50 (2): 109±116, June 2001)

Dr. Amagai (Moderator): I now announce the opening of the 1009th clinico-pathological conference.
The case of Hailey-Hailey disease being presented
today had problems both in the ®elds of dermatology
and internal medicine. The patient had a long history of
Hailey-Hailey disease, and I would like to ®rst ask thedermatologist-in-charge to describe the course of thispatient. Eventually, the patient died of liver injury, andI would like to ask Dr. Wakabayashi, the internist who
treated the patient, to describe the course of the liver
injury in the patient. Later, Dr. Hakuno will speak on
the latest knowledge on Hailey-Hailey disease. Finally,Dr. Hashiguchi, a pathologist, will summarize thelesions associated with liver injury in the patient. I hopethat by the end of our discussion, we can reach somereasonable conclusion as to the direction with whichinvestigation of such cases must proceed.
Now, Dr. Masakazu Kobayashi will summarize thedermatologic course of the disease in the patient.
Dr. Kobayashi (Dermatology): The patient had a45-year history of illness. I shall brie¯y describe thehistory of treatment of the case at the Department of

Dermatology.
The patient was a 59-year-old man, who ®rst noticed
skin rashes in the axillary and perianal regions when hewas 15 years old. At the age of 30, he was diagnosed ashaving Hailey-Hailey disease at another hospital. Despite intensive treatments including systemic steroid
therapy, the patient was not completely cured of thedisease, and at the age of 40, he visited our Department. At the ®rst examination, ®st-sized, well-demarcated whitish erosions with erythematous bases wereobserved bilaterally over the skin of the axillary andinguinal regions. Vesicles and pustules were also notedon or around the erythematous lesions (Fig. 1). Welldemarcated erythematous lesions of various sizes, up to
the size of a human ®st, were also distributed diffusely
over the trunk.
The patient was treated with oral etretinate (50 mg/day) and topical steroid therapy. However, sinceno improvement was noted, etretinate administration
was discontinued. Oral prednisolone therapy (30 mg/day) was started, and the skin lesions showed some
improvement. However, the skin lesions recrudescedThis is the record of the 1009th CPC of Keio University Hospital, held on May 24, 2000.
Reprint requests to: Dr. Masayuki Amagai, Department of Dermatology, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku,
Tokyo 160-8582, Japan
109

110

Amagai M, et al: Generalized Hailey-Hailey disease with fatal liver injury

Fig. 1 Erythema with maceration are recognized on the groin, include small linear erosions and ¯accid blisters.

when the dose of prednisolone was reduced to 15 mg/
day, and oral azathioprine at 100 mg/day was added tothe treatment regimen; oral doxycycline hydrochloride
was also added because of secondary bacterial infectionof the skin lesions. Thereafter, however, the patientdeveloped hepatic dysfunction, and under the suspicionof drug-induced hepatitis, azathioprine and doxycyclinehydrochloride administration was discontinued, and thehepatic function returned to normal.
When the patient was 45 years old, he developed afever of 39  C, and fungi and bacteria were cultured
from the skin lesions. Therapy with ¯ucytosine andamikacin was started, however, the patient again
developed hepatic dysfunction. Under the suspicion of
drug-induced hepatitis, the dose of prednisolone wasincreased to 30 mg/day. The hepatic function returned
to normal, and the dose of prednisolone was thereafter
gradually decreased to 5 mg/day.
At the age of 46 when etretinate therapy was
resumed, the patient again developed hepatic dysfunction. Subsequently, the patient developed repeatedremissions and aggravations of the skin lesions. At theage of 49, prednisolone administration was discontinued, and the patient was put on topical steroid therapy and topical antibiotic ointment application. Whenthe patient was about 54 years old, slightly elevated,well-demarcated, indurated multiple erythematous
lesions with scales, measuring up to the size of a child's
head, began to appear on the lower legs and the trunk(Fig. 2). At the age of 55, the skin lesions worsened
abruptly, and erythema with yellow-white scales spreadover almost the entire body, associated with the development of fever. Foul-smelling exudative and erosive
lesions developed on the lumbar and femoral regions.
Since the fever was thought to be due to infection orskin in¯ammation, combined treatment with prednisolone of 30 mg/day and antibiotics was started, and suc-Fig. 2 Erythematous, sharply marginated and scaly plaques are recognized on the legs. They produce annular lobulated ®gures.

cessful resolution of the fever and marked improvement of the skin lesions were noted. The skin lesions
began to worsen again when the patient was about 58
years old, with the lesions extending over large areas of
the trunk and extremities, and development of erythroderma on the lower half of the body (Fig. 3). Whenthe patient was 59 years old, he developed hepatic dysfunction once again, associated with weight loss, andwas admitted to the Department of Internal Medicineof our hospital.
Dr. Amagai: Thank you very much for your description of the case, Dr. Kobayashi.
The patient initially had characteristic skin lesions
on the axillary regions and the groins, typical sites oflesions in Hailey-Hailey disease, and over time, thelesions extended over the entire body, as described by
Dr. Kobayashi. What disease would you suspect fromsuch a dermatologic presentation?
Mr. Honaga (6th year student): I would suspect tinea
or candidiasis.
Dr. Amagai: In this patient, characteristic skinlesions were observed over the entire body, with theKeio J Med 2001; 50 (2): 109±116

111

Fig. 4 Clinical course of the patient. CCL: Cefaclor, PSL: Prednisolone, VCM: Vancomycin, mPSL: Methyl Prednisolone, AZT: Aztreonam, ST: Sulfamethoxazole-trimethoprim, MEPM: Meropenem.
Fig. 3 Generalized erythemas are recognized on the trunk andextremities, and profuse scales are seen particularly on the trunk.

eventual development of erythroderma, in which a majority of the skin surface becomes reddish and peels off.
Erythroderma occurs by numerous causes, including
atopic dermatitis, autosensitization dermatitis, and psoriasis. We, in fact, considered psoriasis as the mostprobable diagnosis in this case at the beginning. There
are also other diseases that are associated with erythroderma, e.g., pityriasis rubra pilaris, pemphigus foliaceus, infections, malignant lymphoma, and Sezary syndrome. Erythroderma can also be induced by drugs.
Thus, there are numerous causes that one must think ofwhen one sees a patient with erythroderma.
In summary, the patient initially presented skinlesions typical of Hailey-Hailey disease. Because of thedevelopment of psoriasis-like lesions over the entire
body, immunosuppressive agents and etretirate wereused in this patient. In the course of such drug treatment, hepatic dysfunction developed and eventuallybecame the main feature in this patient.
Next, Dr. Wakabayashi, the internist-in-charge ofthe patient, will brie¯y describe the course of illness inthe patient from the ®rst onset of hepatopathy until his

death.
Dr. Wakabayashi (Internal Medicine): I shall describe the medical course of the patient (Fig. 4). Thispatient suffered repeatedly from drug-induced hepatitis, and was referred to the Department of Gastroenterology of our hospital. In July 1993, he was foundto be positive for serum HCV antibody. He was thus
diagnosed as having chronic type-C hepatitis, andrequired repeated hospital admissions. In December
1998, when he was an inpatient at the dermatology
ward, common cold-like symptoms developed on December 31, and slight fever on January 3, 1999, withincreasing serum levels of markers of in¯ammation. On
January 12, the patient developed fever of 38 C Celsius
and cough, and chest radiography showed a groundglass opacity in the right upper lung ®eld. CT revealeda ground-glass opacity and cavitary nodular shadows.
Intravenous infusion of vancomycin and aztreonam(Azactam) was initiated on January 21, however, thepatient's respiratory function worsened, with a decreaseof pO2 to 56 Torr. The results of lung perfusion scintigraphy ruled out the diagnosis of pulmonary embolism.
Bronchoscopy was performed. Pneumocystis carinii
was found in bronchoalveolar lavage specimens, and112

intravenous infusion of pentamidine 4 mg/kg/day was
initiated for the treatment of Pneumocystis carinii
pneumonia. Administration of prednisolone at 80
mg/day was begun on January 28 when the respiratory
function worsened. Thereafter, with improvement of
the respiratory function, the dose of prednisolone was
reduced to 20 mg. Bradycardia, presumably an adverse
effect of pentamidine, was noted on February 3, andpentamidine was replaced by ST mixture. Hepatic dysfunction was noted on February 6, with increased serum
levels of GOT and GPT. Under the suspicion of
drug-induced hepatopathy, vancomycin and aztreonam
were discontinued. The dose of pentamidine was also
reduced, and the drug was discontinued on February 7.
Despite these measures, however, the serum total bilirubin level increased to 5.8 mg/dl. Because the patient
had a history of cholelithiasis, abdominal ultrasonography was performed. Since the diagnosis of cholelithiasis and cholecystitis was con®rmed, meropenem(Meropen) therapy was started. However, despite thistherapy, the serum total bilirubin level remained high,with a predominance of direct bilirubin, and endoscopic
retrograde cholangiopancreatography (ERCP) was
performed keeping in mind the possibility of obstructive jaundice, and the ENBD tube was retained.
Despite all these measures, jaundice persisted, andthe serum bilirubin level continued to rise. Therefore,
prednisolone at the dose of 30 mg/day was begun on
February 17. Although there was temporary improvement, however, the serum bilirubin level began to increase again. The dose of prednisolone was, therefore,
increased to 60 mg/day on February 24. Since the patient remained unresponsive to the treatment, glucagon
insulin therapy was started on March 4, and the dose of
prednisolone increased to 90 mg/day on March 6, bothof which eventually proved to be ineffective. Steroid
pulse therapy with methylprednisolone of 1 g/day wasstarted on March 9, with no improvement, and with thecontinued increase of the serum bilirubin level, plasmapheresis was begun on March 11, and performed 5times. The bilirubin level improved immediately after
plasmapheresis, but increased to the pretreatment levelon the following day, showing that plasmapheresis was
only temporarily effective. We suspected the possibilityof acute aggravation of chronic type-C hepatitis, besides drug-induced hepatopathy. Based on this presumption, intramuscular injection of IFNa (9MU/day)
was begun on March 25. The serum transaminase levels
improved temporarily, but because of the developmentof adverse reactions (fever exceeding 39 degrees Celsius, general malaise and tachycardia), INF dose was
reduced to 6MU daily. However, the adverse reactions
persisted, and IFN therapy was discontinued after three
sessions under judgment that the patient would not
be able to tolerate the full course of the treatment.

Amagai M, et al: Generalized Hailey-Hailey disease with fatal liver injury

The bilirubin level continued to increase, with the total
bilirubin level reaching 48.2 mg/dl on April 4. Then,acute renal failure, presumably re¯ective of multiple
organ failure, developed, and the patient died on April
11. We ®rst considered drug-induced hepatopathy as
the cause of death, however, I believe that some otherdiseases must also be considered. The patient was
known to have chronic type-C hepatitis. Is there a possibility that the hepatopathy was caused by other viralcause than type-C hepatitis?
Mr. Funao (6th year student): Type-B hepatitis andEB virus-induced hepatitis could be other possible
causes of the hepatopathy.
Dr. Wakabayashi: Type-B hepatitis, like type-C
hepatitis, can be associated with acute changes. Considering the medical history of the patient, the possibility of type-A hepatitis is remote. EB virus andcytomegalovirus can be other possible causes of thehepatopathy. The patient had very low lymphocyte
counts, in particular of the CD4 cells. Initially, we suspected HIV infection as the predisposing factor for
Pneumocystis carinii pneumonia, but the patient was
found to be negative for HIV antibody in the serum. At
one point, the CD4 cell count was below 20/ml, andcytomegalovirus antigenemia was positive. Therefore,
cytomegalovirus infection could be reasonably considered as a possibility.
In regard to drug-induced hepatopathy, the moststrongly suspected causative drug was pentamidine. In
addition, the antibiotics vancomycin and aztreonam
cannot be ruled out as other possible causes. It is also
possible that meropenem, administration of which wasstarted after the onset of hepatopathy, further exacerbated the hepatopathy.
Next, concerning the aggravation of chronic type-C
hepatitis, the reserve capacity of the patient's liver at
the time of admission was not very poor in terms of theresults of the ICG test (5.3%). Therefore, it is not likelythat the patient had very advanced hepatopathy when
he was ®rst examined. However, the patient had developed various complications and received steroid therapy. It is possible that the type-C hepatitis became
aggravated when steroids were used in large doses. It
has been reported that a patient with chronic type-C
hepatitis who was on high-dose steroid therapy died offulminant hepatitis due to abrupt aggravation of thehepatitis following rapid tapering of the steroid dose.1
However, the steroid therapy for Pneumocystis carinii
pneumonia in this patient was aimed to improve therespiratory function rather than to eliminate Pneumocystis carinii. Therefore, reasonable tapering of the steroid dose was executed. Moreover, since the patient
had diabetes, the attending doctor in the Department ofRespiratory Medicine attempted tapering of the steroid
dose as early as possible.

Keio J Med 2001; 50 (2): 109±116

Dr. Amagai: Now, I would like to summarize thefeatures of the case in order to reach the conclusion. In
this patient, numerous drugs were used, and more andmore drugs were added, the hepatitis became worse.
There were several possible causative drugs. Viral
causes were also possible. The patient in fact had typeC hepatitis. Thus, there are various possibilities. Druginduced hepatitis was ®rst suspected, and type-C hepatitis was considered later. I would like to invite opinion
regarding the relationship between these two conditions. In addition, is there any possibility that thehepatopathy in this patient was derived from any cause
other than drug and virus?
Dr. Wakabayashi: We can de®nitely not exclude thepossibility of drug-induced hepatopathy. Since druginduced hepatopathy is only diagnosed after excluding
other causes, its possibility can never be disregarded.
As mentioned previously, high-dose steroid therapy
was used for the treatment of chronic type-C hepatitis.
Considered together with the poor immunocompetenceof this patient, it is quite possible that acute aggravationof chronic type-C hepatitis was the actual cause of thehepatopathy in this patient.
Dr. Amagai: Is it possible that the use of multiple
drugs caused the hepatopathy?
Dr. Wakabayashi: Sure it is. Since this patientdeveloped hepatopathy following the administration ofvarious drugs, it is indeed possible that multiple drug
use was responsible for the hepatic dysfunction.
Dr. Amagai: Let us go back to the issue of HaileyHailey disease. Hailey-Hailey disease is a hereditarydisease. Since it is inherited as an autosomal dominantdisease, it is possible that a single gene is responsible.
Despite the intensive effort made at genetic analysis of
this disease during the past decade, the gene responsible for Hailey-Hailey disease was identi®ed just a few
months ago.2 Dr. Hakuno will speak on the latest
knowledge on Hailey-Hailey disease.
Dr. Hakuno (Dermatology): Hailey-Hailey disease,or familial benign chronic pemphigus, falls into the category of inherited skin disorders of keratinization, andis inherited as an autosomal dominant disease. Although there are no skin symptoms at birth, the patientsdevelop skin symptoms after adolescence, usually when
they are in 20s±30s.
As to the clinical picture, itchy erythema occurs infriction areas, i.e., nuchal, axillary, inguinal, and perianal regions, and lesions may fuse to form plaques, andmay be associated with blisters, erosions, scales, or pigmentation. Lesions may often be moist and exudative,
with a foul-smelling exudate. This disease follows achronic course of repeated remissions and exacerbations. The skin lesions often become aggravated in
the summer season and extend over the entire bodysurface, because of the high temperature and humidity,

113

ultraviolet light exposure, or secondary infection.
Clinical differential diagnoses include seborrheic
dermatitis, cutaneous candidiasis, and tinea corporis. If
fungal tests are negative, and the family history, age at
onset, and clinical course are suggestive, the diagnosis
should be established by skin biopsy.
Histopathologically, this disease is characterized byacantholysis, often in the pattern of a dilapidated brickwall. Acantholysis is considered to be derived fromincomplete intercellular adhesion resulting from thedegeneration or disappearance of proteins which constitute the cell-cell adhesion mechanisms, such as desmosomes or adherens junctions, present among thecells in the epidermal prickle cell layer.
Diseases with acantholysis as a major feature arebroadly divided into autoimmune diseases and hereditary diseases. Pemphigus represents the major diseaseof the former group. Currently, pemphigus vulgaris andpemphigus foliaceus are diagnosed by demonstration of
the presence of antibodies in the serum against desmoglein 3 and desmoglein 1, respectively. On the other
hand, the prototypes of the hereditary disease groupare Hailey-Hailey disease and Darier's disease. Although it is known that the Hailey-Hailey disease geneis present at 3q21±q24, and the Darier's disease gene at
12q23±q24.1, the genes themselves had not been identi®ed for a long time. However, it has recently become
apparent that Hailey-Hailey disease and Darier's
disease are caused by mutation of the ATP2C1 and
ATP2A2 genes, respectively, both of which are genes
encoding the ATP-dependent Ca 2 pump, which regulates the intracellular Ca 2 concentration.2,3 There are
a number of Ca 2 pumps in the cytosol that regulate
the intracellular Ca 2 concentration. The Ca 2 pumppresent in the Golgi apparatus is encoded by ATP2C1,
and the Ca 2 pump present in the endoplasmic reticulum is regulated by ATP2A2. It is not yet clear as towhich type of mutations of ATP2C1 and ATP2A2 in
Hailey-Hailey disease and Darier's disease result inacantholysis. However, it is presumed that dysfunctionof the Ca 2 pump leads to high intracellular concentrations of Ca 2 . It is known that intracellular Ca 2 inepidermal cells plays a very important role in the differentiation of the epidermis and intercellular adhesion.
It is possible that impaired regulation of the intracellular Ca 2 concentration causes abnormal differentiation of epidermal cells, activation of various enzymes,
and degeneration or disappearance of Ca 2 -dependent
proteins present in the desmosomes and adherens
junctions (e.g., desmoglein, desmocollin, E-cadherin
and P-cadherin), resulting in acantholysis. Interestingly,
ATP2C1 expression has also been observed in various
other organs besides the skin, including the liver,pancreas and kidney, and theoretically, patients with
Hailey-Hailey disease may have involvement of other114

organ systems as well, besides the skin. Although so
far no involvement of other organ systems has been
demonstrated in Hailey-Hailey disease, further carefulcollection and analysis of clinical cases are necessary.
Since Hailey-Hailey disease is a hereditary disease,treatment is conservative and symptomatic. The basic
treatment is topical steroid therapy combined with topical antibiotic ointment application, aimed to control
the skin lesions and to prevent secondary infection.
When secondary infection is present, oral or intravenous antibiotic therapy may be indicated. In addition,
topical application of activated vitamin D3 derivatives,
oral therapy with vitamin A derivatives, and abrasion
using CO2 laser have also been reported to be effective.
Dr. Amagai: Thank you, Dr. Hakuno. It was a goodand concise summary of the latest knowledge on the
disease.
As Dr. Hakuno has just said, Hailey-Hailey disease
is a hereditary disease. One of the characteristic features of the disease is that its onset is delayed after
birth, manifesting when the patients are in their teens,
20s or 30s, similar to, for example, the case in Huntington's chorea, where the patients have no characteristic
symptoms at birth, but develop neurological symptoms
when they turn 30±40 years old. There are many other
hereditary diseases of the skin. In the most well-knownof them, epidermolysis bullosa simplex, blisters occur
because cell-to-cell adhesion in the skin is impaired due
to mutations in keratin genes. Patients with this disease
already have blisters when they are born. In contrast,
patients with Hailey-Hailey disease appear normal atbirth. The cell-to-cell adhesion disorder becomes apparent in friction areas only when the patient is in his or
her teens or the second or third decade. This is one ofthe very unique features of Hailey-Hailey disease.
There is another characteristic feature of HaileyHailey disease that deserves to mention. As Dr.
Hakuno has pointed out, in cases of epidermolysis bullosa simplex caused by mutation of the keratin gene,
the disease is manifested only in the skin. Other organsystems are not involved. In Hailey-Hailey disease,
however, it has been found that the responsible gene ispresent not only in the skin but also in other organs.
Nonetheless, there are no reports so far in the literature
documenting abnormalities in other organs. This could
also be because no attempts have been made so far
to study the pathology in the other organs. Although
the disease is a hereditary disease, the severity of thesymptoms varies among individual patients according todifferences in the types of mutations and individual
genetic backgrounds. The patient discussed here today
represents a considerably severe case of Hailey-Hailey
disease. Therefore, it cannot be completely ruled outthat the genetic abnormality itself was responsible forthe skin manifestations as well as the hepatic dysfunc-

Amagai M, et al: Generalized Hailey-Hailey disease with fatal liver injury

tion in this patient. It may be necessary to take this into
consideration when encountering the disease in the
future.
Finally, Dr. Hashiguchi, a pathologist, will speak
about the lesions associated with the hepatopathy, withbrief reference to the skin lesions. Dr. Hashiguchi,
would you present the pathological aspect of this disease to the audience, please?
Dr. Hashiguchi (Pathology): The pathological diagnosis is shown in Table 1. There were multiple erosions
and crusts on the skin over the entire body. Acantholysis and hyperkeratosis were observed histologically. A
liver biopsy specimen obtained in January 1999 showed
mild in¯ammation in the portal area and steatosis.
However, macroscopic examination of the liver at autopsy revealed cholestasis and ®brosis (Fig. 5). Chroniccholecystitis and cholelithiasis of the gallbladder werealso noted, but there was no acute suppurative in¯ammation or mechanical obstruction of the extrahepatic
duct that would explain the cholestasis. Histologically,
massive loss of hepatocytes and marked ®brosis wereobserved in the liver (Figs. 6, 7), and in some regions,
regenerating hepatocytes exhibited nodular growth(Fig. 8). These histological changes led us a diagnosis of
subacute hepatic injury, but its cause could not be determined from the histopathological ®ndings.
Dr. Amagai: Are there any questions or commentsthat you would like to make on this case in general?
Mr. Honaga: The patient eventually died of renal
failure; what was the cause of the renal failure?
Dr. Wakabayashi: The patient had severe hyperbilirubinemia, with the total bilirubin level in the serum
eventually exceeding 40 mg/dl. Such severe and persistent hyperbilirubinemia is well known to induce multiple organ failure, in particular, renal failure. This could
explain the occurrence of the acute renal failure in thispatient.
Mr. Narumi (6th year student): Although HaileyTable 1
1.
2.

3.

4.
5.
6.
7.
8.

Pathological Diagnosis

Hailey-Hailey disease (29 years after the onset of symptoms)
Drug-induced hepatic injury  chronic hepatitis, type C
1) Hepatic ®brosis and cholestasis, severe
2) Jaundice3) Splenomegaly (250 g)
Aspergillosis
Abscess formation in the following organs:lung, right (650 g), upper lobe; kidney, bilateral (170: 160 g);
myocardium (510 g); left ventricle; urinary bladder; and thyroid
gland (28 g)
Diabetus mellitus; Hyalinization of the pancreatic islets
Pulmonary congestion and edema, bilateral (490: 650 g)
Cardiac hypertrophy (510 g)
Aortic atherosclerosis, moderate
Chronic cholecytitis  Cholelithiasis; multiple stones (max.
1:4  1  1 cm)

Keio J Med 2001; 50 (2): 109±116

Fig. 5115

Liver showed sever cholestasis and ®brosis.

Hailey disease is known to be an autosomal dominantdisease, this patient had no family history. I would liketo know how often patients with this disease do have afamily history, if such data are available.
Dr. Amagai: This is a good question from the practical viewpoint. In general, sporadic cases can occur
among all autosomal dominant diseases. In simple
terms, in autosomal dominant diseases, when the spermof the father or the ovum of the mother has the genetic
mutation, the offspring manifests the disease. Viewed ina more complex manner, it is possible that cells withand without the mutated gene are mixed in a mosaic
state, or there is genetic mosaicism.
Mr. Narumi: Were the children of this patient examined?
Dr. Nishikawa (Dermatology): The patient had threesons. One of them presented to our Department witheruption. However, on examination it was ordinary
eczemas. None of the family members of the patient
was diagnosed to have Hailey-Hailey disease.
Dr. Amagai: How old are the children now?
Dr. Nishikawa: They are all grown up. The boy I saw
was 15 or 16 years old at the time of the examination.
Dr. Amagai: Is it possible that the sons might develop the disease in the future?
Dr. Nishikawa: I can only say that none of thepatient's three sons have developed the disease to date.
Dr. Amagai: So the children of this patient have not
manifested the disease until now. Are there any otherquestions or comments?
Mr. Tamura (6th year student): I understand that
Hailey-Hailey disease characteristically manifests itself
when the patient is in his 20s±30s. Considering that theskin lesions occur most frequently in the friction areas,
could there be involvement of some other factors suchas extrinsic stress?
Dr. Amagai: Although the gene responsible for the
disease has been identi®ed, and the disease is charac-

Figs. 6, 7 Histologic examination of the liver. With acute injury,
hepatocytes were ``dropped out'' and ®brosis were marked. Severcholestasis was seen. (a: HE, 40, b: HE, 100)

Fig. 8
40)

Hepatocyte regenarative nodules were seen. (Silver stain,

terized by the eventual development of acantholysis,
the events leading up to this process, or the underlying
mechanism at the molecular level, remain completely
unknown. As Dr. Hakuno mentioned, there is an interesting treatment strategy, namely, skin abrasion, which116

has been employed for the treatment of mild and highly
localized cases. In this treatment, the skin in the affected region is removed, and then allowed to regenerate. Although the disease may recur later, there is atemporary relief from the symptoms of the disease. This
could be due to removal of some possible cumulative
effect existent on stem cells. Therefore, it is speculated
that the disease is manifested as a result of some cumulative abnormality in the stem cells.
Dr. Nishikawa: Dr. Hakuno, you mentioned that
the ATP2C1 gene is expressed in the liver, but what is
the level of expression of the gene in the skin and theliver?
Dr. Hakuno: The organs were cited in descendingorder of the level of expression, that is, skin, kidney,
liver and so on. Thus, the level of expression in the liver
is relatively high.2
Dr. Amagai: Now, I would like to conclude the conference. This patient presented here was a very severecase of Hailey-Hailey disease. It is reasonably certainthat the patient had drug-induced hepatitis along with
type-C hepatitis. However, is it also possible that thepatient's liver injury was caused by the gene responsiblefor Hailey Hailey disease?
This patient with Hailey-Hailey disease had worsening hepatopathy over a long clinical course. In general,the disease, also referred to as familial ``benign''
chronic pemphigus, may run its course as a benign
disease when the lesions are localized. However, there
are some cases with severe disease. Besides the casereported here, Dr. Nishikawa has introduced the
Okayama University's case of a patient who ®nally diedof hepatopathy after a long clinical course during which
the severity of the skin lesions paralleled that of thehepatic dysfunction. Taking these into consideration,although drug-induced hepatopathy is a strong possibility in this case, there still remains the question ofwhether the hepatic dysfunction was a result of mutation of the gene responsible for Hailey-Hailey diseasegene. I would like to ask the pathologist for his comments on this.
Dr. Hashiguchi: In some autopsy cases, histologicalexamination of the liver shows subacute hepatic injury,
but the cause is unknown. In the present case, it would
be dif®cult to attribute the hepatic damage to either
drugs or type C hepatitis. Subacute hepatic injury has
been often observed in type B acute hepatitis, however
the patient was negative. There was no clear cause of
the subacute hepatic injury in the present case, however, the genetic change seen in Hailey-Hailey disease
may have contributed to the hepatic injury. So, this wasan important case.
Dr. Amagai: Thank you. Various possibilities as tothe cause of the hepatopathy in this case have been

Amagai M, et al: Generalized Hailey-Hailey disease with fatal liver injury

described. Are there any comments from the viewpointof the internist on the possibilities presented?
Dr. Wakabayashi: It is possible that the gene responsible for Hailey-Hailey disease is expressed in theliver, and some triggering factor causes the hepatopathy
to manifest. However, I cannot say anything de®nitively
because of the lack of availability of substantial data.
One thing that I can say de®nitely is that while theliver function was not very poor at the time of admission even though the patient had chronic hepatitis, thehepatic cirrhosis was very severe at the time of autopsy.
Considering that the biliary stasis and ®brosis weresevere, it would not be unreasonable to consider that
there were some other factors involved, although it ispossible that the biliary stasis accelerated the development of hepatic cirrhosis.
Dr. Amagai: The patient presented here had HaileyHailey disease, a very rare hereditary disease. Andamong the cases of Hailey-Hailey disease, this case wasof particular relevance, because he had severe disease
and eventually died of hepatopathy.
In summary, as a dermatologist, I would like to pointout that while any changes in the skin can be observed
directly, for example, if the skin becomes red, we cansee it, in the case of hepatic dysfunction, the liverchanges may be overlooked unless laboratory abnormalities come to light. Thus, it is possible that changes
similar to those present in the skin were also present in
the liver or other organs, even though they were subclinical. However, examination of other organ systems,e.g., by liver biopsy would not be done, without de®nite
indication. Concerning Hailey-Hailey disease, there has
hardly been any case of hepatic dysfunction reported
previously in the literature, except for the case of
Okayama University. However, it is possible that subclinical changes do in fact occur in various organs, andthat such changes are overlooked because we cannot
see them directly. Thus, while concluding this 1009th
C.P.C, I would like to emphasize that in this sense, theskin is a mirror re¯ecting the state of the internalorgans.
Thank you for your kind attention.
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